Brigit E. Ray, MD, MME

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

Four medications comprise the drug category known as direct oral anticoagulants (DOACs). Dabigatran (Pradaxa)¹ was the first to gain approval. It was approved by the US Food and Drug Administration (FDA) in 2010 for the reduction of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). This was followed by approvals for rivaroxaban (Xarelto)² in 2011, apixaban (Eliquis)³ in 2012, and edoxaban (Savaysa)⁴ in 2015. Betrixaban (Bevyxxa)⁵ was approved in 2017 for venous thromboembolism (VTE) prophylaxis in acutely ill hospitalized patients with restricted mobility, but it was removed from the market in 2020.

IMAGE: © KO STUDIOS

In addition to stroke prevention in nonvalvular AF, each DOAC has been approved for other indications and has been addressed further in guideline-based recommendations outside FDA-approved indications. This review highlights the evolving use of DOACs and the expansion of applications for multiple adult patient populations.

Overview of DOACs

Dabigatran is the only direct thrombin inhibitor; the other agents inhibit factor Xa. TABLE 1^1-4 summarizes FDA-­approved indications and dosing and guideline-based dosing. Dabigatran and edoxaban require parenteral anticoagulation for 5 to 10 days prior to initiation for acute VTE, limiting their use.^1,4TABLE 2^1-4 highlights pharmacokinetic differences among the agents. For example, dabigatran is 80% renally cleared, is somewhat dialyzable, and can accumulate in patients with renal dysfunction.¹ Edoxaban is contraindicated for nonvalvular AF in patients with a creatinine clearance (CrCl) > 95 mL/min because an increased stroke risk was demonstrated.⁴ Therefore, rivaroxaban and apixaban are prescribed most often in the United States.^6,7

Applications in special patient populations

Obesity

As of 2020, more than 40% of adults in the United States were obese (body mass index [BMI] ≥ 30), with 9% classified as class 3 or severely obese (BMI ≥ 40).⁸ Altered drug pharmacokinetics in patients with severe obesity raises concern for undertreatment with fixed-dose DOACs. Phase III DOAC approval trials included patients with obesity, but weight cutoffs differed, making extrapolating efficacy and safety data difficult across different obesity stages.⁹ Although no FDA-labeled dosing adjustments exist for patients with obesity, the International Society on Thrombosis and Haemostasis (ISTH) does provide such recommendations.

ISTH changes position on measuring drug levels. ISTH previously recommended avoiding DOACs in those with a BMI > 40 or body weight > 120 kg. If a DOAC was used, ISTH advised obtaining peak and trough drug levels.¹⁰ However, DOAC drug levels have not been associated with clinical outcomes or sufficient degrees of anticoagulation.¹¹

Men and women are affected equally by fibrolipomas. Prevalence does not differ by race or ethnicity.

In April 2021, ISTH updated guidance on DOACs in obesity, indicating standard doses of rivaroxaban or apixaban can be used for the treatment and prevention of VTE in all patients regardless of weight or BMI. Because data in obesity are lacking for dabigatran and edoxaban, avoid using these agents in patients with a BMI > 40 or weight > 120 kg. Additionally, assessing drug levels is no longer recommended, as there is insufficient evidence that these impact clinical outcomes.¹²

The 2021 American College of Chest Physicians (CHEST) guideline update does not recommend adjustments based on weight,¹³ and the 2019 European Society of Cardiology (ESC) guidelines make no mention of weight when treating acute pulmonary embolism.¹⁴

Continue to: Effectiveness of DOACs for AF in patients with obesity isn't clear

Effectiveness of DOACs for AF in patients with obesity isn’t clear, as most data are from retrospective cohort analyses. In patients weighing > 120 kg, dabigatran has shown efficacy in thrombosis prevention similar to that achieved in those weighing ≤ 120 kg, but it has increased the risk for gastrointestinal (GI) bleeding.¹⁵ Another study indicated a 15-mg dose of rivaroxaban may be associated with increased thromboembolic complications in patients with a BMI ≥ 35.¹⁶ Alternatively, another retrospective study of rivaroxaban demonstrated a small absolute risk reduction in ischemic stroke among patients in all stages of obesity and no difference in significant bleeding events.¹⁷ One further retrospective cohort showed that, in patients with a BMI ≥ 50 kg, the effectiveness of rivaroxaban and apixaban in thrombosis prevention and bleeding safety outcomes was comparable to that seen in those with a BMI < 30.¹⁸

As a result of conflicting data, and a lack of prospective randomized controlled trials (RCTs), ISTH continued recommending international normalized ratio (INR)–based dosing of warfarin for class 3 or severely obese patients with AF. The 2018 CHEST guidelines¹⁹ and the 2020 ESC guidelines²⁰ make no mention of DOAC avoidance in patients with obesity and AF.

Advanced and end-stage renal disease

DOACs are renally dosed based on indication, drug-drug interactions, and degree of renal function (TABLE 3^1-4). For example, patients with AF who are anticoagulated with apixaban are prescribed 2.5 mg twice daily when 2 of the 3 following criteria are met: age ≥ 80 years, body weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. However, no dosage adjustment is necessary for VTE treatment or prophylaxis with apixaban regardless of renal function.³

Data supporting the safety and efficacy of DOACs in end-stage renal disease (ESRD) are sparse. All DOACs are renally cleared to varying degrees (TABLE 2^1-4), theoretically increasing bleeding risk as kidney disease progresses. Apixaban is the least renally cleared of the DOACs and has been evaluated in the greatest number of trials for patients with ESRD for both VTE treatment and prevention and nonvalvular AF.²¹ As a result, the FDA approved standard-dose apixaban (5 mg twice daily) for VTE treatment and prevention and nonvalvular AF in patients with ESRD, even those requiring dialysis. Use the reduced apixaban dose (2.5 mg twice daily) in patients with ESRD and AF only if they are ≥ 80 years of age or their body weight is ≤ 60 kg.³

Patients with cancer

Cancer-associated acute VTE treatment. Cancer is an established risk factor for acute VTE but it also increases the risk for treatment-­associated bleeding compared with patients without cancer.²² Historically, low-molecular-weight heparin (LMWH) was recommended over warfarin and DOACs for cancer-associated thromboses (CAT).²³ Compared with warfarin, LMWH reduced the rate of recurrent VTE and had similar or reduced bleeding rates at 6 to 12 months.^24-26 However, clinicians and patients often chose warfarin to avoid subcutaneous injections.²⁷

CHEST guidelines recommend oral Xa inhibitors over LMWH for the treatment of CAT.¹³ The 2020 guidelines of the National Institute for Health and Care Excellence (NICE) recommend DOACs as an option for CAT along with LMWH or LMWH transitioned to warfarin.²⁸ The American Society of Clinical Oncology (ASCO) recommends rivaroxaban for acute VTE treatment in CAT. No head-to-head trials have evaluated comparative efficacy of DOACs for CAT. However, edoxaban and rivaroxaban are associated with a greater risk for GI bleeding; therefore, apixaban is preferred in patients with GI malignancies.²⁹ Standard DOAC VTE treatment dosing is recommended for all 3 agents.^2-4

When using DOACs for patients with CAT, consider potential drug-drug interactions with chemotherapy regimens. All DOACs­ are transported by p-glycoprotein, while rivaroxaban and apixaban are substrates of cytochrome P450, leading to potentially significant drug-drug interactions.³⁰ These interactions could affect the patient’s chemotherapeutic regimen, decrease the efficacy of the DOAC, or increase the risk for bleeding. Therefore, anticoagulation choice should be made in collaboration with the ­hematology/oncology team.

Continue to: Cancer-associated VTE prophylaxis...

Cancer-associated VTE prophylaxis. VTE prophylaxis for patients with cancer is complex and necessitates a global assessment of cancer location and treatment regimen and setting. Hospitalized patients receiving chemotherapy are at high risk for VTE if mobility is reduced or if other VTE risk factors are present. The International Initiative on Thrombosis and Cancer (ITAC)³¹ and ISTH³² recommend VTE prophylaxis with unfractionated heparin or LMWH (ISTH recommends LMWH more strongly). The 2020 ASCO Guidelines recommend pharmacologic anticoagulation but make no drug-specific recommendation.²⁹ Parenteral treatment in hospitalized patients is not as burdensome as it is in ambulatory patients; therefore, these recommendations are less likely to elicit inpatient opposition.

In the ambulatory setting, patient avoidance of subcutaneous injections necessitates consideration of DOACs for CAT prophylaxis. The Khorana Risk Score (KRS) is a validated tool (scale, 0-7) to predict VTE risk in ambulatory patients receiving chemotherapy.³³ KRS scores ≥ 2 indicate high thrombotic risk and the need for prophylactic anticoagulation. ASCO recommends apixaban, rivaroxaban, or LMWH.²⁹ ISTH and ITAC both recommend apixaban or rivaroxaban over LMWH.^31,34 An RCT published in June 2023 confirmed that, for adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE for 6 months.³⁵ The recommended doses for apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily) for CAT VTE prophylaxis are lower than FDA-approved treatment doses.³¹

Patients with thrombophilia: VTE prevention

Thrombophilias are broadly categorized as inherited or acquired, with inherited thrombophilia being more prevalent. The Factor V Leiden (FVL) variant affects 2% to 7% of the population, and prothrombin gene mutation (PGM) affects 1% to 2% of the population.³⁶ Other forms of inherited thrombophilia, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, occur less commonly (< 0.7% of the population).³⁶ Antiphospholipid syndrome (APS), the most common acquired thrombophilia, affects approximately 2% of the population.³⁶ APS involves multiple antibodies: anticardiolipin antibodies, lupus anticoagulant, and anti-beta-2 glycoprotein 1 antibodies. Establishing risk for thrombosis across the varying types of thrombophilia has proven difficult, but APS is considered the most thrombogenic thrombophilia apart from extremely rare homozygous inherited thrombophilias.³⁶ Therefore, DOAC recommendations are thrombophilia specific.

Assessing DOAC blood levels is no longer recommended for patients with obesity, as there is insufficient evidence that these measures affect clinical outcomes.

A prospective cohort study evaluated DOACs compared with heparin/warfarin for VTE treatment in patients with inherited thrombophilias.³⁷ Although all 4 available DOACs were included, most patients (61.1%) received rivaroxaban. Patients with an array of inherited thrombophilias, including rare homozygous mutations, were enrolled in this trial. While most patients (66.9%) had a “mild thrombophilia” defined as either FVL or PGM, the remainder had more severe thrombophilias.³⁷ VTE recurrence was similar and uncommon in the DOAC and heparin/warfarin groups, consistent with a previous meta-analysis.³⁸ Surprisingly, an increase in the cumulative risk for bleeding was seen in the DOAC group compared with the warfarin group, a finding inconsistent with prior trials.³⁸ There were no major bleeding events in the DOAC group, but 3 such events occurred in the heparin/warfarin group, including 2 intracranial hemorrhages.

Currently NICE, CHEST, and ISTH do not make a recommendation for a preferred agent in patients with an acute VTE and inherited thrombophilia; however, DOACs would not be inappropriate.^23,28,32 The American Society of Hematology (ASH) had planned to release recommendations related to the treatment of thrombophilia in 2020, but they were delayed by the COVID-19 pandemic.³⁹

APS presents challenges for acute VTE anticoagulation. First, it causes a strongly thrombogenic state necessitating therapeutic anticoagulation. Second, for patients with positive lupus anticoagulant, INR monitoring and standardized INR goals may be inadequate.⁴⁰ Therefore, using fixed-dose DOACs without the need for therapeutic monitoring is appealing, but significant concerns exist for using DOACs in patients with APS.^41-45 ISTH and CHEST recommend warfarin for the treatment and prevention of acute VTE in patients with APS, especially those with triple-­positive (anticardiolipin, lupus anticoagulant, and anti-beta-2 glycoprotein 1) APS.^13,46 Package labeling for all DOACs recommends avoidance in triple-positive APS.^1-4

ASTRO-APS is the most recent RCT to compare apixaban and warfarin for patients with APS,⁴⁷ and it was terminated early after 6 of 23 patients in the apixaban group had thrombotic events, while no one in the warfarin group had such an event.⁴⁸ Subsequently, a meta-analysis⁴⁹ demonstrated that patients with thrombotic APS appear to have a greater risk for arterial thrombosis when treated with DOACs compared with warfarin. These 2 studies may lead to changes in recommendations to avoid DOACs in all patients with APS or may prompt more focused trials for DOAC use in patients with APS plus an antiplatelet to mitigate arterial thrombotic risk.

Continue to: Expanded clinical indications

Expanded clinical indications

Superficial vein thrombosis

Superficial thrombophlebitis or superficial vein thrombosis (SVT) is estimated to occur 6 times more frequently than VTE.⁵⁰ Management of patients with isolated, uncomplicated thrombophlebitis who are at low risk for extension of the SVT involves symptomatic treatment with nonsteroidal anti-inflammatory drugs, topical agents, or compression therapy. However, depending on risk for progression, anticoagulation may be recommended.⁵¹

Patients at intermediate risk for extension or propagation of SVT are candidates for anticoagulation. The CHEST guidelines recommend fondaparinux 2.5 mg subcutaneous injections daily for 45 days instead of LMWH or warfarin.¹³ However, if patients decline 6 weeks of daily injections, the guidelines acknowledge that rivaroxaban 10 mg daily may be an alternative.¹³

Certain situations should prompt one to consider using a treatment dose of a DOAC for 3 months. These include cases in which the SVT is located within 3 cm of the deep venous system, expands despite an appropriate prophylactic regimen, or recurs after discontinuation of prophylactic anticoagulation.^13,50

Acute coronary syndrome

The American College of Cardiology/­American Heart Association (ACC/AHA) recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.⁵² Data are mixed regarding longer-term anticoagulation in addition to dual antiplatelet therapy in outpatient settings to prevent thrombosis recurrence in the absence of AF.

For patients at intermediate risk for extension of superficial vein thrombosis who decline daily subcutaneous injections of fondaparinux, rivaroxaban 10 mg/d may be an alternative.

The APPRAISE-2 trial enrolled high-risk patients with ACS within 7 days of the event.⁵³ Apixaban 5 mg twice daily was compared with placebo in patients taking aspirin or aspirin plus clopidogrel. The trial was terminated early because major bleeding events increased with apixaban without reduction in recurrent ischemic events. The ATLAS ACS-TIMI 46 trial evaluated different rivaroxaban doses (5-20 mg daily) in ACS patients.⁵⁴ The study revealed possible thrombosis benefit but also increased risk for bleeding, particularly at higher doses. As a result, another study—ATLAS ACS 2-TIMI 51—was conducted and compared the use of low-dose rivaroxaban (2.5 mg twice daily or 5 mg twice daily) vs placebo for patients with recent ACS.⁵⁵ All patients were receiving low-dose aspirin, and approximately 93% of patients in each group also were receiving clopidogrel or ticlopidine. As in the APPRAISE-2 trial, rivaroxaban increased the rate of major bleeding and intracranial hemorrhage; however, it did not increase the incidence of fatal bleeding. Unlike APPRAISE-2, rivaroxaban significantly reduced the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, or stroke (absolute risk reduction = 1.8%; number needed to treat = 56 for combined rivaroxaban doses).⁵⁵

A secondary subgroup analysis combined data from the ATLAS ACMS-TIMI 46 and ATLAS ACS 2-TIMI 51 trials to evaluate outcomes in patients receiving aspirin monotherapy when combined with rivaroxaban 2.5 mg twice daily or 5 mg twice daily or with placebo.⁵⁶ The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. When the 2 trials were evaluated separately, neither rivaroxaban dose was associated with reduction of the primary efficacy outcomes compared with aspirin alone. However, when the data were pooled, both the combined rivaroxaban doses (particularly the 5-mg dose) were associated with reduced cardiovascular outcomes. From a safety perspective, the 2.5-mg twice-daily dose of rivaroxaban was the only dose not associated with increased major bleeding risk. Thus, the 2.5-mg twice-daily dose of rivaroxaban may not provide sufficient cardiovascular benefit in patients with ACS, while the larger dose may increase the risk for nonfatal major bleeding events.⁵⁶

The European Medicines Agency⁵⁷ approved rivaroxaban 2.5 mg twice daily for ACS, and the 2020 ESC guidelines⁵⁸ consider it an appropriate therapeutic option in addition to aspirin for patients at high ischemic risk and low bleeding risk. ACS is not an FDA-approved indication for DOACs, and the ACC/AHA Guideline for the Management of ACS, last updated in 2014, does not include DOACs for ACS unless patients have AF.⁵² Ongoing trials are further investigating rivaroxaban for ACS, so the use of DOACs in the post-acute phase of ACS may become clearer in the future.⁵⁹

Continue to: Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia

Historically, nonheparin parenteral anticoagulants argatroban, bivalirudin, and fondaparinux were recommended for patients at risk for or who had heparin-induced thrombocytopenia (HIT). Argatroban is the only drug FDA approved for the treatment and prophylaxis of HIT; recommendations for the others are based on guideline recommendations.^23,60,61 The nonheparin parenteral anticoagulants cost between $700 and $1500 per day; therefore most patients with HIT are transitioned to warfarin.⁶² However, protein C and S inhibition and a subsequent prothrombotic state conveyed by warfarin initiation necessitates a minimum 5-day bridge to therapeutic warfarin with a nonheparin parenteral anticoagulant.

In vitro tests show that DOACs do not promote development of HIT antibodies⁶³ or affect platelet activation or aggregation.⁶⁴ A literature summary of DOACs for HIT determined that in 104 patients, all but 1 achieved platelet recovery (defined as > 150,000/mcL) within a median time of 7 days. Therapeutically, DOACs prevented new or recurrent VTE in 102/104 cases (98%), and only 3% of patients experienced significant bleeding events.⁶²

The ACC/AHA recommend combination antiplatelet therapy and anticoagulation for management of acute coronary syndrome in hospitalized patients.

The 2018 ASH guidelines for VTE management in HIT include (with very low certainty of evidence) dabigatran, rivaroxaban, or apixaban for consideration in addition to previously recommended nonheparin parenteral anticoagulants.⁶¹ The dosing of each agent is contingent upon treatment of patients with HIT and an acute thrombosis (HITT) or HIT in the absence of VTE. For patients with HITT, treatment doses for acute VTE should be used for the appropriate duration of therapy (ie, 3 months). Importantly, dabigatran requires a 5-day pretreatment period with a parenteral anticoagulant, so it is not an ideal option. When treating isolated HIT (in the absence of VTE), ASH recommends all agents be dosed twice daily—dabigatran 150 mg twice daily (no 5-day parenteral pretreatment necessary), rivaroxaban 15 mg twice daily, or apixaban 5 mg twice daily—until platelet recovery (≥ 150,000/mcL) is achieved.⁶¹

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

A1C has been used to estimate 3-month glycemic control in patients with diabetes. However, A1C monitoring alone does not provide insight into daily glycemic variation, which is valuable in clinical management because tight glycemic control (defined as A1C < 7.0%) has been shown to reduce the risk of microvascular complications. Prior to the approval of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors by the US Food and Drug Administration for the treatment of type 2 diabetes (T2D), reduction in the risk of macrovascular complications (aside from nonfatal myocardial infarction) was more difficult to achieve than it is now; some patients had a worse outcome with overly aggressive glycemic control.¹

Previously, the use of a continuous glucose monitor (CGM) was limited to patients with type 1 diabetes who required basal and bolus insulin. However, technological advances have led to more patient-friendly and affordable devices, making CGMs more available. As such, the American Diabetes Association (ADA), in its 2022 Standards of Medical Care in Diabetes, recommends that clinicians offer continuous glucose monitoring to adults with T2D who require multiple daily injections, and based on a given patient’s ability, preferences, and needs.²

In this article, we discuss, first, the intricacies of CGMs and, second, what the evidence says about their use so that physicians can confidently recommend, and educate patients on, effective utilization of CGMs to obtain an individualized target of glycemic control.

Continuous glucose monitoring: A glossary

CGMs are characterized by who possesses the device and how data are recorded. This review is not about professional CGMs, which are owned by the health care provider and consist of a sensor that is applied in the clinic and returned to clinic for downloading of data¹; rather, we focus on the novel category of nonprofessional, or personal, CGMs.

Three words to remember. Every CGM has 3 common components:

• The reader (also known as a receiver) is a handheld device that allows a patient to scan a sensor (see definition below) and instantaneously collect a glucose reading. The patient can use a standalone reader; a smartphone or other smart device with an associated app that serves as a reader; or both.
• A sensor is inserted subcutaneously to measure interstitial glucose. The lifespan of a sensor is 10 to 14 days.
• A transmitter relays information from the sensor to the reader.

The technology behind a CGM

CGM sensors measure interstitial glucose by means of a chemical reaction involving glucose oxidase and an oxidation-reduction cofactor, measuring the generation of hydrogen peroxide.³ Interstitial glucose readings lag behind plasma blood glucose readings by 2 to 21 minutes.^4,5 Although this lag time is often not clinically significant, situations such as aerobic exercise and a rapidly changing glucose level might warrant confirmation by means of fingerstick measurement.⁵ It is common for CGM readings to vary slightly from venipuncture or fingerstick glucose readings.

What CGMs are availableto your patients?

Intermittently scanned CGMs (isCGMs) measure the glucose level continuously; the patient must scan a sensor to display and record the glucose level.⁶ Prolonged periods without scanning result in gaps in glycemic data.^7,8

Continue to: Two isCGM systems...

Two isCGM systems are available: the FreeStyle Libre 14 day and the FreeStyle ­Libre 2 (both from Abbott).^a Both consist of a reader and a disposable sensor, applied to the back of the arm, that is worn for 14 days. If the patient has a compatible smartphone or other smart device, the reader can be replaced by the smart device with the downloaded ­FreeStyle Libre or FreeStyle Libre 2 app.

To activate a new sensor, the patient applies the sensor, then scans it. Once activated, scanning the sensor provides the current glucose reading and recalls the last 8 hours of data. In addition to providing an instantaneous glucose reading, the display also provides a trend arrow indicating the direction and degree to which the glucose level is changing (TABLE 1^10,14,15). This feature helps patients avoid hypoglycemic episodes by allowing them to preemptively correct if the arrow indicates a rapidly declining glucose level.

Continuous glucose monitor readings often vary slightly from venipuncture or fingerstick glucose readings.

For the first 12 hours after a new sensor is activated, and when a glucose reading is < 70 mg/dL, patients should be instructed to avoid making treatment decisions and encouraged to utilize fingerstick glucose readings. FreeStyle Libre 14 day does not allow a glucose level alarm to be set; the system cannot detect these events without scanning the sensor.¹⁰ Bluetooth connectivity does allow FreeStyle Libre 2 users to set a glucose alarm if the reader or smart device is within 20 feet of the sensor. A default alarm is set to activate at 70 mg/dL (“low”) and 240 mg/dL (“high”); low and high alarm settings are also customizable. Because both FreeStyle Libre devices store 8 hours of data, patients must scan the sensor every 8 hours for a comprehensive glycemic report.¹⁴

FreeStyle Libre CGMs allow patients to add therapy notes, including time and amount of insulin administered and carbohydrates ingested. Readers for both devices function as a glucometer that is compatible with Abbott FreeStyle Precision Neo test strips.

Real-time CGMs (rtCGMs) measure and display glucose levels continuously for the duration of the life of the sensor, without the need to scan. Three rtCGM systems are available: Dexcom G6, Medtronic Guardian 3, and Senseonics Eversense E3.

Continue to: Dexcom G6...

Dexcom G6 is the first Dexcom CGM that does not require fingerstick calibration and the only rtCGM available in the United States that does not require patient calibration. This system comprises a single-use sensor replaced every 10 days; a transmitter that is transferred to each new sensor and replaced every 3 months; and an optional receiver that can be omitted if the patient prefers to utilize a smart device.

Dexcom G6 never requires a patient to scan a sensor. Instead, the receiver (or smart device) utilizes Bluetooth technology to obtain blood glucose readings if it is positioned within 20 feet of the transmitter. Patients can set both hypoglycemic and hyperglycemic alarms to predict events within 20 minutes. Similar to the functionality of the FreeStyle Libre systems, Dexcom G6 provides the opportunity to log lifestyle events, including insulin dosing, carbohydrate ingestion, exercise, and sick days.¹⁵

Medtronic Guardian 3 comprises the multi-use Guardian Connect Transmitter that is replaced annually and a single-use Guardian Sensor that is replaced every 7 days. Guardian 3 requires twice-daily fingerstick glucose calibration, which reduces the convenience of a CGM.

Continuous glucose monitor (CGM) manufacturers recommend that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist.

Guardian 3 allows the user to set alarm levels, providing predictive alerts 10 to 60 minutes before set glucose levels are reached. Patients must utilize a smart device to connect through Bluetooth to the CareLink Connect app and remain within 20 feet of the transmitter to provide continuous glucose readings. The CareLink Connect app allows patients to document exercise, calibration of fingerstick readings, meals, and insulin administration.¹⁶

Senseonics Eversense E3 consists of a 3.5 mm × 18.3 mm sensor inserted sub­cutaneously in the upper arm once every 180 days; a removable transmitter that attaches to an adhesive patch placed over the sensor; and a smart device with the Eversense app. The transmitter has a 1-year rechargeable battery and provides the patient with on-body vibration alerts even when they are not near their smart device.

Continue to: The Eversense E3 transmitter...

The Eversense E3 transmitter can be removed and reapplied without affecting the life of the sensor; however, no glucose data will be collected during this time. Once the transmitter is reapplied, it takes 10 minutes for the sensor to begin communicating with the transmitter. Eversense provides predictive alerts as long as 30 minutes before hyperglycemic or hypoglycemic events. The device requires twice-daily fingerstick calibrations.¹⁷

A comparison of the specifications and capabilities of the personal CGMs discussed here is provided in TABLE 2.^10,14-17

The evidence, reviewed

Clinical outcomes evidence with CGMs in patients with T2D is sparse. Most studies that support improved clinical outcomes enrolled patients with type 1 diabetes who were treated with intensive insulin regimens. Many studies utilized rtCGMs that are capable of incorporating a hypoglycemic alarm, and results might not be generalizable to ­isCGMs.^18,19 In this article, we review only the continuous glucose monitoring literature in which subjects had T2D.

Evidence for is CGMs

The REPLACE trial compared outcomes in patients with T2D who used an isCGM vs those who self-monitored blood glucose (SMBG); both groups were being treated with intensive insulin regimens. Both groups had similar glucose reductions, but the time in the hypoglycemic range (see “Clinical targets,” in the text that follows) was significantly shorter in the isCGM group.²⁰

A randomized controlled trial (RCT) that compared intermittently scanned continuous glucose monitoring and SMBG in patients with T2D who received multiple doses of insulin daily demonstrated a significant A1C reduction of 0.82% with an isCGM and 0.33% with SMBG, with no difference in the rate of hypoglycemic events, over 10 weeks.²¹

Continue to: Chart review

Chart review. Data extracted from chart reviews in Austria, France, and ­Germany demonstrated a mean improvement in A1C of 0.9% among patients when using a CGM after using SMBG previously.²²

A retrospective review of patients with T2D who were not taking bolus insulin and who used a CGM had a reduction in A1C from 10.1% to 8.6% over 60 to 300 days.²³

Evidence for rtCGMs

The DIAMOND study included a subset of patients with T2D who used an rtCGM and were compared to a subset who received usual care. The primary outcome was the change in A1C. A 0.3% greater reduction was observed in the CGM group at 24 weeks. There was no difference in hypoglycemic events between the 2 groups; there were few events in either group.²⁴

An RCT demonstrated a similar reduction in A1C in rtCGM users and in nonusers over 1 year.²⁵ However, patients who used the rtCGM by protocol demonstrated the greatest reduction in A1C. The CGM utilized in this trial required regular fingerstick calibration, which likely led to poorer adherence to protocol than would have been the case had the trial utilized a CGM that did not require calibration.

A prospective trial demonstrated that utilization of an rtCGM only 3 days per month for 3 consecutive months was associated with (1) significant improvement in A1C (a decrease of 1.1% in the CGM group, compared to a decrease of 0.4% in the SMBG group) and (2) numerous lifestyle modifications, including reduction in total caloric intake, weight loss, decreased body mass index, and an increase in total weekly exercise.²⁶ This trial demonstrated that CGMs might be beneficial earlier in the course of disease by reinforcing lifestyle changes.

Continue to: The MOBILE trial

The MOBILE trial demonstrated that use of an rtCGM reduced baseline A1C from 9.1% to 8.0% in the CGM group, compared to 9.0% to 8.4% in the non-CGM group.²⁷

Practical utilization of CGMs

Patient education

Detailed patient education resources—for initial setup, sensor application, methods to ensure appropriate sensor adhesion, and app and platform assistance—are available on each manufacturer’s website.

Clinical targets

In 2019, the Advanced Technologies & Treatments for Diabetes Congress determined that what is known as the time in range metric yields the most practical data to help clinicians manage glycemic control.²⁸ The time in range metric comprises:

• time in the target glucose range (TIR)
• time below the target glucose range (TBR)
• time above the target glucose range (TAR).

A sensor that becomes dislodged can malfunction or lose accuracy. Patients should not try to reapply the sensor; they should remove and discard it and apply a new one.

TIR glucose ranges are modifiable and based on the A1C goal. For example, if the A1C goal is < 7.0%, the TIR glucose range is 70-180 mg/dL. If a patient maintains TIR > 70% for 3 months, the measured A1C will correlate well with the goal. Each 10% fluctuation in TIR from the goal of 70% corresponds to a difference of approximately 0.5% in A1C. Therefore, TIR of approximately 50% predicts an A1C of 8.0%.²⁸

A retrospective review of 1440 patients with CGM data demonstrated that progression of retinopathy and development of microalbuminuria increased 64% and 40%, respectively, over 10 years for each 10% reduction in TIR—highlighting the importance of TIR and consistent glycemic control.²⁹ Importantly, the CGM sensor must be active ≥ 70% of the wearable time to provide adequate TIR data.³⁰

Continue to: Concerns about accuracy

There is no universally accepted standard for determining the accuracy of a CGM; however, the mean absolute relative difference (MARD) is the most common statistic referenced. MARD is calculated as the average of the absolute error between all CGM values and matched reference values that are usually obtained from SMBG.³¹ The lower the MARD percentage, the better the accuracy of the CGM. A MARD of ≤ 10% is considered acceptable for making therapeutic decisions.³⁰

Package labeling for all CGMs recommends that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist. If a sensor becomes dislodged, it can malfunction or lose accuracy. Patients should not try to re-apply the sensor; instead, they should remove and discard the sensor and apply a new one. TABLE 2^10,14-17 compares MARD for CGMs and lists substances that might affect the accuracy of a CGM.

Patient–provider data-sharing platforms

FreeStyle Libre and Libre 2. Providers create a LibreView Practice ID at www.Libre View.com. Patient data-sharing depends on whether they are using a smart device, a reader, or both. Patients can utilize both the smart device and the reader but must upload data from the reader at regular intervals to provide a comprehensive report that will merge data from the smart device (ie, data that have been uploaded automatically) and the reader.⁷

Dexcom G6. Clinicians create a ­Dexcom CLARITY account at https://clarity.dexcom.com and add patients to a practice list or gain access to a share code generated by the patient. Patients must download the Dexcom CLARITY app to create an account; once the account is established, readings will be transmitted to the clinic automatically.¹⁵ A patient who is utilizing a nonsmart-device reader must upload data manually to their web-based CLARITY account.

Family and caregiver access

Beyond sharing CGM data with clinic staff, an important feature available with ­FreeStyle ­Libre and Dexcom systems is the ability to share data with friends and caregivers. The relevant platforms and apps are listed in ­TABLE 2.^10,14-17

Continue to: Insurance coverage, cost, and accessibility

Medicare Part B has established criteria by which patients with T2D qualify for a CGM (TABLE 3³²). A Medicare patient who has been determined to be eligible is responsible for 20% of the out-of-pocket expense of the CGM and supplies once their deductible is met. Once Medicare covers a CGM, the patient is no longer able to obtain fingerstick glucose supplies through Medicare; they must pay the cash price for any fingerstick supplies that are determined to be necessary.³²

Once Medicare covers a continuous glucose monitor, the patient is no longer able to obtain fingerstick glucose supplies through Medicare.

Patients with private insurance can obtain CGM supplies through their preferred pharmacy when the order is written as a prescription (the same as for fingerstick glucometers). That is not the case for patients with Medicare because not all US distributors and pharmacies are contracted to bill Medicare Part B for CGM supplies. A list of distributors and eligible pharmacies can be found on each manufacturer’s website.

Risk–benefit analysis

CGMs are associated with few risks overall. The predominant adverse effect is contact dermatitis; the prevalence of CGM-­associated contact dermatitis is difficult to quantify and differs from device to device.

FreeStyle Libre. In a retrospective review of records of patients with diabetes, researchers determined that a cutaneous adverse event occurred in approximately 5.5% of 1036 patients who utilized a FreeStyle Libre sensor.³³ Of that percentage, 3.8% of dermatitis cases were determined to be allergic in nature and related to isobornyl acrylate (IBOA), a chemical constituent of the sensor’s adhesive that is not used in the FreeStyle Libre 2. Among patients who wore a sensor and developed allergic contact dermatitis, interventions such as a barrier film were of limited utility in alleviating or preventing further cutaneous eruption.³³

Dexcom G6. The prevalence of Dexcom G6–associated allergic contact dermatitis is more difficult to ascertain (the IBOA adhesive was replaced in October 2019) but has been reported to be less common than with FreeStyle Libre,³⁴ a finding that corroborates our anecdotal clinical experience. Although Dexcom sensors no longer contain IBOA, cases of allergic contact dermatitis are still reported.³⁵ We propose that the lower incidence of cutaneous reactions associated with the Dexcom G6 sensor might be due to the absence of IBOA and shorter contact time with skin.

Continue to: In general, patients should be...

In general, patients should be counseled to rotate the location of the sensor and to use only specific barrier products that are recommended on each manufacturer’s website. The use of other barriers that are not specifically recommended might compromise the accuracy of the sensor.

Summing up

As CGM technology improves, it is likely that more and more of your patients will utilize one of these devices. The value of CGMs has been documented, but any endorsement of their use is qualified:

• Data from many older RCTs of patients with T2D who utilize a CGM did not demonstrate a significant reduction in A1C^20,24,36; however, real-world observational data do show a greater reduction in A1C.
• From a safety standpoint, contact dermatitis is the primary drawback of CGMs.
• CGMs can provide patients and clinicians with a comprehensive picture of daily glucose trends, which can help patients make lifestyle changes and serve as a positive reinforcement for the effects of diet and exercise. Analysis of glucose trends can also help clinicians confidently make decisions about when to intensify or taper a medication regimen, based on data that is reported more often than 90-day A1C changes.

Health insurance coverage will continue to dictate access to CGM technology for many patients. When a CGM is reimbursable by the patient’s insurance, consider offering it as an option—even for patients who do not require an intensive insulin regimen.

^a The US Food and Drug Administration cleared a new Abbott CGM, FreeStyle Libre 3, earlier this year; however, the device is not yet available for purchase. With advances in monitoring technology, several other manufacturers also anticipate introducing novel CGMs. (See “Continuous glucose monitors: The next generation.” )

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

A1C has been used to estimate 3-month glycemic control in patients with diabetes. However, A1C monitoring alone does not provide insight into daily glycemic variation, which is valuable in clinical management because tight glycemic control (defined as A1C < 7.0%) has been shown to reduce the risk of microvascular complications. Prior to the approval of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors by the US Food and Drug Administration for the treatment of type 2 diabetes (T2D), reduction in the risk of macrovascular complications (aside from nonfatal myocardial infarction) was more difficult to achieve than it is now; some patients had a worse outcome with overly aggressive glycemic control.¹

Previously, the use of a continuous glucose monitor (CGM) was limited to patients with type 1 diabetes who required basal and bolus insulin. However, technological advances have led to more patient-friendly and affordable devices, making CGMs more available. As such, the American Diabetes Association (ADA), in its 2022 Standards of Medical Care in Diabetes, recommends that clinicians offer continuous glucose monitoring to adults with T2D who require multiple daily injections, and based on a given patient’s ability, preferences, and needs.²

In this article, we discuss, first, the intricacies of CGMs and, second, what the evidence says about their use so that physicians can confidently recommend, and educate patients on, effective utilization of CGMs to obtain an individualized target of glycemic control.

Continuous glucose monitoring: A glossary

CGMs are characterized by who possesses the device and how data are recorded. This review is not about professional CGMs, which are owned by the health care provider and consist of a sensor that is applied in the clinic and returned to clinic for downloading of data¹; rather, we focus on the novel category of nonprofessional, or personal, CGMs.

Three words to remember. Every CGM has 3 common components:

• The reader (also known as a receiver) is a handheld device that allows a patient to scan a sensor (see definition below) and instantaneously collect a glucose reading. The patient can use a standalone reader; a smartphone or other smart device with an associated app that serves as a reader; or both.
• A sensor is inserted subcutaneously to measure interstitial glucose. The lifespan of a sensor is 10 to 14 days.
• A transmitter relays information from the sensor to the reader.

The technology behind a CGM

CGM sensors measure interstitial glucose by means of a chemical reaction involving glucose oxidase and an oxidation-reduction cofactor, measuring the generation of hydrogen peroxide.³ Interstitial glucose readings lag behind plasma blood glucose readings by 2 to 21 minutes.^4,5 Although this lag time is often not clinically significant, situations such as aerobic exercise and a rapidly changing glucose level might warrant confirmation by means of fingerstick measurement.⁵ It is common for CGM readings to vary slightly from venipuncture or fingerstick glucose readings.

What CGMs are availableto your patients?

Intermittently scanned CGMs (isCGMs) measure the glucose level continuously; the patient must scan a sensor to display and record the glucose level.⁶ Prolonged periods without scanning result in gaps in glycemic data.^7,8

Continue to: Two isCGM systems...

Two isCGM systems are available: the FreeStyle Libre 14 day and the FreeStyle ­Libre 2 (both from Abbott).^a Both consist of a reader and a disposable sensor, applied to the back of the arm, that is worn for 14 days. If the patient has a compatible smartphone or other smart device, the reader can be replaced by the smart device with the downloaded ­FreeStyle Libre or FreeStyle Libre 2 app.

To activate a new sensor, the patient applies the sensor, then scans it. Once activated, scanning the sensor provides the current glucose reading and recalls the last 8 hours of data. In addition to providing an instantaneous glucose reading, the display also provides a trend arrow indicating the direction and degree to which the glucose level is changing (TABLE 1^10,14,15). This feature helps patients avoid hypoglycemic episodes by allowing them to preemptively correct if the arrow indicates a rapidly declining glucose level.

Continuous glucose monitor readings often vary slightly from venipuncture or fingerstick glucose readings.

For the first 12 hours after a new sensor is activated, and when a glucose reading is < 70 mg/dL, patients should be instructed to avoid making treatment decisions and encouraged to utilize fingerstick glucose readings. FreeStyle Libre 14 day does not allow a glucose level alarm to be set; the system cannot detect these events without scanning the sensor.¹⁰ Bluetooth connectivity does allow FreeStyle Libre 2 users to set a glucose alarm if the reader or smart device is within 20 feet of the sensor. A default alarm is set to activate at 70 mg/dL (“low”) and 240 mg/dL (“high”); low and high alarm settings are also customizable. Because both FreeStyle Libre devices store 8 hours of data, patients must scan the sensor every 8 hours for a comprehensive glycemic report.¹⁴

FreeStyle Libre CGMs allow patients to add therapy notes, including time and amount of insulin administered and carbohydrates ingested. Readers for both devices function as a glucometer that is compatible with Abbott FreeStyle Precision Neo test strips.

Real-time CGMs (rtCGMs) measure and display glucose levels continuously for the duration of the life of the sensor, without the need to scan. Three rtCGM systems are available: Dexcom G6, Medtronic Guardian 3, and Senseonics Eversense E3.

Continue to: Dexcom G6...

Dexcom G6 is the first Dexcom CGM that does not require fingerstick calibration and the only rtCGM available in the United States that does not require patient calibration. This system comprises a single-use sensor replaced every 10 days; a transmitter that is transferred to each new sensor and replaced every 3 months; and an optional receiver that can be omitted if the patient prefers to utilize a smart device.

Dexcom G6 never requires a patient to scan a sensor. Instead, the receiver (or smart device) utilizes Bluetooth technology to obtain blood glucose readings if it is positioned within 20 feet of the transmitter. Patients can set both hypoglycemic and hyperglycemic alarms to predict events within 20 minutes. Similar to the functionality of the FreeStyle Libre systems, Dexcom G6 provides the opportunity to log lifestyle events, including insulin dosing, carbohydrate ingestion, exercise, and sick days.¹⁵

Medtronic Guardian 3 comprises the multi-use Guardian Connect Transmitter that is replaced annually and a single-use Guardian Sensor that is replaced every 7 days. Guardian 3 requires twice-daily fingerstick glucose calibration, which reduces the convenience of a CGM.

Continuous glucose monitor (CGM) manufacturers recommend that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist.

Guardian 3 allows the user to set alarm levels, providing predictive alerts 10 to 60 minutes before set glucose levels are reached. Patients must utilize a smart device to connect through Bluetooth to the CareLink Connect app and remain within 20 feet of the transmitter to provide continuous glucose readings. The CareLink Connect app allows patients to document exercise, calibration of fingerstick readings, meals, and insulin administration.¹⁶

Senseonics Eversense E3 consists of a 3.5 mm × 18.3 mm sensor inserted sub­cutaneously in the upper arm once every 180 days; a removable transmitter that attaches to an adhesive patch placed over the sensor; and a smart device with the Eversense app. The transmitter has a 1-year rechargeable battery and provides the patient with on-body vibration alerts even when they are not near their smart device.

Continue to: The Eversense E3 transmitter...

The Eversense E3 transmitter can be removed and reapplied without affecting the life of the sensor; however, no glucose data will be collected during this time. Once the transmitter is reapplied, it takes 10 minutes for the sensor to begin communicating with the transmitter. Eversense provides predictive alerts as long as 30 minutes before hyperglycemic or hypoglycemic events. The device requires twice-daily fingerstick calibrations.¹⁷

A comparison of the specifications and capabilities of the personal CGMs discussed here is provided in TABLE 2.^10,14-17

The evidence, reviewed

Clinical outcomes evidence with CGMs in patients with T2D is sparse. Most studies that support improved clinical outcomes enrolled patients with type 1 diabetes who were treated with intensive insulin regimens. Many studies utilized rtCGMs that are capable of incorporating a hypoglycemic alarm, and results might not be generalizable to ­isCGMs.^18,19 In this article, we review only the continuous glucose monitoring literature in which subjects had T2D.

Evidence for is CGMs

The REPLACE trial compared outcomes in patients with T2D who used an isCGM vs those who self-monitored blood glucose (SMBG); both groups were being treated with intensive insulin regimens. Both groups had similar glucose reductions, but the time in the hypoglycemic range (see “Clinical targets,” in the text that follows) was significantly shorter in the isCGM group.²⁰

A randomized controlled trial (RCT) that compared intermittently scanned continuous glucose monitoring and SMBG in patients with T2D who received multiple doses of insulin daily demonstrated a significant A1C reduction of 0.82% with an isCGM and 0.33% with SMBG, with no difference in the rate of hypoglycemic events, over 10 weeks.²¹

Continue to: Chart review

Chart review. Data extracted from chart reviews in Austria, France, and ­Germany demonstrated a mean improvement in A1C of 0.9% among patients when using a CGM after using SMBG previously.²²

A retrospective review of patients with T2D who were not taking bolus insulin and who used a CGM had a reduction in A1C from 10.1% to 8.6% over 60 to 300 days.²³

Evidence for rtCGMs

The DIAMOND study included a subset of patients with T2D who used an rtCGM and were compared to a subset who received usual care. The primary outcome was the change in A1C. A 0.3% greater reduction was observed in the CGM group at 24 weeks. There was no difference in hypoglycemic events between the 2 groups; there were few events in either group.²⁴

An RCT demonstrated a similar reduction in A1C in rtCGM users and in nonusers over 1 year.²⁵ However, patients who used the rtCGM by protocol demonstrated the greatest reduction in A1C. The CGM utilized in this trial required regular fingerstick calibration, which likely led to poorer adherence to protocol than would have been the case had the trial utilized a CGM that did not require calibration.

A prospective trial demonstrated that utilization of an rtCGM only 3 days per month for 3 consecutive months was associated with (1) significant improvement in A1C (a decrease of 1.1% in the CGM group, compared to a decrease of 0.4% in the SMBG group) and (2) numerous lifestyle modifications, including reduction in total caloric intake, weight loss, decreased body mass index, and an increase in total weekly exercise.²⁶ This trial demonstrated that CGMs might be beneficial earlier in the course of disease by reinforcing lifestyle changes.

Continue to: The MOBILE trial

The MOBILE trial demonstrated that use of an rtCGM reduced baseline A1C from 9.1% to 8.0% in the CGM group, compared to 9.0% to 8.4% in the non-CGM group.²⁷

Practical utilization of CGMs

Patient education

Detailed patient education resources—for initial setup, sensor application, methods to ensure appropriate sensor adhesion, and app and platform assistance—are available on each manufacturer’s website.

Clinical targets

In 2019, the Advanced Technologies & Treatments for Diabetes Congress determined that what is known as the time in range metric yields the most practical data to help clinicians manage glycemic control.²⁸ The time in range metric comprises:

• time in the target glucose range (TIR)
• time below the target glucose range (TBR)
• time above the target glucose range (TAR).

A sensor that becomes dislodged can malfunction or lose accuracy. Patients should not try to reapply the sensor; they should remove and discard it and apply a new one.

TIR glucose ranges are modifiable and based on the A1C goal. For example, if the A1C goal is < 7.0%, the TIR glucose range is 70-180 mg/dL. If a patient maintains TIR > 70% for 3 months, the measured A1C will correlate well with the goal. Each 10% fluctuation in TIR from the goal of 70% corresponds to a difference of approximately 0.5% in A1C. Therefore, TIR of approximately 50% predicts an A1C of 8.0%.²⁸

A retrospective review of 1440 patients with CGM data demonstrated that progression of retinopathy and development of microalbuminuria increased 64% and 40%, respectively, over 10 years for each 10% reduction in TIR—highlighting the importance of TIR and consistent glycemic control.²⁹ Importantly, the CGM sensor must be active ≥ 70% of the wearable time to provide adequate TIR data.³⁰

Continue to: Concerns about accuracy

There is no universally accepted standard for determining the accuracy of a CGM; however, the mean absolute relative difference (MARD) is the most common statistic referenced. MARD is calculated as the average of the absolute error between all CGM values and matched reference values that are usually obtained from SMBG.³¹ The lower the MARD percentage, the better the accuracy of the CGM. A MARD of ≤ 10% is considered acceptable for making therapeutic decisions.³⁰

Package labeling for all CGMs recommends that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist. If a sensor becomes dislodged, it can malfunction or lose accuracy. Patients should not try to re-apply the sensor; instead, they should remove and discard the sensor and apply a new one. TABLE 2^10,14-17 compares MARD for CGMs and lists substances that might affect the accuracy of a CGM.

Patient–provider data-sharing platforms

FreeStyle Libre and Libre 2. Providers create a LibreView Practice ID at www.Libre View.com. Patient data-sharing depends on whether they are using a smart device, a reader, or both. Patients can utilize both the smart device and the reader but must upload data from the reader at regular intervals to provide a comprehensive report that will merge data from the smart device (ie, data that have been uploaded automatically) and the reader.⁷

Dexcom G6. Clinicians create a ­Dexcom CLARITY account at https://clarity.dexcom.com and add patients to a practice list or gain access to a share code generated by the patient. Patients must download the Dexcom CLARITY app to create an account; once the account is established, readings will be transmitted to the clinic automatically.¹⁵ A patient who is utilizing a nonsmart-device reader must upload data manually to their web-based CLARITY account.

Family and caregiver access

Beyond sharing CGM data with clinic staff, an important feature available with ­FreeStyle ­Libre and Dexcom systems is the ability to share data with friends and caregivers. The relevant platforms and apps are listed in ­TABLE 2.^10,14-17

Continue to: Insurance coverage, cost, and accessibility

Medicare Part B has established criteria by which patients with T2D qualify for a CGM (TABLE 3³²). A Medicare patient who has been determined to be eligible is responsible for 20% of the out-of-pocket expense of the CGM and supplies once their deductible is met. Once Medicare covers a CGM, the patient is no longer able to obtain fingerstick glucose supplies through Medicare; they must pay the cash price for any fingerstick supplies that are determined to be necessary.³²

Once Medicare covers a continuous glucose monitor, the patient is no longer able to obtain fingerstick glucose supplies through Medicare.

Patients with private insurance can obtain CGM supplies through their preferred pharmacy when the order is written as a prescription (the same as for fingerstick glucometers). That is not the case for patients with Medicare because not all US distributors and pharmacies are contracted to bill Medicare Part B for CGM supplies. A list of distributors and eligible pharmacies can be found on each manufacturer’s website.

Risk–benefit analysis

CGMs are associated with few risks overall. The predominant adverse effect is contact dermatitis; the prevalence of CGM-­associated contact dermatitis is difficult to quantify and differs from device to device.

FreeStyle Libre. In a retrospective review of records of patients with diabetes, researchers determined that a cutaneous adverse event occurred in approximately 5.5% of 1036 patients who utilized a FreeStyle Libre sensor.³³ Of that percentage, 3.8% of dermatitis cases were determined to be allergic in nature and related to isobornyl acrylate (IBOA), a chemical constituent of the sensor’s adhesive that is not used in the FreeStyle Libre 2. Among patients who wore a sensor and developed allergic contact dermatitis, interventions such as a barrier film were of limited utility in alleviating or preventing further cutaneous eruption.³³

Dexcom G6. The prevalence of Dexcom G6–associated allergic contact dermatitis is more difficult to ascertain (the IBOA adhesive was replaced in October 2019) but has been reported to be less common than with FreeStyle Libre,³⁴ a finding that corroborates our anecdotal clinical experience. Although Dexcom sensors no longer contain IBOA, cases of allergic contact dermatitis are still reported.³⁵ We propose that the lower incidence of cutaneous reactions associated with the Dexcom G6 sensor might be due to the absence of IBOA and shorter contact time with skin.

Continue to: In general, patients should be...

In general, patients should be counseled to rotate the location of the sensor and to use only specific barrier products that are recommended on each manufacturer’s website. The use of other barriers that are not specifically recommended might compromise the accuracy of the sensor.

Summing up

As CGM technology improves, it is likely that more and more of your patients will utilize one of these devices. The value of CGMs has been documented, but any endorsement of their use is qualified:

• Data from many older RCTs of patients with T2D who utilize a CGM did not demonstrate a significant reduction in A1C^20,24,36; however, real-world observational data do show a greater reduction in A1C.
• From a safety standpoint, contact dermatitis is the primary drawback of CGMs.
• CGMs can provide patients and clinicians with a comprehensive picture of daily glucose trends, which can help patients make lifestyle changes and serve as a positive reinforcement for the effects of diet and exercise. Analysis of glucose trends can also help clinicians confidently make decisions about when to intensify or taper a medication regimen, based on data that is reported more often than 90-day A1C changes.

Health insurance coverage will continue to dictate access to CGM technology for many patients. When a CGM is reimbursable by the patient’s insurance, consider offering it as an option—even for patients who do not require an intensive insulin regimen.

^a The US Food and Drug Administration cleared a new Abbott CGM, FreeStyle Libre 3, earlier this year; however, the device is not yet available for purchase. With advances in monitoring technology, several other manufacturers also anticipate introducing novel CGMs. (See “Continuous glucose monitors: The next generation.” )

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]

A1C has been used to estimate 3-month glycemic control in patients with diabetes. However, A1C monitoring alone does not provide insight into daily glycemic variation, which is valuable in clinical management because tight glycemic control (defined as A1C < 7.0%) has been shown to reduce the risk of microvascular complications. Prior to the approval of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors by the US Food and Drug Administration for the treatment of type 2 diabetes (T2D), reduction in the risk of macrovascular complications (aside from nonfatal myocardial infarction) was more difficult to achieve than it is now; some patients had a worse outcome with overly aggressive glycemic control.¹

Previously, the use of a continuous glucose monitor (CGM) was limited to patients with type 1 diabetes who required basal and bolus insulin. However, technological advances have led to more patient-friendly and affordable devices, making CGMs more available. As such, the American Diabetes Association (ADA), in its 2022 Standards of Medical Care in Diabetes, recommends that clinicians offer continuous glucose monitoring to adults with T2D who require multiple daily injections, and based on a given patient’s ability, preferences, and needs.²

In this article, we discuss, first, the intricacies of CGMs and, second, what the evidence says about their use so that physicians can confidently recommend, and educate patients on, effective utilization of CGMs to obtain an individualized target of glycemic control.

Continuous glucose monitoring: A glossary

CGMs are characterized by who possesses the device and how data are recorded. This review is not about professional CGMs, which are owned by the health care provider and consist of a sensor that is applied in the clinic and returned to clinic for downloading of data¹; rather, we focus on the novel category of nonprofessional, or personal, CGMs.

Three words to remember. Every CGM has 3 common components:

• The reader (also known as a receiver) is a handheld device that allows a patient to scan a sensor (see definition below) and instantaneously collect a glucose reading. The patient can use a standalone reader; a smartphone or other smart device with an associated app that serves as a reader; or both.
• A sensor is inserted subcutaneously to measure interstitial glucose. The lifespan of a sensor is 10 to 14 days.
• A transmitter relays information from the sensor to the reader.

The technology behind a CGM

CGM sensors measure interstitial glucose by means of a chemical reaction involving glucose oxidase and an oxidation-reduction cofactor, measuring the generation of hydrogen peroxide.³ Interstitial glucose readings lag behind plasma blood glucose readings by 2 to 21 minutes.^4,5 Although this lag time is often not clinically significant, situations such as aerobic exercise and a rapidly changing glucose level might warrant confirmation by means of fingerstick measurement.⁵ It is common for CGM readings to vary slightly from venipuncture or fingerstick glucose readings.

What CGMs are availableto your patients?

Intermittently scanned CGMs (isCGMs) measure the glucose level continuously; the patient must scan a sensor to display and record the glucose level.⁶ Prolonged periods without scanning result in gaps in glycemic data.^7,8

Continue to: Two isCGM systems...

Two isCGM systems are available: the FreeStyle Libre 14 day and the FreeStyle ­Libre 2 (both from Abbott).^a Both consist of a reader and a disposable sensor, applied to the back of the arm, that is worn for 14 days. If the patient has a compatible smartphone or other smart device, the reader can be replaced by the smart device with the downloaded ­FreeStyle Libre or FreeStyle Libre 2 app.

To activate a new sensor, the patient applies the sensor, then scans it. Once activated, scanning the sensor provides the current glucose reading and recalls the last 8 hours of data. In addition to providing an instantaneous glucose reading, the display also provides a trend arrow indicating the direction and degree to which the glucose level is changing (TABLE 1^10,14,15). This feature helps patients avoid hypoglycemic episodes by allowing them to preemptively correct if the arrow indicates a rapidly declining glucose level.

Continuous glucose monitor readings often vary slightly from venipuncture or fingerstick glucose readings.

For the first 12 hours after a new sensor is activated, and when a glucose reading is < 70 mg/dL, patients should be instructed to avoid making treatment decisions and encouraged to utilize fingerstick glucose readings. FreeStyle Libre 14 day does not allow a glucose level alarm to be set; the system cannot detect these events without scanning the sensor.¹⁰ Bluetooth connectivity does allow FreeStyle Libre 2 users to set a glucose alarm if the reader or smart device is within 20 feet of the sensor. A default alarm is set to activate at 70 mg/dL (“low”) and 240 mg/dL (“high”); low and high alarm settings are also customizable. Because both FreeStyle Libre devices store 8 hours of data, patients must scan the sensor every 8 hours for a comprehensive glycemic report.¹⁴

FreeStyle Libre CGMs allow patients to add therapy notes, including time and amount of insulin administered and carbohydrates ingested. Readers for both devices function as a glucometer that is compatible with Abbott FreeStyle Precision Neo test strips.

Real-time CGMs (rtCGMs) measure and display glucose levels continuously for the duration of the life of the sensor, without the need to scan. Three rtCGM systems are available: Dexcom G6, Medtronic Guardian 3, and Senseonics Eversense E3.

Continue to: Dexcom G6...

Dexcom G6 is the first Dexcom CGM that does not require fingerstick calibration and the only rtCGM available in the United States that does not require patient calibration. This system comprises a single-use sensor replaced every 10 days; a transmitter that is transferred to each new sensor and replaced every 3 months; and an optional receiver that can be omitted if the patient prefers to utilize a smart device.

Dexcom G6 never requires a patient to scan a sensor. Instead, the receiver (or smart device) utilizes Bluetooth technology to obtain blood glucose readings if it is positioned within 20 feet of the transmitter. Patients can set both hypoglycemic and hyperglycemic alarms to predict events within 20 minutes. Similar to the functionality of the FreeStyle Libre systems, Dexcom G6 provides the opportunity to log lifestyle events, including insulin dosing, carbohydrate ingestion, exercise, and sick days.¹⁵

Medtronic Guardian 3 comprises the multi-use Guardian Connect Transmitter that is replaced annually and a single-use Guardian Sensor that is replaced every 7 days. Guardian 3 requires twice-daily fingerstick glucose calibration, which reduces the convenience of a CGM.

Continuous glucose monitor (CGM) manufacturers recommend that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist.

Guardian 3 allows the user to set alarm levels, providing predictive alerts 10 to 60 minutes before set glucose levels are reached. Patients must utilize a smart device to connect through Bluetooth to the CareLink Connect app and remain within 20 feet of the transmitter to provide continuous glucose readings. The CareLink Connect app allows patients to document exercise, calibration of fingerstick readings, meals, and insulin administration.¹⁶

Senseonics Eversense E3 consists of a 3.5 mm × 18.3 mm sensor inserted sub­cutaneously in the upper arm once every 180 days; a removable transmitter that attaches to an adhesive patch placed over the sensor; and a smart device with the Eversense app. The transmitter has a 1-year rechargeable battery and provides the patient with on-body vibration alerts even when they are not near their smart device.

Continue to: The Eversense E3 transmitter...

The Eversense E3 transmitter can be removed and reapplied without affecting the life of the sensor; however, no glucose data will be collected during this time. Once the transmitter is reapplied, it takes 10 minutes for the sensor to begin communicating with the transmitter. Eversense provides predictive alerts as long as 30 minutes before hyperglycemic or hypoglycemic events. The device requires twice-daily fingerstick calibrations.¹⁷

A comparison of the specifications and capabilities of the personal CGMs discussed here is provided in TABLE 2.^10,14-17

The evidence, reviewed

Clinical outcomes evidence with CGMs in patients with T2D is sparse. Most studies that support improved clinical outcomes enrolled patients with type 1 diabetes who were treated with intensive insulin regimens. Many studies utilized rtCGMs that are capable of incorporating a hypoglycemic alarm, and results might not be generalizable to ­isCGMs.^18,19 In this article, we review only the continuous glucose monitoring literature in which subjects had T2D.

Evidence for is CGMs

The REPLACE trial compared outcomes in patients with T2D who used an isCGM vs those who self-monitored blood glucose (SMBG); both groups were being treated with intensive insulin regimens. Both groups had similar glucose reductions, but the time in the hypoglycemic range (see “Clinical targets,” in the text that follows) was significantly shorter in the isCGM group.²⁰

A randomized controlled trial (RCT) that compared intermittently scanned continuous glucose monitoring and SMBG in patients with T2D who received multiple doses of insulin daily demonstrated a significant A1C reduction of 0.82% with an isCGM and 0.33% with SMBG, with no difference in the rate of hypoglycemic events, over 10 weeks.²¹

Continue to: Chart review

Chart review. Data extracted from chart reviews in Austria, France, and ­Germany demonstrated a mean improvement in A1C of 0.9% among patients when using a CGM after using SMBG previously.²²

A retrospective review of patients with T2D who were not taking bolus insulin and who used a CGM had a reduction in A1C from 10.1% to 8.6% over 60 to 300 days.²³

Evidence for rtCGMs

The DIAMOND study included a subset of patients with T2D who used an rtCGM and were compared to a subset who received usual care. The primary outcome was the change in A1C. A 0.3% greater reduction was observed in the CGM group at 24 weeks. There was no difference in hypoglycemic events between the 2 groups; there were few events in either group.²⁴

An RCT demonstrated a similar reduction in A1C in rtCGM users and in nonusers over 1 year.²⁵ However, patients who used the rtCGM by protocol demonstrated the greatest reduction in A1C. The CGM utilized in this trial required regular fingerstick calibration, which likely led to poorer adherence to protocol than would have been the case had the trial utilized a CGM that did not require calibration.

A prospective trial demonstrated that utilization of an rtCGM only 3 days per month for 3 consecutive months was associated with (1) significant improvement in A1C (a decrease of 1.1% in the CGM group, compared to a decrease of 0.4% in the SMBG group) and (2) numerous lifestyle modifications, including reduction in total caloric intake, weight loss, decreased body mass index, and an increase in total weekly exercise.²⁶ This trial demonstrated that CGMs might be beneficial earlier in the course of disease by reinforcing lifestyle changes.

Continue to: The MOBILE trial

The MOBILE trial demonstrated that use of an rtCGM reduced baseline A1C from 9.1% to 8.0% in the CGM group, compared to 9.0% to 8.4% in the non-CGM group.²⁷

Practical utilization of CGMs

Patient education

Detailed patient education resources—for initial setup, sensor application, methods to ensure appropriate sensor adhesion, and app and platform assistance—are available on each manufacturer’s website.

Clinical targets

In 2019, the Advanced Technologies & Treatments for Diabetes Congress determined that what is known as the time in range metric yields the most practical data to help clinicians manage glycemic control.²⁸ The time in range metric comprises:

• time in the target glucose range (TIR)
• time below the target glucose range (TBR)
• time above the target glucose range (TAR).

A sensor that becomes dislodged can malfunction or lose accuracy. Patients should not try to reapply the sensor; they should remove and discard it and apply a new one.

TIR glucose ranges are modifiable and based on the A1C goal. For example, if the A1C goal is < 7.0%, the TIR glucose range is 70-180 mg/dL. If a patient maintains TIR > 70% for 3 months, the measured A1C will correlate well with the goal. Each 10% fluctuation in TIR from the goal of 70% corresponds to a difference of approximately 0.5% in A1C. Therefore, TIR of approximately 50% predicts an A1C of 8.0%.²⁸

A retrospective review of 1440 patients with CGM data demonstrated that progression of retinopathy and development of microalbuminuria increased 64% and 40%, respectively, over 10 years for each 10% reduction in TIR—highlighting the importance of TIR and consistent glycemic control.²⁹ Importantly, the CGM sensor must be active ≥ 70% of the wearable time to provide adequate TIR data.³⁰

Continue to: Concerns about accuracy

There is no universally accepted standard for determining the accuracy of a CGM; however, the mean absolute relative difference (MARD) is the most common statistic referenced. MARD is calculated as the average of the absolute error between all CGM values and matched reference values that are usually obtained from SMBG.³¹ The lower the MARD percentage, the better the accuracy of the CGM. A MARD of ≤ 10% is considered acceptable for making therapeutic decisions.³⁰

Package labeling for all CGMs recommends that patients have access to a fingerstick glucometer to verify CGM readings when concerns about accuracy exist. If a sensor becomes dislodged, it can malfunction or lose accuracy. Patients should not try to re-apply the sensor; instead, they should remove and discard the sensor and apply a new one. TABLE 2^10,14-17 compares MARD for CGMs and lists substances that might affect the accuracy of a CGM.

Patient–provider data-sharing platforms

FreeStyle Libre and Libre 2. Providers create a LibreView Practice ID at www.Libre View.com. Patient data-sharing depends on whether they are using a smart device, a reader, or both. Patients can utilize both the smart device and the reader but must upload data from the reader at regular intervals to provide a comprehensive report that will merge data from the smart device (ie, data that have been uploaded automatically) and the reader.⁷

Dexcom G6. Clinicians create a ­Dexcom CLARITY account at https://clarity.dexcom.com and add patients to a practice list or gain access to a share code generated by the patient. Patients must download the Dexcom CLARITY app to create an account; once the account is established, readings will be transmitted to the clinic automatically.¹⁵ A patient who is utilizing a nonsmart-device reader must upload data manually to their web-based CLARITY account.

Family and caregiver access

Beyond sharing CGM data with clinic staff, an important feature available with ­FreeStyle ­Libre and Dexcom systems is the ability to share data with friends and caregivers. The relevant platforms and apps are listed in ­TABLE 2.^10,14-17

Continue to: Insurance coverage, cost, and accessibility

Medicare Part B has established criteria by which patients with T2D qualify for a CGM (TABLE 3³²). A Medicare patient who has been determined to be eligible is responsible for 20% of the out-of-pocket expense of the CGM and supplies once their deductible is met. Once Medicare covers a CGM, the patient is no longer able to obtain fingerstick glucose supplies through Medicare; they must pay the cash price for any fingerstick supplies that are determined to be necessary.³²

Once Medicare covers a continuous glucose monitor, the patient is no longer able to obtain fingerstick glucose supplies through Medicare.

Patients with private insurance can obtain CGM supplies through their preferred pharmacy when the order is written as a prescription (the same as for fingerstick glucometers). That is not the case for patients with Medicare because not all US distributors and pharmacies are contracted to bill Medicare Part B for CGM supplies. A list of distributors and eligible pharmacies can be found on each manufacturer’s website.

Risk–benefit analysis

CGMs are associated with few risks overall. The predominant adverse effect is contact dermatitis; the prevalence of CGM-­associated contact dermatitis is difficult to quantify and differs from device to device.

FreeStyle Libre. In a retrospective review of records of patients with diabetes, researchers determined that a cutaneous adverse event occurred in approximately 5.5% of 1036 patients who utilized a FreeStyle Libre sensor.³³ Of that percentage, 3.8% of dermatitis cases were determined to be allergic in nature and related to isobornyl acrylate (IBOA), a chemical constituent of the sensor’s adhesive that is not used in the FreeStyle Libre 2. Among patients who wore a sensor and developed allergic contact dermatitis, interventions such as a barrier film were of limited utility in alleviating or preventing further cutaneous eruption.³³

Dexcom G6. The prevalence of Dexcom G6–associated allergic contact dermatitis is more difficult to ascertain (the IBOA adhesive was replaced in October 2019) but has been reported to be less common than with FreeStyle Libre,³⁴ a finding that corroborates our anecdotal clinical experience. Although Dexcom sensors no longer contain IBOA, cases of allergic contact dermatitis are still reported.³⁵ We propose that the lower incidence of cutaneous reactions associated with the Dexcom G6 sensor might be due to the absence of IBOA and shorter contact time with skin.

Continue to: In general, patients should be...

In general, patients should be counseled to rotate the location of the sensor and to use only specific barrier products that are recommended on each manufacturer’s website. The use of other barriers that are not specifically recommended might compromise the accuracy of the sensor.

Summing up

As CGM technology improves, it is likely that more and more of your patients will utilize one of these devices. The value of CGMs has been documented, but any endorsement of their use is qualified:

• Data from many older RCTs of patients with T2D who utilize a CGM did not demonstrate a significant reduction in A1C^20,24,36; however, real-world observational data do show a greater reduction in A1C.
• From a safety standpoint, contact dermatitis is the primary drawback of CGMs.
• CGMs can provide patients and clinicians with a comprehensive picture of daily glucose trends, which can help patients make lifestyle changes and serve as a positive reinforcement for the effects of diet and exercise. Analysis of glucose trends can also help clinicians confidently make decisions about when to intensify or taper a medication regimen, based on data that is reported more often than 90-day A1C changes.

Health insurance coverage will continue to dictate access to CGM technology for many patients. When a CGM is reimbursable by the patient’s insurance, consider offering it as an option—even for patients who do not require an intensive insulin regimen.

^a The US Food and Drug Administration cleared a new Abbott CGM, FreeStyle Libre 3, earlier this year; however, the device is not yet available for purchase. With advances in monitoring technology, several other manufacturers also anticipate introducing novel CGMs. (See “Continuous glucose monitors: The next generation.” )

CORRESPONDENCE
Kevin Schleich, PharmD, BCACP, Departments of Pharmaceutical Care and Family Medicine, University of Iowa, 200 Hawkins Drive, 01102-D PFP, Iowa City, IA, 52242; [email protected]