Pharmacology Consult

ICHECK’D: Mnemonic approach assists in caring for patients receiving direct oral anticoagulant

Since 2010, the FDA has approved four direct oral anticoagulants as alternatives to warfarin: dabigatran etexilate, rivaroxaban, apixaban and edoxaban tosylate.

Direct oral anticoagulants are selective inhibitors of one clotting factor, either thrombin (IIa) or activated factor X (Xa). Multiple clinical trials comparing warfarin or low-molecular-weight heparin vs. a direct oral anticoagulant have demonstrated either noninferiority or superiority of the direct oral anticoagulant. Based on these clinical trials, the FDA approved direct oral anticoagulants for the following indications: prevention of an embolic event (usually stroke) in nonvalvular atrial fibrillation; initial treatment of and prevention of recurrent venous thromboembolism; and VTE prophylaxis after hip and/or knee replacement.

Use of the direct oral anticoagulants has increased rapidly since dabigatran (Pradaxa, Boehringer Ingelheim), the first agent, was approved by the FDA in 2010. In nonvalvular AF, the proportion of direct oral anticoagulant prescriptions at least matches the use of warfarin. A recent registry study also found that prescription of direct oral anticoagulants has overtaken warfarin prescriptions globally for the indication of stroke prevention in nonvalvular AF.

Safety, appropriate use

However, with increasing use of direct oral anticoagulants, there are concerns regarding safety and appropriate use of these medications. Examples include:

Deborah DeCamillo

Direct oral anticoagulants do not require the same monitoring as warfarin, which may result in fewer interactions with providers, and less opportunity to verify appropriate dosing, reinforce the importance of adherence, and evaluate for adverse effects or drug-drug interactions.

With short half-lives, a missed dose of a direct oral anticoagulant can increase a patient’s risk for under-anticoagulation.

A variety of medical specialties may prescribe a direct oral anticoagulant (internal medicine, hematology, oncology, orthopedics, family medicine, geriatric medicine, neurology, emergency, cardiology, physician assistants, nurse practitioners), many of whom may not be familiar with dose adjustments.

There are potential new indications (eg, PCI stent placement, CAD, peripheral artery disease) currently undergoing clinical trials.

Patient safety remains the primary concern when prescribing medications. Nurses, physicians and pharmacists all have a different focus regarding medications, and much variability exists in dosing direct oral anticoagulants.

Several studies have detailed the risk for major bleeding when direct oral anticoagulants are prescribed without significant oversight, particularly related to inappropriate dosing based on renal function. Calculating the creatinine clearance using the Cockcroft-Gault formula, using actual body weight, with three of the four direct oral anticoagulants — dabigatran, rivaroxaban (Xarelto, Janssen Pharmaceuticals) and edoxaban (Savaysa, Daiichi Sankyo) — is essential since this is how renal function was determined in the clinical studies of these agents. One study demonstrated that using glomerular filtration rate instead of the Cockcroft-Gault formula can lead to failure to reduce direct oral anticoagulant doses and potentially cause higher bleeding rates. In another report, a majority of patients with nonvalvular AF who had a change in renal function did not have their direct oral anticoagulant dose appropriately changed. Other evidence comes from a study that used a large data warehouse and found that inconsistent direct oral anticoagulant dosing may be associated with no benefit in safety and worse effectiveness in patients with nonvalvular AF and severe kidney disease. It has also been found that off-label dosing of a direct oral anticoagulants is associated with an increased risk for adverse events.

Idea behind ICHECK’D

Elizabeth Renner

We conducted a PubMed literature search to look for tools that assist clinicians either prescribing or administering a direct oral anticoagulant. A direct oral anticoagulant monitoring checklist for providers to use for their patients with nonvalvular AF and website tools that assist with choosing a direct oral anticoagulant or monitoring a patient while on a direct oral anticoagulant already exist. These include the American College of Cardiology AnticoagEvaluator, MAQI2 Toolkit and Thrombosis Canada. However, most of the tools are appropriate for patients with nonvalvular AF and do not include patients with VTE.

Since an existing tool applicable to all clinicians and indications was not found, we created a tool using the mnemonic “ICHECK’D,” accompanied by the Table on page 13 in this Pharmacology Consult, to verify appropriate direct oral anticoagulant use and dosing per the FDA package inserts.

ICHECK’D:

  • I = indication: Why is the patient receiving the direct oral anticoagulant (AF, VTE or VTE prophylaxis)?
  • C = concomitant medications: Is the patient receiving any inducers or inhibitors of cytochrome P450 enzyme subtype 3A4 (CYP3A4) or p-glycoprotein (P-gp)?
  • H = history (medical history): Does the patient have a mechanical/prosthetic heart valve, moderate to severe mitral stenosis, pregnant/nursing, have hepatic impairment (Child-Pugh class B or higher)?
  • E = education (for patient/caregiver): Review risk for bleeding and procedures when dose may need to be held.
  • C = compliance: Missing or skipping doses may increase the risk for a blood clot since direct oral anticoagulants have a short half-life.
  • K = kidney function: Serum creatinine value needed before direct oral anticoagulant initiation and while receiving the direct oral anticoagulant in follow-up.
  • Nonvalvular AF: When creatinine clearance calculation is needed, Cockcroft-Gault formula using actual body weight should be utilized.
  • VTE: Only dabigatran is dosed using creatinine clearance via Cockcroft-Gault formula (using actual weight).
  • D = dose correct for indication: Monitor for any changes that may be needed based on above.
  • Nonvalvular AF: based on kidney function.
  • Acute VTE: based on loading dose followed by maintenance dose.

Assess and reassess

The patient receiving a direct oral anticoagulant should be assessed and reassessed. We feel this tool can assist clinicians caring for and monitoring these patients.

The Table can be used as a quick reference guide in all clinical areas.

Disclosures: The authors report no relevant financial disclosures.

Editor’s Note: This tool is a suggested shorthand to remember items when prescribing a direct oral anticoagulant but has not been proven to benefit patients. It is not endorsed by Cardiology Today, its editors, publisher or editorial board.

Since 2010, the FDA has approved four direct oral anticoagulants as alternatives to warfarin: dabigatran etexilate, rivaroxaban, apixaban and edoxaban tosylate.

Direct oral anticoagulants are selective inhibitors of one clotting factor, either thrombin (IIa) or activated factor X (Xa). Multiple clinical trials comparing warfarin or low-molecular-weight heparin vs. a direct oral anticoagulant have demonstrated either noninferiority or superiority of the direct oral anticoagulant. Based on these clinical trials, the FDA approved direct oral anticoagulants for the following indications: prevention of an embolic event (usually stroke) in nonvalvular atrial fibrillation; initial treatment of and prevention of recurrent venous thromboembolism; and VTE prophylaxis after hip and/or knee replacement.

Use of the direct oral anticoagulants has increased rapidly since dabigatran (Pradaxa, Boehringer Ingelheim), the first agent, was approved by the FDA in 2010. In nonvalvular AF, the proportion of direct oral anticoagulant prescriptions at least matches the use of warfarin. A recent registry study also found that prescription of direct oral anticoagulants has overtaken warfarin prescriptions globally for the indication of stroke prevention in nonvalvular AF.

Safety, appropriate use

However, with increasing use of direct oral anticoagulants, there are concerns regarding safety and appropriate use of these medications. Examples include:

Deborah DeCamillo

Direct oral anticoagulants do not require the same monitoring as warfarin, which may result in fewer interactions with providers, and less opportunity to verify appropriate dosing, reinforce the importance of adherence, and evaluate for adverse effects or drug-drug interactions.

With short half-lives, a missed dose of a direct oral anticoagulant can increase a patient’s risk for under-anticoagulation.

A variety of medical specialties may prescribe a direct oral anticoagulant (internal medicine, hematology, oncology, orthopedics, family medicine, geriatric medicine, neurology, emergency, cardiology, physician assistants, nurse practitioners), many of whom may not be familiar with dose adjustments.

There are potential new indications (eg, PCI stent placement, CAD, peripheral artery disease) currently undergoing clinical trials.

Patient safety remains the primary concern when prescribing medications. Nurses, physicians and pharmacists all have a different focus regarding medications, and much variability exists in dosing direct oral anticoagulants.

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Several studies have detailed the risk for major bleeding when direct oral anticoagulants are prescribed without significant oversight, particularly related to inappropriate dosing based on renal function. Calculating the creatinine clearance using the Cockcroft-Gault formula, using actual body weight, with three of the four direct oral anticoagulants — dabigatran, rivaroxaban (Xarelto, Janssen Pharmaceuticals) and edoxaban (Savaysa, Daiichi Sankyo) — is essential since this is how renal function was determined in the clinical studies of these agents. One study demonstrated that using glomerular filtration rate instead of the Cockcroft-Gault formula can lead to failure to reduce direct oral anticoagulant doses and potentially cause higher bleeding rates. In another report, a majority of patients with nonvalvular AF who had a change in renal function did not have their direct oral anticoagulant dose appropriately changed. Other evidence comes from a study that used a large data warehouse and found that inconsistent direct oral anticoagulant dosing may be associated with no benefit in safety and worse effectiveness in patients with nonvalvular AF and severe kidney disease. It has also been found that off-label dosing of a direct oral anticoagulants is associated with an increased risk for adverse events.

Idea behind ICHECK’D

Elizabeth Renner

We conducted a PubMed literature search to look for tools that assist clinicians either prescribing or administering a direct oral anticoagulant. A direct oral anticoagulant monitoring checklist for providers to use for their patients with nonvalvular AF and website tools that assist with choosing a direct oral anticoagulant or monitoring a patient while on a direct oral anticoagulant already exist. These include the American College of Cardiology AnticoagEvaluator, MAQI2 Toolkit and Thrombosis Canada. However, most of the tools are appropriate for patients with nonvalvular AF and do not include patients with VTE.

Since an existing tool applicable to all clinicians and indications was not found, we created a tool using the mnemonic “ICHECK’D,” accompanied by the Table on page 13 in this Pharmacology Consult, to verify appropriate direct oral anticoagulant use and dosing per the FDA package inserts.

ICHECK’D:

  • I = indication: Why is the patient receiving the direct oral anticoagulant (AF, VTE or VTE prophylaxis)?
  • C = concomitant medications: Is the patient receiving any inducers or inhibitors of cytochrome P450 enzyme subtype 3A4 (CYP3A4) or p-glycoprotein (P-gp)?
  • H = history (medical history): Does the patient have a mechanical/prosthetic heart valve, moderate to severe mitral stenosis, pregnant/nursing, have hepatic impairment (Child-Pugh class B or higher)?
  • E = education (for patient/caregiver): Review risk for bleeding and procedures when dose may need to be held.
  • C = compliance: Missing or skipping doses may increase the risk for a blood clot since direct oral anticoagulants have a short half-life.
  • K = kidney function: Serum creatinine value needed before direct oral anticoagulant initiation and while receiving the direct oral anticoagulant in follow-up.
  • Nonvalvular AF: When creatinine clearance calculation is needed, Cockcroft-Gault formula using actual body weight should be utilized.
  • VTE: Only dabigatran is dosed using creatinine clearance via Cockcroft-Gault formula (using actual weight).
  • D = dose correct for indication: Monitor for any changes that may be needed based on above.
  • Nonvalvular AF: based on kidney function.
  • Acute VTE: based on loading dose followed by maintenance dose.

Assess and reassess

The patient receiving a direct oral anticoagulant should be assessed and reassessed. We feel this tool can assist clinicians caring for and monitoring these patients.

The Table can be used as a quick reference guide in all clinical areas.

Disclosures: The authors report no relevant financial disclosures.

Editor’s Note: This tool is a suggested shorthand to remember items when prescribing a direct oral anticoagulant but has not been proven to benefit patients. It is not endorsed by Cardiology Today, its editors, publisher or editorial board.