Anticoagulation Safety

Etiology

How serious is the problem with oral anticoagulants?

From published studies, the incidence of major bleeding in patients treated with warfarin ranges from 0.4% to 7.2% per year. Minor bleeding rates have been found to be high as 15% per year. This wide range in bleeding inside is primarily due to patient-specific comorbid factors. To be consistent in reporting, however, most clinicians define major bleeding as bleeding that required admission, a fatal hemorrhage, bleeding at a critical site like the brain or retroperitoneum, or bleeding that requires transfusion of at least 2 units of packed red blood cells. A major bleed is associated with a several-fold increase in death for up to 12 months following the incident.[4][5]

Many studies have shown that the risk of bleeding is increased in patients treated with warfarin. This risk of bleeding in patients treated with atrial fibrillation has been calculated to be about 0.3-0.5% per year and is often associated with intracranial bleeding, which is a major cause of disability and death.

Patients with deep vein thrombosis who are treated with warfarin appear to have a higher risk for bleeding than those treated for atrial fibrillation. This is thought to be due to the concomitant comorbid conditions in these patients. The risk of bleeding in venous thrombosis has been calculated to be about 1.31 per 100 person-years, with a case fatality rate of 13.4 %.[6]

Even though intracranial hemorrhage is devastating, it is not the most common site of bleeding following the use of oral anticoagulants; the most common site is the gastrointestinal tract. However, the mortality associated with an intracranial bleed is 50%, compared with 5.1% with gastrointestinal tract bleeding.

The association between venous thrombosis and malignancy is well established. Many studies report a high incidence of both minor and major bleeding in patients with cancer who are treated with oral anticoagulants. There appears to be greater fluctuation in the INR in these patients, which could be due to the comorbidity and/or concomitant medications.

In one large retrospective 5-year study, nearly 48.8% of adverse drug events that involved anticoagulation were due to medication errors. In the same study, the 30-day mortality was increased by 11% of patients who experienced an adverse drug effect due to the anticoagulation drug. Other studies have revealed that emergency hospitalization as a result of bleeding due to warfarin is common. Data on the long-term safety of the newly available oral anticoagulation are very limited or not available. Thus, it is obvious that most of the data on the newer anticoagulants will reflect fewer adverse events or appear positive.

Prior to 2010, warfarin was the only approved oral anticoagulant on the market but since then several newer oral anticoagulants have been introduced like dabigatran, apixaban, edoxaban, and rivaroxaban.  Warfarin acts by altering the clotting factors 2,7,9,10 and protein C and S. Comparatively, the target-specific oral anticoagulants except for dabigatran work by inhibiting activation of platelets and fibrin clot formation by reversible inhibition of factor Xa. On the other hand, dabigatran works by reversibly inhibiting thrombin which results in decreased thrombin-mediated platelet aggregation.[7]

Epidemiology

What are the differences between warfarin and the newer oral anticoagulants?

One of the major differences between warfarin and the target-specific oral anticoagulants is that the latter cannot be monitored using the INR or other blood coagulation tests. In addition, these agents also do not require modification in diet. Cost is also a factor; the newer oral anticoagulants are prohibitively expensive compared to warfarin. So far these newer oral anticoagulants have shown to be safe, but long-term data are lacking. Another important fact is that most healthcare workers who prescribe these oral anticoagulants have little idea on how to deal with them when a patient who is booked for surgery suffers trauma or has a sudden bleeding emergency. Unlike warfarin which can be reversed with plasma or vitamin K, the factor X inhibitors or direct thrombin inhibitors have reversal agents that are more expensive and less readily available.[4][8][7]

Another difference between warfarin and the newer oral anticoagulants is the time to reach peak therapeutic effect. Warfarin often takes 4-6 days to reach the peak effects, but the newer oral anticoagulants have peak therapeutic effects in less than 24 hours. However, one area of similarity between the two classes of drugs is that they both have the potential for significant drug interactions.

Finally, after dosing with warfarin, monitoring can also be affected by the diet. Foods that contain vitamin K like kale and spinach can delay the peak therapeutic effect. On the other hand, the target-specific oral anticoagulants are highly protein-bound and this makes it difficult to remove them even with dialysis.

Where do most adverse events regarding anticoagulants occur?

• Medical and surgical units
• Telemetry
• Rehabilitation
• Emergency room
• Outpatient clinics

 Which oral anticoagulants are used today?

• Warfarin
• Rivaroxaban
• Dabigatran
• Apixaban

The newer oral anticoagulants, in general, have been associated with lower rates of major bleeding and fewer intracranial hemorrhagic events. There is also one study that shows that the use of dabigatran in elderly patients and those with kidney dysfunction may increase the risk of intracranial bleeding.

 What factors are usually considered when selecting an oral anticoagulant?

• Risk of bleeding
• Presence of a mechanical heart valve
• Renal and liver dysfunction
• Body weight
• A propensity to dyspepsia or a history of peptic ulcer disease
• Patient preference
• Patient compliance
• Past success with oral anticoagulation

What types of medication errors have been associated with oral anticoagulants leading to adverse events?

• Dose omission
• Extra dose
• Wrong dose/overdose
• Lab error in monitoring
• Medication is given at the wrong time
• Underdose
• Prescription refill delayed
• Wrong patient
• Drug-drug interaction

It should be noted that warfarin has been the mainstay of anticoagulant therapy for decades, while other oral anticoagulants have been introduced over the past few years. Therefore, in most of the published literature, the number of adverse events involving warfarin is much greater than the number of events involving newer anticoagulants.

When and why does bleeding occur after the use of oral anticoagulants?

Studies reveal that the first 90 days are the most variable because the INR is still labile and this increases the risk of bleeding. The same dose of warfarin can have unpredictable effects on the INR in different individuals making it difficult to develop a standardized dosage. Further, many patients require alternating doses, and this makes it difficult to have a standard dose. Because the risk of bleeding is highest within the first three months,  there should be more frequent monitoring of the INR during this period to prevent bleeding episodes.

Another risk factor is the intensity of anticoagulation. When the INR is more than 2, the risk of bleeding is much greater than when the INR is less than 2. However, when the INR is less than 2, this also increases the risk of stroke in patients with atrial fibrillation. Since warfarin cannot be stopped in atrial fibrillation and an INR less than 2 is not effective to prevent a stroke, other strategies need to be employed like discontinuing platelet agents like aspirin if there is a significant concern for bleeding. 

Patient characteristics can also increase bleeding. Studies show that bleeding risk is increased with the following:

• Advanced age
• Diabetes
• Anemia
• Hypertension
• Congestive heart failure
• Female sex
• Transient ischemic attack
• History of stroke
• Renal failure
• Liver disease
• Non-compliance is most common in middle-aged patients
• Lack of patient education about atrial fibrillation and the risk of stroke
• Varying INR monitoring protocols
• Diet

Further patients admitted with sepsis and other hypermetabolic state tend to have an unpredictable response to warfarin, and the bleeding potential is always present.

Drugs that can increase the risk of bleeding include the use of:

• Antidepressants
• Antibiotics
• Acetaminophen
• NSAIDs
• Fenofibrate
• Proton pump inhibitors
• Alcohol
• Influenza vaccine

Genetic Variation

Over the years several enzyme genetic variations that affect the metabolism of warfarin have been identified. Polymorphism of the cytochrome P4502CP enzymes slows down the metabolism of warfarin, which increases the risk of bleeding. Similarly, alterations of the vitamin K epoxide reductase complex subunit one gene and the VKORC1 enzyme also alter metabolism. The clinical significance of these genetic variations is known because there are limited data. Plus not all laboratories are established to detect these genetic changes, thus making its universal use unrealistic.

Pathophysiology

So how do we reduce the risk of adverse events involving oral anticoagulants?

Almost every healthcare institution has faced issues with the use of oral anticoagulation, and over the years many have developed strategies to reduce the risk of harm to patients. While the education of healthcare workers is important, it also relies on the fact that individuals will remain compliant with the education on the prevention of harm. Most experts feel that strategies that are based on the entire system (i.e., involve everyone from the pharmacist to the eventual patient) are far more effective as they function at many levels, and the errors can hopefully be picked up before the drug even gets to the patient. Some of the risk prevention strategies designed to prevent harm from oral anticoagulants include the following:

• The pharmacists should review each of the patient’s medications whenever an oral anticoagulant is prescribed as this may help reduce drug interactions.
• Place alerts in the system whenever two drugs of the same class are prescribed.
• Avoiding duplication of therapy is critical to decreasing bleeding with oral anticoagulants.
• Eliminate the use of verbal orders for oral anticoagulants. Verbal orders can be misunderstood, misinterpreted, or not correctly transcribed. Unless there is an emergency, the use of verbal orders should be permitted.
• If a verbal order is permitted, then the nurse who takes this order must first enter it electronically and read it back to the prescriber to make sure there is no mistake in dose, frequency, or duration.
• Standardize the way orders on oral anticoagulants are written since many drugs are prescribed based on body weight and/or renal function-  make sure that this information is always present on the chart before ordering oral anticoagulants.
• The computer system must have all the latest labs so the prescriber can see them when prescribing oral anticoagulants.
• When the patient is an elderly individual, then check the renal function and body weight. Many seniors require lower doses because of low body mass and when renal function is diminished (Routledge et al., 2004)
• Develop a system for ‘hold’ order to prevent duplication or inadvertent dosing of the patient despite the hold order. The ‘hold’ order should be written in different color ink, and it must be renewed every day. A reminder should be placed near the ‘hold’ order to check lab values first. If the hospital uses an electronic medical record, a ‘hold’ order should be placed in the form of a nursing communication. 
• Create an anticoagulation management service program for monitoring and dosing of oral anticoagulants. The first step is to assess the current clinical practice and develop guidelines on the use of oral anticoagulants. The anticoagulation management service should frequently audit the charts to make sure that the protocol is working as planned.
• Develop a standard protocol for emergency reversal of anticoagulation and how to restart them. The effects of vitamin K may last 5-7 days; hence one must develop guidelines on how and when to start anticoagulation.
• Do not write an order for 'resume all medications' in the blank order. All medications have to be individually checked with the nurse’s list first to see if the patient needs them and then transcribed in the chart.
• During handoffs, nurses should develop a protocol for high-risk medications like oral anticoagulants. The oncoming nurse should be told about the dose and any pending labs.
• Do not permit the use of abbreviations when writing out any medication. Abbreviations can be misunderstood or misinterpreted leading to either double dosing or dose omission.
• All patients on oral anticoagulants should have an alert placed in the chart indicating that the patient is on a high-risk medication.
• The dosing of warfarin should be done at a set time every day as this can allow one to look at the laboratory results first and make any necessary dose adjustments.
• To ensure there is no redundancy in the system, the pharmacist should check the automated dispensing cabinets every day and verify all new orders with the nurse. 
• The nurse should also speak to the pharmacist when an order for an oral anticoagulant is made so that there is no duplication of the order. 
• It is important to use currently recommended electronic healthcare technology for all orders as this can help avert dosing and duplicate errors. More important computerized systems also have alerts for potential drug interactions and abnormal lab errors.
• To reduce errors in the pharmacy, barcode scanning must be used as it also helps with the correct dosage and proper drug selection.

Bleeding Risk Assessment Tools

Even though oral anticoagulants are effective drugs, there is a concern that these drugs may cause bleeding problems while on therapy. Hence, today several bleeding risk assessment tools based on patient risk factors have been developed. These tools are now being incorporated into clinical decision-making. These tools help the clinician better quantify the individual risk of hemorrhage and help classify the patient as low or high risk. The one thing to appreciate is that all the presently available bleeding risk assessment tools were developed for patients treated with warfarin and to date, it is not known whether these same tools can be applied to the newer oral anticoagulants.[9][10][11]

The three widely used Bleeding risk Assessment tools include the following:

• Has-Bled Score
• Hemorrhages
• Atria

All of these bleeding risk tools are relatively easy to use than their predecessors. With all these tools, one can obtain the common risk factors from the patient medical history or routinely obtained laboratory investigations that are performed in patients with atrial fibrillation or deep vein thrombosis. The Atria and HAS-Bled score utilizes fewer variables and no genetic testing is necessary. The HAS-Bled tool has been validated in several clinical trials and is currently the most frequently used tool to screen for risk of bleeding. Further, the Has-Bled tool also incorporates labile INR, which is obtained following the start of warfarin therapy.

The atria bleeding risk tool is best suited for use in high-risk patients. The one major limitation of the Atria tool is that the score does not include comorbid conditions like blood pressure or the use of medications that can increase the risk of bleeding. Currently, Atria is not very widely used and is awaiting clinical validation.

The Hemorr2hages score is comprehensive, and while it takes into account the comorbidity and medications that can increase bleeding, it also requires genetic testing for liver enzymes. The downside is that genetic testing is not always practical in emergency situations and many hospitals lack the capability to conduct such testing.

Bleeding Risk Tools in Clinical Practice

So far there is no evidence that one risk bleeding tool is better than the other and the choice to use one is based on experience and personal preference. Many of the risk factors in the different tools overlap. Older age is a common risk factor with all risk bleeding tools. Other similar risk factors in the tools include the history of bleeding, renal disease, and anemia. All of them require the need to monitor INR and place control limits on the levels. However, these risk tools may not be applicable to patients on the newer oral anticoagulants who do not require INR monitoring. In addition, genetic testing is not only prohibitively expensive; it may not be available in most healthcare institutions. While several validation studies have been performed in subgroups of participants in clinical trials, the overall observation is that these bleeding risk tools only have a modest predictive value in patients with atrial fibrillation.

To enhance the effectiveness of these bleeding risk tools, it is important to understand that even if these tools predict bleeding, will anticoagulation therapy be discontinued? Remember the negative consequence of thromboembolism are also serious and in many cases outweigh the consequence of hemorrhage. Today no risk tool has been designed to predict the risk of hemorrhage in the brain. Although some risk tools may predict the risk of an intracranial bleed, the threshold at which this bleeding will occur is not known. In reality, these risk bleeding tools are more useful in patients at low risk of thromboembolism where the net benefit of anticoagulation is small, and the risk of bleeding is real. These bleeding risk tools may also identify low-risk patients who can be told that their risk of bleeding is low

Therapeutic Monitoring

• Whenever an oral anticoagulant is to be prescribed, baseline laboratory test, coagulation profile, and renal function should be obtained.
• If INR is being used to monitor treatment, the levels should be available in 24 hours. Levels of INR do not change rapidly and hence ordering INR levels every few hours is not recommended.
• To assist with anticoagulation with warfarin, a template should be made to help the healthcare worker know the therapeutic INR for different conditions.

Histopathology

When there is an error in anticoagulation dosing, the result can be either hemorrhage or thrombosis. Hemorrhage is most common in the gastrointestinal tract and can be profuse. Often the site is a prior peptic ulcer, angiodysplasia, or AV malformation. The thrombosis usually results in an ischemic stroke, mesenteric ischemia, or an acutely cold leg. These diagnoses are made from imaging studies, and histopathology is not required to confirm the diagnosis. 

History and Physical

If the dose of the anticoagulation is high, the patient may develop internal bleeding after a few days. Obvious signs of bleeding are not present in the first 24 hours after ingestion of the drug. Besides intracranial hemorrhage, the patient may have:

• Epistaxis
• Subconjunctival hemorrhage
• Vaginal bleeding
• Bleeding from the gums
• Hematuria

Evaluation

In all cases of anticoagulation associated adverse events, the following tests are needed:

• Complete blood count
• Coagulation profile (prothrombin time. activated partial thromboplastin time, d-dimer)
• Platelet count
• CT scan of the head to rule out intracranial bleeding
• Echocardiogram if valve thrombosis is suspected
• Echocardiogram to assess for the presence of left atrial thrombus
• Nuclear scan to look for the source of bleeding in the GI tract

Other studies depend on patient presentation.

Treatment / Management

If the patient is bleeding, the patient may require immediate discontinuation of the oral anticoagulants. Recombinant factor Vlla has been used to lower the INR. The most readily available source of this is plasma transfusion. Vitamin K can be used to reverse warfarin-induced bleeding. Fresh frozen plasma is often administered to patients with bleeding due to the newer anticoagulants but is of limited efficacy. Some institutions give prothrombin complex concentrate to patients with severe gastrointestinal bleeding, this can be beneficial in severe, life-threatening bleeds related to vitamin K antagonists. There is no evidence to suggest newer oral anti-coagulant bleeds respond to prothrombin complex, concentrate. 

If bleeding is severe, intravenous resuscitation is necessary. Neurological signs will need to be monitored to look for the presence of an intracranial bleed. Epistaxis may require nasal packing.[12][13][14](A1)

Andexanet alfa is developed for the reversal of factor Xa inhibitors like apixaban and rivaroxaban. It is usually given as a bolus followed by a two-hour infusion. Almost 82% of patients have excellent to good hemostatic efficacy at 12 hours. [15] The common side effects of andexanet are urinary tract infection and pneumonia. Idarucizumab is a monoclonal antibody designed for the reversal of dabigatran.

Differential Diagnosis

The differential diagnosis includes:

• Subarachnoid hemorrhage
• Epistaxis
• Hemophilia
• Liver failure
• Factor V and X deficiency
• Dysfibrinogenemia
• Vitamin K deficiency
• Peptic ulcer disease

Complications

Complications of oral anticoagulants include:

Bleeding

• Gastrointestinal tract
• Pericardial tamponade
• Retroperitoneal hematoma
• Intracranial bleeding
• Hemothorax

Thrombosis

• Valve thrombosis
• Stroke ischemic
• Acutely cold leg
• Mesenteric ischemia