Newer anticoagulants and risk of ICH in elderly with Atrial fibrillation

Germine Soliman

Case

An 81 yo pleasant lady with a PMH of HTN, OA, COPD, obesity and Paroxysmal afib, presenting for a complaint of recurrent falls. Started a year ago. Patient falls 5-6 times a month, mostly mechanical. Patient has many risk factors for falls: peripheral neuropathy, vertigo, tremors started a year ago, OA of shoulders and knees on Percocet and Gabapentin, on ambien for sleep.

Cont.

Patient has history of atrial fibrillation, on Xarelto.

She is following with a cardiologist but patient hasn’t told him about the falls.

She has been on Xarelto for a year and no incidents of bleeding.

Patient has no history of strokes.

Clinical question

Should our patient, with a history of recurrent falls, discontinue Xarelto to avoid the risk of intracranial hemorrhage?

Web search: JAMA

Uptodate

NEJM

Pubmed

Keywords: Rivaroxaban, newer anticoagulants and elderly,

newer anticoagulants and intracranial hemorrhage.

IntroductionNewer anticoagulants

Options for anticoagulation have been expanding steadily over the past few decades, providing a greater number of agents for prevention and management of thromboembolic disease.

In addition to heparins and vitamin K antagonists, anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have been developed.

Cont.

Other acronyms that have been created to refer to the orally acting direct thrombin inhibitors and direct factor Xa inhibitors together include direct oral anticoagulants (DOACs), target-specific oral anticoagulants (TSOACs), oral direct inhibitors (ODIs), and NOACs, which stands for "novel oral anticoagulants," "new(er) oral anticoagulants," and "non-vitamin K antagonist oral anticoagulants"

DOACS’mechanism of action

1- Thrombin direct inhibtors

prevent thrombin from cleaving fibrinogen to fibrin. They bind to thrombin directly, rather than by enhancing the activity of antithrombin, as is done by heparin.

Parenteral DTIs include bivalirudin (Angiomax), argatroban (Argatra, Novastan, Arganova, Exembol), and desirudin (Iprivask, Revasc).

The only oral DTI available for clinical use is dabigatran etexilate (Pradaxa); another oral agent, ximelagatran (Exanta), was withdrawn from the market in 2006 due to hepatotoxicity and cardiovascular events.

2- Direct factor Xa inhibitor

Prevent factor Xa from cleaving prothrombin to thrombin. They bind directly to factor Xa, rather than enhancing the activity of antithrombin III, as is done by heparin.

There are no parenteral direct factor Xa inhibitors in clinical use.

Several oral agents are available, including rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana, Savaysa). Of note, the generic names for these agents all end in "Xa-ban" (eg, rivaroxaban, apixaban, edoxaban).

Settings in vitamin K antagonist may be preferable in patients with Afib.

Patients who are receiving warfarin with excellent stable INR control and minimal bleeding side effects may have little to gain by switching to a different agent.

Prosthetic heart valves – The direct thrombin inhibitors and direct factor Xa inhibitors are not used in patients with prosthetic heart valves, due to greater risk of valve thrombosis, which may be fatal.

Cont. Renal impairment – is a common setting in

which warfarin may be preferable to the DOACs. Direct thrombin inhibitors and direct factor Xa inhibitors are renallyexcreted to variable degrees.

For patients with moderate renal impairment (creatinine clearance 30-50 mL/minute), the DOACs appear to be at least as safe as warfarin.

Of the DOACs, apixaban is the least dependent on renal clearance.

Cont.

For patients with severe renal impairment (creatinine clearance <30 mL/minute), there is insufficient evidence to predict how DOACs may compare with warfarin. Warfarin is generally preferred over a DOAC in those with a creatinine clearance <30 mL/min who require long-term anticoagulation.

Product labeling for dabigatran and the direct factor Xa inhibitors state that the agents are not to be used in individuals creatinine clearance <15 mL/min.

Cont. Compliance – Use of DOACs may be challenging in patients

who are unable to take their medication as prescribed. The lack of routine monitoring and short half-lives of these agents make it more difficult to determine if a patient is taking them appropriately. In addition, missing one or two doses can leave the patient inadequately anticoagulated; in contrast, missing a couple of doses of warfarin is unlikely to substantially increase the time outside the therapeutic range.

Cost – Vitamin K antagonists are typically much less expensive than DOACs.

Assessing bleeding risk The major safety concern with the use of all anticoagulants is the

increased risk of bleeding, especially major bleeding, which includes events that require hospitalization, transfusion, surgery, or involves particularly sensitive anatomic locations.

Intracranial hemorrhage is the most serious bleeding complication since the likelihood of mortality or subsequent major disability is substantially higher than bleeding at other sites.

In most contemporary studies, this risk is about 0.2 to 0.4 percent per year, or perhaps slightly higher. While this risk is not trivial, it is substantially lower than the risk of ischemic stroke in the vast majority of AF patients with CHA2DS2-VASc >=2 who are not anticoagulated.

Pathogenesis of ICH Cerebral microbleeds — As people age, small arterioles within

the brain weaken and rupture with worrisome regularity. Most ruptures result in subclinical foci of self-limited bleeding, termed "microbleeds", which can be found at autopsy or detected using special gradient sequence MRI techniques.

Advancing age, especially age >75 years, and hypertension are the strongest predictors of this phenomenon.

These microbleeds are believed to be the result of an underlying angiopathy that predisposes patients to intracerebral bleeding. Occasionally, leakage of blood from an arteriolar rupture is not stopped by normal hemostatic mechanisms and/or compression by surrounding tissue and a larger ICH ensues. This phenomenon underlies the pathogenesis of spontaneous ICH, an especially devastating type of stroke.

Cont.

Anticoagulants increase the likelihood that spontaneously-occurring arteriolar ruptures will enlarge to cause clinically evident ICH, but anticoagulants do not appear to increase the incidence of asymptomatic cerebral microbleeds. Thus, anticoagulant therapy appears to "unmask" the inherent rate of spontaneous cerebral microbleeds as their most serious complication.

As a result, patients at the highest risk for spontaneous ICH are those who are also at highest risk for anticoagulant-associated intracerebral bleeding.

ICH and ethinicty

The incidence of spontaneous ICH varies by ethnicity, being highest in Asians, intermediate in blacks, and lowest in whites. Mexican Americans also have a higher incidence of ICH than non-Hispanic whites.

Patients at higher risk for ICH Thrombocytopenia or known coagulation defect associated with

bleeding

Active bleeding or recent surgery with a concern for ongoing bleeding

Prior severe bleeding (including ICH) while on an oral anticoagulant

Suspected aortic dissection

Malignant hypertension

Combined use of anticoagulant and antiplatelet agents

Diabetes mellitus

Falls with attendant head trauma (subdural hematoma)

Excessive alcohol consumption

ICH and age

The risk of ICH in anticoagulated patients increases with advancing age. However, the absolute ICH rate in very elderly patients varies in different reports.

In the Birmingham Atrial Fibrillation Treatment in the Aged (BAFTA) randomized trial, the ICH rate was 0.6 percent per year among 488 patients >75 years old (mean age 81.5 years) who were given warfarin, achieved a median INR of 2.3, and were followed for 2.7 years. This was similar to the ICH rate of 0.5 percent per year in subjects randomly assigned to receive aspirin.

Cont.

In contrast, when a cohort of 472 warfarin-naïve patients with atrial fibrillation with a mean age of 77 years were given warfarin, the ICH rate was 2.5 percent per year even though 58 percent of the INR values were within the target therapeutic range of 2 to 3.

The most likely explanation for the difference in ICH rates in BAFTA versus the cohort followed at the Massachusetts General Hospital was that first-year exposure to warfarin, the period when the risk for serious bleeding is greatest, made up only 22 percent of the BAFTA exposure versus 100 percent of the latter. In addition, blood pressure control during follow-up in BAFTA was remarkably good, with an average systolic blood pressure averaging 137 mmHg.

ICH in elderly with falls Patients with a history of multiple falls tend to be older and have more

comorbidities and an increased risk of stroke. However, such patients respond favorably to treatment with warfarin.

This was shown in a retrospective analysis of 1245 Medicare beneficiaries with atrial fibrillation who were documented to be at high risk for falls. In those subjects with a CHADS2 score of 2 or more, treatment with warfarin was significantly protective against the composite endpoint of out-of-hospital death or hospitalization for stroke, myocardial infarction, or hemorrhage (hazard ratio 0.75; 95% CI 0.61-0.91).

Cont. A risk of falling, with the potential for the development

of a subdural hematoma, is often considered a contraindication to the use of anticoagulation in the elderly, although this risk is often overestimated by clinicians.

In one study, a history of falls was not an independent predictor of bleeding in patients taking warfarin . In addition, one study that reviewed 49 published anticoagulation studies of patients with atrial fibrillation found that ICH (subdural hematoma or intracerebral hemorrhage) was uncommon.

Cont.

A Markov decision analytic model demonstrated that, regardless of the patient's age or baseline risk of stroke, the risk of falling was not an important factor for determining the optimal antithrombotic therapy (ie, aspirin, warfarin, or no therapy).

The risk of a subdural hematoma from falling is so small that patients with atrial fibrillation with an average risk of stroke (5 percent per year in the absence of anticoagulation) would have to fall approximately 300 times in a year for the risk of anticoagulation to outweigh its benefits.

Evaluating head trauma — The patient on anticoagulation who has fallen and has closed head injury should be considered for the possibility of delayed intracerebral hemorrhage, subdural hematoma, or other intracranial bleeding.

ICH and concomitant use of ASA and anticoagulants

Approximately 20 percent of older adult patients receiving warfarin also take aspirin. However, the risk of adding aspirin to warfarin is unclear, as shown in the following studies:

In a retrospective study of a large hospital discharge cohort of 10,093 older adult patients (mean age 77 years) receiving warfarin for atrial fibrillation, use of antiplatelet therapy was associated with a threefold increase in ICH (0.9 versus 0.3 percent per year; relative risk 3.0, 95% CI 1.6-5.5).

A case-control study did not find concomitant aspirin use to be a predictor of ICH during anticoagulation.

Cont.

Although the data are inconsistent, it is likely that concomitant use of aspirin and warfarin increases the risk of ICH.

In younger patients with prosthetic cardiac valves or coronary artery disease who have an inherently low ICH risk, the absolute rates of ICH with combined warfarin-aspirin therapy are low. However, in older patients or in patients with target INRs >3.0, the use of aspirin in conjunction with warfarin should be reserved for patients in whom the benefits clearly outweigh the increased risk of ICH; for example, those with a highly thrombogenicmechanical heart valve or those with newly implanted coronary stents.

ICH and warfarin

Over anticoagulation with warfarin ( INR > 3), prior stroke, and increasing patient age are three of the most important predictors of major bleeding, including ICH .

The risk of bleeding in contemporary practice was evaluated in a cohort of over 16,000 patients who received a diagnosis of AF between 2005 and 2010. The incidence of major bleeding with current, recent, past, or no warfarin exposure was 3.8, 4.5, 2.7, and 2.9 per 100 patient-years, respectively .

The annual risk of ICH in patients with AF who are not anticoagulated is estimated to be 0.2 percent; that risk approximately doubles with anticoagulation with warfarin.

Cont. Intracranial hemorrhage, primarily intracerebral and less

frequently subdural or subarachnoid, is the most serious and lethal complication of antithrombotic therapy. Intracerebral hemorrhage (ICH) causes approximately 90 percent of the deaths and most of the permanent disability in patients with warfarin-associated bleeding.

Over half of the patients with warfarin-associated ICH die within the first 30 to 90 days—a substantially higher mortality rate than that of spontaneous ICH in those not receiving anticoagulants, or that of warfarin-associated extracranial hemorrhage.

In one study, for example, the 90-day mortality rate for supratentorial ICH was 52 versus 26 percent for those taking or not taking warfarin at the time of ICH, respectively.

Cont.

In a second study, the 90-day mortality rates for ICH patients were 62 and 17 percent for those taking or not taking warfarin, respectively.

Warfarin-associated ICHs are larger, on average, than spontaneous ICHs, and the extent of the bleed is directly proportional to the INR at the time of bleeding. Available data are conflicting about whether the concomitant use of antiplatelet agents increases the severity and early mortality associated with ICH.

Cont. There is no lower threshold of anticoagulation intensity that

does not accentuate the risk of warfarin-associated ICH. Although INRs above 4.0 are associated with high rates of ICH in older adults, most warfarin-associated ICHs occur at anticoagulation intensities that are within the conventional therapeutic range (ie, INRs in the range of 2.0 to 3.0).

Therefore, regardless of the quality of warfarin management, as evidenced by the percentage of time that the INR is in the therapeutic range, the risk of ICH is lower with the new oral anticoagulants (eg, oral direct thrombin inhibitors and oral factor Xa inhibitors). This observation is one of the drivers for a switch from warfarin to the new agents (eg, dabigatran, rivaroxaban) for stroke prevention in patients with atrial fibrillation.

ICH and DOACs

Dabigatran, rivaroxaban, apixaban — have been approved for the prevention of stroke in patients with non-valvular atrial fibrillation based on the results of the RE-LY, ROCKET-AF, and ARISTOTLE trials, respectively.

In the RE-LY trial, which compared two twice daily dose regimens of dabigatran with warfarin, the lower dose of dabigatran (110 mg) was non-inferior to adjusted-dose warfarin for stroke prevention, and was associated with fewer major bleeding complications (2.71 percent and 3.36 percent, respectively). The higher dose dabigatran regimen (150 mg) significantly reduced the rate of stroke compared with warfarin and was associated with a similar rate of major bleeding (3.11 percent).

Cont. In the ROCKET-AF trial, once-daily rivaroxaban was

compared with warfarin in high-risk atrial fibrillation; over half of the patients had a history of prior stroke, transient ischemic attacks, or systemic embolism [25]. Rivaroxaban was non-inferior to warfarin for stroke prevention and was associated with similar rates of major bleeding (5.6 and 5.4 percent, respectively).

In the ARISTOTLE trial, which compared twice daily apixaban with warfarin, use of apixabansignificantly reduced the rate of stroke compared with warfarin (1.27 and 1.60 percent, respectively); and apixaban was associated with a significantly lower rate of major bleeding (2.13 and 3.09 percent, respectively).

Cont.

When used in patients with atrial fibrillation, the dabigatran dose should be adjusted based on renal function to reduce the risk of ICH. Amiodarone, an antiarrhythmic drug that is frequently used in patients with atrial fibrillation, potentiates the anticoagulant effect of dabigatran, but the effect of this interaction on ICH risk is uncertain because amiodarone use was not restricted in the RE-LY trial.

Renal function is less of a concern for rivaroxaban and apixaban, because renal clearance of these agents is only 33 and 27 percent, respectively.

Nonetheless, to reduce the risk of ICH, the dose of rivaroxaban should be reduced from 20 mg to 15 mg daily in patients whose creatinine clearance is between 15 and 50 mL/min, and the dose of apixaban should be reduced from 5 mg twice daily to 2.5 mg twice daily in patients who have at least two of the following: age of 80 years or more, weight of 60 kg or less, and/or serum creatinine over 1.5 mg/dL.

RELY trial

ROCKET AF trial

Jama November,2016

Objective and design

Conclusion

In this large direct comparison of patients with AF treated with dabigatran or rivaroxaban, rivaroxaban use was associated with statistically significant increases in the risk of ICH and major extracranial bleeding, including major gastrointestinal bleeding, and possibly with increased mortality in older patients or those with higher baseline risk of stroke.

The greater anticoagulant effect observed with rivaroxaban treatment may be due to the higher dose required for once-daily dosing.

Reversal agents for DOACS In most cases of major DOAC-associated bleeding, we

suggest the use of an antifibrinolytic agent and the removal of excess drug using hemodialysis (for dabigatran) and/or oral activated charcoal (for all agents), especially if the last anticoagulant dose was taken in the previous few hours.

More potent therapies, such as idarucizumab (for dabigatran) and activated or unactivated prothrombin complex concentrates (aPCCs or PCCs, respectively) reserved for the most serious/life-threatening cases of DOAC-associated bleeding such as ongoing bleeding that is likely to lead to death or permanent disability if not stopped immediately.

REDUCING THE RISK OF ICH DURING ANTICOAGULANT THERAPY

The frequency of warfarin-associated ICH is increasing due to the more widespread use of warfarin in older adult patients with atrial fibrillation, and the concomitant use of aspirin and other antiplatelet agents in older patients. Relatively small differences in the ICH rate of 1 to 2 percent per year can shift the balance of therapeutic benefit versus harm. The following principles should be followed in order to minimize the risk of ICH]:

Consider the use of dabigatran, rivaroxaban, or apixaban in place of warfarin because the risk of ICH is lower with these agents.

If the new oral anticoagulants are selected, limiting the concomitant use of aspirin will lower the risk of ICH.

Cont.

If warfarin is used, good control of warfarin intensity and limiting the use of aspirin will reduce the risk of ICH.

Blood pressure control is especially important for avoiding ICH. The use of anticoagulants in older adult patients should be contingent upon a commitment to aggressive blood pressure management.

If patients on anticoagulants have a history of falls, a multidisciplinary risk factor screening/intervention program for reducing the risk of falls may be of value.

Our patient

A follow up appointment, patient is still falling but she had a new complaint of coughing blood, xray was ordered which showed 3 cm Rt lung mass…