Patient Description

Mr. F is a 78-year-old retired Canadian man with chronic hypertension who recently experienced transient inability to speak and right-sided weakness lasting about 15 minutes. During evaluation, persistent atrial fibrillation was diagnosed. His ventricular rate averaged 78 beats-per-minute on no rate-control medications. Echocardiography and carotid ultrasonography were performed and both were unremarkable. The diagnosis was a transient ischemic attack (TIA). During the days following presentation, cardiac rhythm continued to be atrial fibrillation.

Although there was a known history of occasional palpitations, atrial fibrillation had never before been recognized. Mr. F’s medical history included hypertension controlled with hydrochlorothiazide and perindopril (blood pressure averaging 135/78 mm Hg), and chronic Parkinson’s disease, for which he was taking two medications (levodopa and rasagaline). He lives at home with his spouse and requires the use of a walker when outside of his home. Due to imbalance, he has fallen several times in the past but without substantial head injury.

Clinical Decision Point 1:  Assessing the Risk and Benefit of Anticoagulation Therapy

Question 1: Considering the patient’s gait instability and history of falling, should he be considered for anticoagulation therapy in the setting of a recent TIA and atrial fibrillation?

1. Yes
2. No, his stroke risk is not sufficiently high to warrant anticoagulation
3. No, anyone with gait problems predisposing to falling should not be considered for anticoagulation

Discussion

(a) Predisposition to falling increases this patient’s risk for intracranial hemorrhage during anticoagulation.^1,2 Offsetting this concern, however, is his high risk of stroke (8.5% to >10% per year)^3,4 without anticoagulation. These two factors—risk of intracranial hemorrhage versus benefit of stroke prevention—comprise the risk-benefit ratio that are the crux of the decision regarding initiating anticoagulation therapy in this patient. Despite the relative contraindication posed by his predisposition to falling, this author would favor careful anticoagulation in this setting.

The burden of atrial fibrillation on individuals and the healthcare system is costly due to its high prevalence and its association with a high risk of ischemic stroke resulting from the formation of intracardiac thrombi in the left atrial appendage.⁵ Atrial fibrillation is the most common clinically significant cardiac rhythm disorder, affecting 2.5 million people in the United States.⁵ The prevalence increases after the age of 60 years and is nearly 10% in patients older than 80 years; the median age is 72 years.⁵ Across all age groups, atrial fibrillation increases the risk of ischemic stroke 4- to 5-fold from baseline⁵ and accounts for a 23.5% increased risk of stroke in individuals age 80 to 89 years compared with age-matched individuals without atrial fibrillation.⁶

The primary independent risk factors for ischemic stroke in patients with atrial fibrillation include: advancing age, hypertension, diabetes, and prior stroke or TIA (Figure 1).⁷ Among these factors, prior embolism is the greatest risk, conferring a 2.5-fold increased risk of recurrent stroke.⁷ Although these risk factors are the same risk factors for stroke in the absence of atrial fibrillation, the risk is several-fold higher when atrial fibrillation is present.⁷

Figure 1. Independent Risk Factors for Stroke in Patients with Atrial Fibrillation Based on Pooled Data from Multiple Studies⁷

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Abbreviations: BP, blood pressure; CI, confidence interval; RR, relative risk; TIA, transient ischemic attack.

These risk factors plus the presence of congestive heart failure are utilized by the CHADS₂ scoring system to objectively stratify risk of stroke in patients with nonvalvular atrial fibrillation.³ In this system, each factor has an assigned point value based on the strength of its risk association; 1 point each for presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus, and 2 points for prior ischemic stroke or TIA.³ The scoring system’s name—CHADS₂—creates an easy to remember mnemonic: the first letter of each risk factor plus the subscript “2” to denote the double point attributed to prior stroke. The points for an individual patient are identified and added based on his/her personal history in order to arrive at an overall stroke prediction estimate. Based on pooled data of 1733 patients in the National Registry of Atrial Fibrillation, the adjusted stroke rate increases approximately 1.5-fold with each 1-point increase in CHADS₂ score, from 1.9 in patients with a score of 0 to 18.2 in patients with a score of 6³ (Figure 2). Approximately one third of the cerebrovascular events in this study were TIAs.³

Figure 2. Adjusted Stroke Rate* Stratified by CHADS₂ Score³

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Abbreviation: CI, confidence interval
*Adjusted stroke rate is the expected annual stroke rate per 100 patient-years, assuming that aspirin was not taken.

Patients with a CHADS₂ score of 0 are considered to have a low risk for stroke, patients with a score of 1 have a moderate risk, and patients with a score of 2 or greater have a high risk of stroke.⁷ This patient’s CHADS₂ score is 4 based on his age (1 point), history of hypertension (1 point), and prior stroke or TIA (2 points), thereby placing him in the category of high risk for stroke.

Given the relative risk reductions associated with antithrombotic therapy (warfarin, 68%⁸); aspirin, 21%⁹), such risk stratification is essential to determine the absolute benefit of anticoagulant therapy for an individual patient.³ Evidenced-based practice guidelines issued by the American College of Chest Physicians in 2008 recommend long-term anticoagulation with an oral vitamin K antagonist, such as warfarin, for patients with a CHADS₂ score of 2 or greater.⁵ Anticoagulation should be targeted to an international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0) and should continue lifelong unless a contraindication emerges.⁵

Of the potential hemorrhagic complications associated with anticoagulants, intracranial hemorrhage accounts for 90% of fatalities and nearly all disabling events due to hemorrhage.⁵ In trials of anticoagulant therapy in atrial fibrillation studies, which excluded patients predisposed to falling, the rate of intracranial hemorrhage was 0.3 per 100 patient-years with aspirin and 0.4 to 0.5 per 100 patient-years with warfarin.² This risk causes concern in patients and clinicians, particularly when the patient is predisposed to falling. A history of falling is itself a risk factor for future falls, and 2% to 10% of older patients who fall will experience head trauma.¹ Approximately half of all cases of subdural hematomas, the most common type of fall-associated intracranial hemorrhage, are due to head trauma.¹ The decision to treat a patient with atrial fibrillation in the setting of a history of falls, therefore, becomes more complex than assessing only the patient’s CHADS₂ score.

Limited data are available on the risk and benefit of anticoagulation in patients predisposed to falling. Data from two studies, however, suggest that the benefit of anticoagulant therapy exceeds the risk of intracranial hemorrhage in these patients. Gage et al conducted a retrospective review of elderly patients with atrial fibrillation, including 1245 who were at high risk of falling, 33.5% of whom were on warfarin, and 18,261 other patients, 48.9% of whom were on warfarin.² The risk of intracranial hemorrhage was 1.9-fold higher in patients with a high risk of falling compared with other patients, and the risk of traumatic intracranial hemorrhage was 4.1-fold higher. The overall rate of intracranial hemorrhage in patients with a high risk of falling was 2.8% per 100 patient-years compared with 1.1 in other patients (P <.0001). The rate of traumatic intracranial hemorrhage was 2.0 and 0.34 per 100 patient-years in patients with and without a high risk of falling, respectively [P <.0001]. Importantly, the risk of intracranial hemorrhage was not affected by warfarin or aspirin (hazard ratio for warfarin, 1.0; hazard ratio for aspirin, 1.1). Among the patients at high risk of falling, those with a CHADS₂ score of 2 to 6 who received warfarin had a 25% relative risk reduction in composite outcome (out-of-hospital death or hospitalization for stroke, myocardial infarction, or hemorrhage) compared with those who did not receive warfarin (P = .004).

Man-Son-Hing et al used a Markov decision analysis to determine whether a risk of falling should influence anticoagulation therapy in patients with atrial fibrillation and a high risk of falling.¹⁰ Based on assessments of intracranial bleeding risk from falls and the stroke reduction benefit from anticoagulation therapy, study authors calculated that a patient must fall approximately 295 times in 1 year for the risk of warfarin to outweigh the benefit.

What can be done to minimize the risk of bleeding in patients predisposed to falls?

Audio Commentary by Robert G. Hart, MD

Case Continues

The patient was started on anticoagulation therapy with warfarin. He and his spouse were warned about the potential dangers of falling during anticoagulation and were instructed to take extra care and to use the walker at all times.

During the initial 6 months of warfarin therapy, the patient’s INRs fluctuated markedly above and below the target therapeutic range of 2 to 3, ranging from 1.4 to 4.8, despite good adherence. He developed a persistent right-sided headache and mild confusion and was taken to an emergency department where his INR was determined to be 4.1. There was no antecedent recent fall. A brain computed tomography (CT) scan was performed and showed a chronic right convexity subdural hematoma (Figure 3).

Figure 3. Brain CT Image 

Graphic courtesy of R. G. Hart, MD.

Warfarin was discontinued, and the patient was started on vitamin K. The subdural hematoma was drained via a burr hole. The patient’s headache and confusion resolved.

Clinical Decision Point 2:  Anticoagulation Following Intracranial Bleeding

Question 2: Should warfarin anticoagulation be resumed in this patient? If so, when?

1. No, the risk of recurrent intracranial bleeding with anticoagulation outweighs the risk of stroke in the absence of anticoagulation
2. Yes, restart warfarin 1 week after the drainage of the burr hole
3. Yes, resume warfarin if a follow-up CT scan after 1 month shows no recurrence of the subdural hematoma
4. “a” or “c”; either response may be correct based on clinician judgment 

Discussion

(d) The risk versus benefit of restarting warfarin is challenging to estimate in a patient with gait instability and subdural hematoma during warfarin anticoagulation. No long-term prospective randomized studies have addressed the safety of restarting warfarin after intracranial hemorrhage,¹¹ of which subdural hematoma is one subtype. Furthermore, it is unlikely that such a trial will ever be conducted due to ethical considerations.¹¹ While the immediate risk of bleeding in the acute stage of intracranial hemorrhage, including subdural hematoma, necessitates discontinuation and reversal of anticoagulation, as time passes the risk of thrombosis must again be addressed because the risk continues in accordance with the patient’s baseline clinical need for anticoagulation.¹² It cannot be overemphasized that clinicians must determine the relative risk of recurrent hemorrhage against the risk for thrombosis for each individual patient.

Decision-analysis models, in which quantitative methods are applied to determine expected consequences of two or more treatment strategies, can help clinicians make treatment decisions in the absence of comparative clinical trial data.¹³ The challenge for the clinician when using such models is to determine the model’s relevance to an individual patient and adjust for variations in risk factors.¹⁴ Eckman et al used a decision-analysis model to study the question of whether or not to anticoagulate following intracerebral hemorrhage in patients with nonvalvular atrial fibrillation (Figure 4).¹¹ Data sources included a prospective study of 435 consecutive patients with intracerebral hemorrhage, a prospective study of 71 consecutive patients with lobar hemorrhage, and a retrospective review of four studies following 823 patients with deep hemorrhage. Using standard logistic-regression methods, data normalized for age and gender were used to project expected outcomes of a hypothetical 69-year-old man, with separate analyses for lobar and deep hemorrhage. The model assumed a baseline relative risk for warfarin-associated intracerebral hemorrhage of 2 and a baseline risk of ischemic stroke if untreated of 4.5% per year. The efficacy measure was quality-adjusted life years (QALY).

Figure 4. Overall Quality-Adjusted Life Years with and Without Warfarin Following Lobar and Deep Intracerebral Hemorrhage Based on Decision-Analysis Model¹¹

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*Based on hypothetical 69-year-old man with newly diagnosed nonvalvular atrial fibrillation; separate analyses for history of lobar hemorrhage or deep hemorrhage.

Abbreviation: QALY, quality-adjusted life years.

Using this model, no anticoagulation was preferred for patients with lobar hemorrhage (no anticoagulation, 5.44 QALY; anticoagulation, 3.54 QALY).¹¹ In sensitivity analysis, the “no anticoagulation” recommendation was robust across variations in risk for ischemic stroke and recurrent intracerebral hemorrhage, effect of warfarin on stroke or hemorrhage, stroke outcome, and poststroke quality of life. In contrast, results were more equivocal for patients with deep hemorrhage. No anticoagulation was preferred with the baseline assumption for these patients (no anticoagulation, 7.84 QALY; anticoagulation, 7.53 QALY). In sensitivity analysis, however, anticoagulation was preferred when the relative risk of warfarin-associated intracerebral hemorrhage was less than 1.6, the baseline rate of recurrent intracerebral hemorrhage was less than 1.4% per year, or the baseline risk of ischemic stroke was greater than 6.5% per year, demonstrating that some patients with a higher risk of ischemic stroke may benefit from restarting warfarin.

This patient’s clinical features differ in three distinct ways from the model’s base case, including a higher risk of ischemic stroke and a higher risk of warfarin-associated bleeding, as well as a different type of intracranial bleeding (ie, a subdural hematoma). In this author’s expert opinion, these features suggest it is appropriate to restart warfarin in this patient if the follow-up CT scan at 1 month shows no recurrence of bleeding. Firstly, with a history of prior TIA and a CHADS₂ score of 4, his stroke risk is unacceptably high in the absence of anticoagulation. Secondly, the subdural hematoma occurred with an INR well above the target therapeutic range, and hence the risk of recurrence of warfarin-associated bleeding may be mitigated in this patient if the INR is maintained at less than 3.0 (although this is unknown).¹⁵ Finally, in contrast to primary intracerebral hemorrhage (the other major subtype of intracranial bleeding), subdural hematomas, while serious, can often be detected early and successfully treated if there is a high index of suspicion.¹⁶ However, given the lack of prospective data concerning the risks and benefits of anticoagulation for this patient, it also would not be incorrect to permanently discontinue anticoagulation therapy based on the risk of recurrent intracranial bleeding, particularly if the patient continues to fall.

Restarting warfarin as early as 1 week after the burr hole drainage would not be correct because subdural hematomas are notorious for reaccumulating in the initial weeks after drainage.¹² Resumption of anticoagulation should be postponed for some interval (I recommend at least 4 weeks), and a CT scan repeated to document absence of recurrence before initiating warfarin.

What is known about the best time to restart warfarin and how does this time frame differ for subdural hematoma versus other types of intracranial hemorrhage?

Audio Commentary by Robert G. Hart, MD

Case Continues

Warfarin was restarted about 4 weeks later after a repeat brain CT showed resolution of the subdural hematoma.

Is there a role for aspirin instead of warfarin in this patient?

Audio Commentary by Robert G. Hart, MD

The patient’s INR continued to fluctuate despite the best efforts of his physician, often exceeding 4.0 and in the therapeutic range of 2 to 3 less than half of the time.

What strategies have been shown to be effective in helping patients maintain target INR levels?

Audio Commentary by Robert G. Hart, MD

Clinical Decision Point 3: Anticoagulation Options for Poor INR Control

Question 3: Should warfarin be continued? Is there a role for dabigatran?

1. Continue warfarin
2. Discontinue warfarin and switch to clopidogrel plus aspirin
3. Discontinue warfarin and switch to one of the new oral anticoagulants (either dabigatran or rivaroxaban), if possible, because of their lower risk of subdural hematoma compared with warfarin

Discussion

(c) Continued INR fluctuation, often well above the therapeutic range, in a patient with prior subdural hematoma during overanticoagulation shifts the balance of benefit versus risk of warfarin against its use. This author would not recommend continuing warfarin in this setting unless something could be done, such as frequent home INR monitoring, to obtain substantially better anticoagulation control. Poor anticoagulation control on warfarin manifested by fluctuating INRs is an appropriate reason for switching from warfarin to dabigatran, an oral thrombin inhibitor that does not require INR monitoring due to decreased vulnerability to drug and diet interactions.¹⁷ The American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines recently updated their recommendations on the management of patients with atrial fibrillation to include dabigatran as an alternative to warfarin.¹⁸ Dabigatran is also included as an alternative to warfarin in the current European Society of Cardiology guidelines.¹⁹ In November 2011, rivaroxaban became the latest oral anticoagulant to be approved by the FDA.²⁰

Given that INR monitoring is not required with dabigatran, how should patients with atrial fibrillation who are receiving dabigatran be monitored?

Audio Commentary by Robert G. Hart, MD

Dabigatran is an oral thrombin inhibitor. A serum esterase that is independent of cytochrome P450 converts the prodrug to its active form.¹⁷ In the RE-LY trial (N = 18,113), a noninferiority trial comparing dabigatran at two twice-daily dosing levels with warfarin, dabigatran was associated with a significantly lower risk of intracranial bleeding: 69% reduction with the 110-mg dose and 60% reduction with the 150-mg dose.²¹ The lower dose was associated with a similar rate of stroke compared with warfarin, whereas the higher dose was associated with a significantly lower rate of stroke compared with warfarin.²¹ It is important to note, however, that the lower dabigatran dose is not approved by the FDA nor is it available in the United States,²² although it is available in other countries, including Canada. Dyspepsia was the only adverse effect significantly more common with dabigatran than with warfarin.²¹

Rivaroxaban inhibits factor Xa, without the need of a cofactor, by binding directly to factor Xa.²³ In its registration phase III trial enrolling 14,264 patients with atrial fibrillation, rivaroxaban in a once-daily oral 20-mg dose proved noninferior to warfarin for the prevention of stroke.²⁴ There was no difference between the two drugs in the risk of major bleeding (approximately 3.5%), but intracranial bleeding (0.5% versus 0.7%; P = .02) and fatal bleeding (0.2% versus 0.5%; P = .003) were significantly less frequent with rivaroxaban.²⁴

Apixaban is a novel direct factor Xa inhibitor with phase III data recently reported by Granger et al.²⁵ The trial enrolled 18,201 patients with atrial fibrillation and demonstrated the superiority of apixaban to warfarin in preventing stroke or embolism and reducing bleeding. The risk of intracranial bleeding was 0.33% with apixaban versus 0.80% with warfarin (P <.001); the risk of major or clinically relevant bleeding was 18.1% with apixaban versus 25.8% with warfarin (P <.001).

The combination of clopidogrel and aspirin, both antiplatelet agents but with different mechanisms of action,²⁶ has been shown to offer less protection against stroke than warfarin²⁶ but more protection than aspirin alone²⁷ in the ACTIVE W and ACTIVE A trials, respectively. Importantly, this combination is associated with a 0.4% per year risk of intracranial bleeding,²⁷ a risk similar to that associated with warfarin.² This option, therefore, would not be a good choice for this patient with a prior subdural hematoma.

Case Continues

The patient was started on dabigatran 110 mg twice daily, a dose that is available in Canada where he resides. In the United States, only the 150-mg dose is available, and this dose would still be preferable to warfarin because of the lower risk of intracranial bleeding. Because of the recurrence risk for intracranial hemorrhage, including subdural hematoma, the patient and his family were warned to seek medical attention urgently for headache lasting more than 2 hours, weakness on one side of the body, slurred speech, unusual sleepiness, or confusion. He was referred to a fall prevention clinic for education and physical therapy aimed at minimizing falls. To date, he is doing well, with reduced falls and no recurrence of subdural hematoma or TIA.

What impact does controlling blood pressure have on the risk of intracranial bleeding? What systolic and diastolic pressure levels would be appropriate targets for this patient?

Audio Commentary by Robert G. Hart, MD

Conclusion

Frequent falls are a risk factor of anticoagulation-associated intracranial hemorrhage, but the concern is often overemphasized, resulting in nonuse of anticoagulation in patients who would likely benefit from stroke reduction. Although it is a difficult benefit-versus-risk decision, in this author’s expert opinion, concern about falling as a reason to withhold anticoagulation therapy is too broadly applied. New oral anticoagulants dabigatran and rivaroxaban are associated with significantly lower rates of intracranial hemorrhage compared with warfarin anticoagulation and are attractive options in patients with special risks of intracranial bleeding.

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