ANTICOAGULANT-RELATED INTRACEREBRAL HEMORRHAGE IS A WORSENING PROBLEM

CASE HISTORY

Mr Smith is a 74-year-old man who presented to the emergency department (ED) with sudden onset of headache and vomiting. Although generally healthy and active, Mr Smith was diagnosed with atrial fibrillation (AF) 3 years ago in the setting of long-standing hypertension but in the absence of valvulopathy to account for this arrhythmia. In a discussion with his cardiologist at the time, Mr Smith chose to forgo attempts at cardioversion and had been doing very well on a regimen of a long-acting calcium channel blockade and warfarin therapy to reduce his risk of embolic stroke. His international normalized ratio (INR) had been monitored closely in the local anticoagulation clinic. He was now undergoing monthly checks since his INR had been maintained within the therapeutic range for the last year.

On presentation by ambulance to the ED, the only additional history of note was that Mr Smith was recovering from a diarrheal illness that he had experienced over the previous 3 days. On the day of presentation, Mr Smith reported feeling unwell shortly after awakening as a result of a gradually worsening headache and 2 bouts of vomiting. He asked his wife to call 911 and have an ambulance take him to the hospital. Upon arrival in the ED, Mr Smith was alert, with a score of 15 on the Glasgow Coma Scale, but he demonstrated marked pallor, left-sided upper extremity weakness, and a left-sided facial droop. His vital signs were within an acceptable range. Laboratory investigation results were within reference ranges, with the exception of an INR of 4.1. Upon returning from an urgent noncontrast brain CT scan that revealed a large, deep, right hemispheric intracerebral hemorrhage (ICH) with mass effect, his level of consciousness deteriorated significantly, which necessitated an endotracheal intubation and a prompt transfer to the intensive care unit. Mr Smith was treated with vitamin K and frozen plasma products early in his ED course.

ANTICOAGULATION-ASSOCIATED INTRACEREBRAL HEMORRHAGE: EPIDEMIOLOGY AND RISK FACTORS

Nontraumatic ICH is a devastating complication of anticoagulant therapy. It occurs annually in 1 (0.3-0.6%)of 150-350 patients who are on long-term antithrombotic therapy with an oral anticoagulant (OAC) such as warfarin.¹ All types of ICH combined account for 10-15% of all strokes in North America and 40% of strokes in Asia.² Anticoagulation with an OAC is believed to be the primary causative factor in 12% of all cases of ICH.¹

Two risk factors are clearly established for the development of oral anticoagulant–associated intracerebral hemorrhage (OAC-ICH): advancing age and intensity of warfarin therapy.¹ A history of hypertension and remote cerebrovascular disease have also been implicated as risk factors for the development of OAC-ICH, but their influence is relatively modest by comparison.1 With regard to the contribution that advancing age makes to the risk of OAC-ICH, a study of nearly 14,000 patients from a managed care organization found that octogenarians were at increased risk of both primary (not OAC-associated) ICH and OAC-ICH; those aged 80 years or older had a 4-fold increase in event rates compared to rates of patients younger than 80 years and those who were not taking anticoagulants.³ Intensity of anticoagulation has also been firmly demonstrated to have a strong association with the risk of OAC-ICH. In a pooled analysis of 2 trials, investigators report that INR values in excess of 3.1 are associated with a 40% increase in the risk of ICH, and that, in a consistent dose-response manner, derangements in the range of 4-4.5 are associated with a nearly 9-fold increased risk of CNS bleeding.¹ In another analysis, the risk of ICH doubles with each 0.5-point increase in the INR above the recommended limit of 2.⁴

The burden of illness associated with OAC-ICH

OAC usage not only increases the risk of developing an ICH but augments the severity of the bleeding by impairing endogenous thrombus-forming mechanisms. The morbidity and mortality associated with OAC-ICH is staggering; the impact far exceeds that of either an ischemic stroke or a primary ICH in a given patient. In one study, the mortality associated with OAC-ICH was reported to be twice that of other types of ICH (52% vs 28%).⁵ At least 80% of previously functional patients who experience an OAC-ICH are unable to return home after their event.⁵

Factors modulating an increase in the incidence and severity of OAC-ICH in the coming years

Epidemiologic research has suggested that AF, the most common indication for long-term anticoagulation, is on the rise. Among Medicare patients aged 65 years or older, AF prevalence increased from 3.2% in 1992 to 6% in 2002, with an even higher prevalence in older subsets of the study population.⁷ A recent analysis of another database from the midwestern United States suggests that these estimates are 30% short of the more likely anticipated increase, which will triple the number of patients with AF in the United States (from current figures) to nearly 16 million by 2050.⁸ Furthermore, this rising prevalence in AF can be only partially explained by the aging of the population. The results of this study suggest that the growing rate of obesity might be playing a role in the increasing prevalence of AF.⁸

The 2006 Guidelines on the Management of AF from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology have established 2 important tenets in the treatment of AF that are relevant to this discussion. The first is the unquestionable importance of reducing thromboembolic complications in patients with AF who are at risk for stroke because of the use of OACs.⁹ This at-risk population includes those who are older than 65 years and have concomitant risk factors for stroke such as diabetes, heart failure, and hypertension. This group accounts for the vast majority of the population of patients with AF. Even recent trials that have compared combinations of antiplatelet therapies against anticoagulation have determined that antiplatelet therapies are no match for warfarin when it comes to reducing the risk of embolic stroke.¹⁰ The other clear message in these guidelines is related to the question of rhythm versus rate control in AF; this debate now clearly favors rate control as the preferred and best-tolerated approach in most patients. As a result of this tendency to let newly discovered AF persist without attempts at conversion to sinus rhythm and the increasing prevalence of AF in the community, the number of patients on warfarin therapy will only continue to climb. Not surprisingly, epidemiologic studies confirm that, in patients with AF, warfarin use has increased significantly for each year examined from 24.5% in 1992 to 56.3% in 2002.⁷

The prevalence of supratherapeutic and, hence, dangerous INRs in the general population of patients taking OACs can help shape expectations of future prevalence and scope of OAC-ICH. INRs can be notoriously difficult to control and stabilize, becoming significantly deranged as a result of concomitant dietary and medication-related factors as well as concurrent illness.¹¹ The literature on this question is disconcerting and suggests that anywhere from 11-58% of patients in anticoagulation clinics are reported to have supratherapeutic INRs.¹² Furthermore, in a study of patients who frequented an ED, a 30% prevalence of INRs in excess of 3 was reported.¹²

CONCLUSION

Vitamin K antagonists are a proven and efficacious intervention in preventing the thrombotic complications of AF and other conditions that predispose patients to clot formation. Unfortunately, these agents are associated with the distinct but unavoidable and devastating risk of ICH. This risk can be attenuated by meticulous monitoring of anticoagulation levels and aggressive management of hypertension, but these interventions cannot eliminate this complication. Most significantly, the aging of the population and the associated increase in the burden of cardiovascular illness translates into the unquestionable rise in the prevalence of AF. This changing demographic and pattern of OAC use will, unfortunately, result in an increased frequency and severity of OAC-ICH in the foreseeable future.

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5. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164(8):880-4.

6. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004;141(10):745-52.

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9. Fuster V, Ryden LE, Cannom DS, et al, and the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and European Society of Cardiology Committee for Practice Guidelines. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. A report of the ACC/AHA Task Force on Practice Guidelines and the ESC Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-354.

10. ACTIVE Writing Group on behalf of the ACTIVE Investigators; Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-12.

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12. Newman DH, Zhitomirsky I. The prevalence of nontherapeutic and dangerous international normalized ratios among patients receiving warfarin in the emergency department. Ann Emerg Med. 2006;48(2):182-9, 189.