Efficacy and Safety of Vitamin K Antagonists in Elderly Patients with Atrial Fibrillation

Oral vitamin K antagonists like warfarin are extremely effective in reducing the risk of stroke among patients with AF. The early AF trials consistently demonstrated benefit with an overall 68% risk reduction in stroke.

Despite the dramatic benefit of oral VKA, multiple studies have convincingly shown that only about 50-60% of at-risk patients with AF are receiving anticoagulant therapy.  In many parts of the world, the need for frequent INR monitoring represents a substantial barrier to its use.  Old age is often cited as a reason for not prescribing oral VKA because of perceived bleeding risk.  This is a true clinical dilemma because these are often the patients at highest risk of stroke. 

Factors influencing Warfarin under use among elderly patients with atrial fibrillation

  1. Lack of consensus on absolute versus relative contraindications to anticoagulant therapy: e.g., fall risk, prior hemorrhage
  2. Barriers to INR monitoring: e.g., dependence on caregivers for transportation, logistical constraints, cost
  3. Suboptimal candidacy for anticoagulant therapy and inability to tolerate medication long-term
  4. Fear of hemorrhage

The paradox facing clinicians and patients is that many of the risk factors for intracranial hemorrhage are also risk factors for ischemic stroke.  Age, hypertension, and prior stroke all increase the risk for both hemorrhagic and non-hemorrhagic stroke.  Although leukoaraiosis and amyloid angiopathy are associated with increased risk of intracerebral hemorrhage, their utility for risk stratification remains unclear.

Risk factors for intracranial hemorrhage

INR intensity
Aspirin therapy
Ischemic cerebrovascular disease
Vasculopathy-Leukoaraiosis, amyloid angiopathy

Major hemorrhage

Published rates of ICH and other major hemorrhage from randomized trials and observational cohort studies have been reassuringly low.  Therefore, the risk versus benefit of anticoagulant therapy weighs in favor of anticoagulant use for the majority of patients at high risk of stroke. However, there are important caveats to the rates of major bleeding that have been published.  Overall, few patients greater than 80 years of age have been enrolled in randomized trials and cohort studies.  In addition, recent trials and most observational cohorts have largely reported the outcomes of prevalent users of warfarin.  Because most major bleeding occurs early in the course of anticoagulation, enrollment of predominantly long-time users of warfarin will result in lower estimates of hemorrhage.

Strategies to optimize risk and benefit

Challenges of Warfarin Use
Variable dose response-individualized dosing
Interactions with medications and diet
Narrow therapeutic window
Need for frequent monitoring
Long half-life

Age-related differences in rate of INR normalization

Older age has been shown in multiple studies to be a predictor of major hemorrhage.  Although multifactorial, age-related differences in the rate of INR normalization following an elevated INR may partly underlie this risk.

Risk factors associated with prolonged return

Risk factors associated with prolonged return to the therapeutic range following an INR of 6.0 or greater included older age, lower warfarin dose requirements, decompensated heart failure, an actively treated malignancy, and degree of elevation of the index INR.  For each decade of age, the risk of having an INR greater than 4.0 on Day 2 increased by 18%.  The clinical implications of this study are that elderly patients, especially those who require lower doses of warfarin to attain an INR of 2.0-3.0, are at highest risk for prolonged exposure to risk-laden levels of anticoagulation.

Strategies to optimize risk and benefit. Improved anticoagulation control

Lower target intensity?
Minimize concomitant antiplatelet therapy 
Improved risk stratification
Aggressive blood pressure control

Atrial Fibrillation: Morbidity and Mortality

~15% of all strokes occur in people with AF
Risk of stroke in untreated AF patients averages ~ 5% per year
Risk of stroke in AF patients by age group
1.5% in 50 to 59 year age group
23.5% in 80 to 89 year age group

AF is associated with a 50 to 90% increase in 
risk of death after adjustment for coexisting CV conditions.

Wolf PA, et al. Stroke 1991; 22: 983-988, Benjamin EB, et al. Circulation 1998; 98:946-952. American Heart Association.  Heart Disease and Stroke Statistics-2006 Update. Dallas, TX: American Heart Association;2006. ©2006 American Heart Association

Lecture held on ESC Congress, Vienna, Sunday 2 Sept., 2007: Management of Anticoagulation in Atrial Fibrillation

Elaine M. Hylek, MD, MPH, Associated Professor, Department Medicine,
Boston University Medical Center (Boston, US) (Sept., 2007)