Increased stroke risk for older women

MONTREAL, CANADA. Atrial fibrillation (AF), on its own, does not increase the risk of suffering a stroke. However, about 80% of patients with AF also have hypertension, heart disease, diabetes, or other comorbid conditions that substantially increase the risk of stroke. For example, hypertension by itself increases stroke risk by a factor of 4 to 6, while long-term diabetes is associated with a 3-fold increase in stroke. It seems to be firmly engrained in medical minds that AF patients have a 5-fold increase in the risk of stroke compared to the general population. While this may be true for an 80-year-old afibber with heart disease, diabetes, and hypertension, it is patently untrue for a middle-aged, otherwise healthy lone afibber. Nevertheless, the pressure is on to have all afibbers, irrespective of the absence or presence of comorbid conditions, be on warfarin, or one of the newly-developed anticoagulants, for life.

Stroke risk is usually assessed using the CHADS2 scoring system which assigns 1 point each to the presence of congestive heart failure, hypertension, diabetes, age of 75 years or older, and 2 points for a history of stroke or transient ischemic attack (TIA).

A new scoring system, CHA2DS2-VASc, has recently come to the fore. This score assigns 1 point each to the presence of congestive heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years, female gender, and 2 points for a history of thromboembolism and age 75 years or older. Thus, according to this new system, an otherwise healthy 65-year-old female afibber with no comorbid conditions supposedly has the same risk as an afibbers who has already suffered a stroke and must be on warfarin for the rest of her life.

Now a group of researchers from three Canadian universities reports that older women with recently diagnosed AF have a significantly higher risk of stroke than do older men. Their study included 39,398 men and 44,115 women admitted to hospital with AF as a primary diagnosis (24%) or with coronary artery disease, valvular heart disease, heart attack, chronic kidney disease, or high cholesterol as the primary diagnosis and AF as the secondary diagnosis (76%). The average age of the male study participants was 77 years and that of the female participants was 80 years. The average CHADS2 score for men was 1.7 vs 2.0 for women. Components of the CHADS2 score were:

-
Women
Men
Congestive heart failure
27.8%
28.9%
Hypertension
63.9%
51.3%
Age 75 years or older
74.2%
61.4%
Diabetes
22.1%
24.6%
History of stroke
8.0%
6.9%

Warfarin was prescribed at discharge from hospital for 60.6% of women and 58.2% of men. The study participants were followed for 1 year during which a total of 2570 stroke (2.02%/year) occurred among the women and 1696 (1.61%/year) occurred among the men. NOTE: Stroke was defined as ischemic stroke (cerebral thrombosis), embolism, artery occlusion, transient ischemic stroke, or retinal infarction. The rates of hemorrhagic stroke (intracerebral hemorrhage) were 1.42% among the men and 1.33% among the women.

Stroke risk was found to increase significantly with age, rising from 1.05%/year among women aged 65 to 69 years (corresponding figure for men was 1.17%/year) to 2.38%/year for women aged 75 years or older (corresponding figure for men was 1.95%/year). Not surprisingly, stroke risk also increased significantly with increasing CHADS2 score from 1.03%/year for women with a score of 0 (corresponding number for men was 0.86%/year) to 4.91%/year for women with a score of 5 (corresponding number for men was 4.88%/year). NOTE: Only 0.17% of the total patient population had a CHADS2 score of 5 or higher, so it would seem to be gross exaggeration to claim that all AF patients have a 5-fold increased risk of stroke.

As shown below, it is clear that women aged 75 years or older have a higher risk of stroke than do age-matched men, and that this excess risk is reduced by the use of warfarin.

Stroke Incidence - Below age of 75 years
-
No warfarin
Warfarin
Women
1.47%/year
1.10%/year
Men
1.48%/year
1.04%/year

Stroke Incidence - At or above 75 years
-
No warfarin
Warfarin
Women
2.91%/year
2.05%/year
Men
2.20%/year
1.78%/year

The authors conclude that the risk of stroke among older women with recently diagnosed AF is greater than that of age-matched men irrespective of whether warfarin therapy is implemented.
Avgil Tsadok, M, et al. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. Journal of the American Medical Association, Vol. 307, No. 18, May 9, 2012, pp. 1952-58

Editor’s comment: It is unfortunate that the authors of the Montreal report did not provide details of the distribution of hemorrhagic strokes other than to say that most of them occurred in patients on warfarin. However, based on results from similar studies, it is likely that about two-thirds of hemorrhagic strokes occurred in the warfarin group. Thus, the incidence of hemorrhagic stroke would be 0.44%/year in women not on warfarin and 0.89%/year for women on warfarin. The corresponding numbers for men would be 0.47%/year and 0.95%/year.

It is now well established that the benefits of warfarin are, often to a considerable extent, reduced by its inherent propensity to cause intracranial bleeding (hemorrhagic stroke). Two recent studies have used the concept of Net Clinical Benefit (NCB) to determine the real, overall benefit of warfarin therapy.[1,2] NCB considers both the benefit (reduction in ischemic stroke) and harm (increase in hemorrhagic stroke) in administering the drug. NCB is defined as:

NCB = (TE rate off warfarin – TE rate on warfarin) – W x (ICH rate on warfarin – ICH rate off warfarin)

  • TE rate is the annualized rate of thromboembolic events (ischemic stroke and systemic emboli).
  • W is a weighting factor designed to reflect the fact that the consequences of a hemorrhagic stroke (intracranial bleeding) are far more serious than that of an ischemic stroke. W is usually assumed to be 1.5.
  • ICH rate is the annualized rate of intracranial bleeding (incl. hemorrhagic stroke).

Using the above formula, and assuming that hemorrhagic stroke incidence is independent of age, the following NCBs can be calculated.

NCB of Warfarin Therapy
-
Age 75 years or younger
Age 75 years or older
Women
- 0.31%/year
+ 0.18%/year
Men
- 0.24%/year
- 0.26%/year

The above calculation shows that the average NCB of warfarin therapy in recently diagnosed female afibbers, at or above the age of 75 years, is indeed slightly beneficial at 0.18%/year. It would appear to be detrimental for men at all ages, and for women below the age of 75 years. Of course, these numbers are average and whether or not warfarin therapy would be beneficial for an individual afibber would clearly depend on his or her age and CHADS2 score. Thus, warfarin therapy would likely be beneficial for an older woman (age 75 years or older) with a CHADS2 score of 3 or higher, but would almost certainly be detrimental for women with a CHADS2 score below 3 unless the reason for their CHADS2 score of 2 was a history of stroke or TIA. The same cut-off points would apply to men.
[1] Singer, DE, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of Internal Medicine, Vol. 151, September 1, 2009, pp. 297-305, pp. 355-56
[2] Olesen, JB, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a “real world” nationwide cohort study. Thrombosis and Haemostasis, Vol. 106, No. 4, October 2011, pp. 739-49