A Grey Area: warfarin for atrial fibrillation in dialysis patients

I recently wrote a short post detailing safety concerns surrounding warfarin use for atrial fibrillation (AF) in dialysis patients. I focussed mostly on the emerging evidence that it may promote vascular and valvular calcification by the inhibition of vitamin-K dependent gamma-carboxylation, as well as recent observational data linking warfarin use to higher mortality rates in ESRD. I finished the piece with this line: "adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score greater than 2". The use of the CHADS score to stratify dialysis patients with AF has been addressed in a study in this month's Kidney International, and the results suggest that even this restrictive approach may not be safe.
Briefly, CHADS2 is a risk score that stratifies members of the general population with AF by stroke risk, in order to permit informed clinical decision-making regarding the risks/benefits of warfarin anticoagulation. Its name is an acronym derived from the component independent stroke risk factors, namely Congestive heart failure, Hypertension, Age over 75 years, Diabetic status, and history of Stroke (or TIA). This study highlights several caveats regarding the use of CHADS2 (and warfarin use in general) in the dialysis population, information you’ll need next time you’re thrashing out this thorny issue with your Cardiology colleagues.
The authors examined 17,500 dialysis patients from the international DOPPS study, among whom the prevalence of AF was 12% and the incidence of new-onset AF was 1 case per 100 patient years.

1. CHADS2 divides this representative sample of dialysis patients 50:50 into high ( greater than 4 per 100 pt-yrs) and low (less than 2) risk for stroke. 
2. In the low-risk group, the risk of stroke equals the rate below which anticoagulation is not recommended for AF in the general population and, as such, would support a decision not to anticoagulate a dialysis patient with AF and a low CHADS2 score. 
3. Two key components of the CHADS2 score, HTN and heart failure, did not independently predict stroke in this study. As a result, CHADS2 may overcall stroke risk in some low-risk HD patients, and caution should be exercised when calling a patient high risk based on these 2 conditions. A dialysis-specific CHADS score that drops hypertension and heart failure would likely improve its discriminatory power, but requires further study. 
4. Warfarin anticoagulation did not reduce stroke risk in this study. In fact, there was a strong tendency to more frequent cerebrovascular events, particularly in the elderly. Whether this surprising finding was caused by a direct effect of warfarin on the rate of hemorrhagic stroke, or that patients who were prescribed warfarin were already an inherently high-risk group, the fact remains that one needs to be very cautious when prescribing anticoagulation to these patients. It would appear that in some patients identifyed as being at higher stroke risk (particularly older patients), the risks of anticoagulation still outweigh the benefits. 

The upshot of this study is that CHADS2 appears to function adequately in identifying patients at low-risk for stroke, and provides support to a clinical decision to withhold warfarin in that context. However, its ability to identify high-risk patients suitable for anticoagulation is highly questionable, as 3 of its 5 component factors (HTN, heart failure and possibly age) perform poorly in the dialysis population. How to approach the issue of anticoagulation in such patients remains a gray area.

How low can we go for blood pressure control?

The much awaited results from the ACCORD-BP trial were recently presented at the ACC scientific session in Atlanta and published online in the NEJM on March 14th. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) was a major initiative (estimated cost of $300 million) funded by the NIH to answer important questions about the "intensive" management of glycemic control (HgbA1c less than 6 vs. 7-7.9) blood pressure control (SBP less than 120 vs. less than 140) and dyslipidemia (statin + fibrate vs. statin alone) in high risk patients with type 2 diabetes. The NIH stopped the intensive blood sugar lowering strategy on February 6, 2008, due to safety concerns. The results were published in the NEJM on June 12, 2008 and actually showed an INCREASE in mortality and no decrease in cardiovascular events in the intensive glycemic arm (A1c less than 6) compared to the standard glycemic (A1c 7-7.9). The blood pressure and lipid treatment trials continued until the planned end of the study in June 2009. The results of were published online in the NEJM on March 11th. The BP arm study examined the well-established epidemiological data that lower BP is associated with lower cardiovascular events.

Can you achieve more cardiovascular protection by reaching an even lower blood pressure target (less than 120/80)? Unfortunately, this trial compared this to a SBP of less than 140/80, which was the current guideline for BP control when ACCORD began.

Participants
• 4733 high-risk patients with DM2 (mean age, 62; 48% women)
• HgbA1c >7.5%
• >40 y/o with established CVD or
• >55 y/o with evidence of atherosclerosis, albuminuria, LVH or at least 2 additional risk factors for CVD (dyslipidemia, HTN, smoking or obesity).
• SBP between 130 -180 mmHg taking three or fewer meds for HTN

Exclusion criteria
• BMI >45, Creatinine >1.5 mg/dL, and other serious illness.

Study
• Patients were assigned to intensive BP control (target SBP less than 120) or standard BP control (target SBP less than 140)
• Mean follow-up was 4.7 years.
• Any FDA approved antihypertensive agent could be used to achieve targets
• Primary outcome was the first occurrence of a major cardiovascular event, which was defined as the composite of nonfatal MI, nonfatal stroke, or cardiovascular death.

Results
• Mean SBP and DBP at baseline were 139 and 76 mmHg in both groups.
• At 1 year, average SBP levels were 119 vs 134 mmHg (Intensive vs. Standard). This was achieved by prescribing more meds in the intensive group (at 1 yr 3.4 vs 2.1 meds).
• At 5 years, the rate of adverse cardiovascular events was 1.9% /yr vs. 2.1% /yr (HR, 0.88; P=0.2).
• Death rates were similar in the two groups.
• No secondary analysis was strongly positive, except that stroke incidence was significantly lower in the intensive-care group than in the standard-care group (0.32% vs. 0.53%).
• The intensive group had a higher rate of adverse events (3.3% vs. 1.3%), with more decrements in renal function and more episodes of syncope, bradycardia, hyperkalemia, and hypotension.

Several limitations of the ACCORD BP trial
1. Trial had an open-label design
2. The rate of cardiovascular events was lower than the expected rate in the standard group which reduced the statistical power calculation.
3. Patients <40>79 y/o were not included
4. SBP goal of less than 140 was used and not less than 130 which is currently recommended by JNC7

The ACCORD trial represents an important effort to understand the limit of cardiovascular risk modification in patients with type 2 diabetes. Is it pushing the limit of the J-shaped curve or is it possible that a larger trial or one in a higher-risk population might have shown a significant benefit? A beneficial effect was seen for the secondary end point of total stroke. Although the number of stroke events during the trial were quite small (36 vs. 64). It is also possible that 5 years of followup is not enough time to see a beneficial effect and following these patients over 10 to 20 years this effect will become evident. Lowering systolic blood pressure to levels below 120 mmHg is not without risk as seen by the more frequent hypokalemia, hypotension and syncope in the intensive group. This study implies that pushing blood pressure control to levels lower than a systolic blood pressure of 120 mmHg should not be used in high-risk patients with type 2 diabetes. However, the findings do not answer the question as to what the optimal blood pressure target is for these patients. Furthermore, this trial excluded patients with significant kidney disease. A comforting fact from the trial is that the overall cardiovascular event rate was low in both groups, showing what can be achieved with good treatment strategies. For now, we can continue to aggressively treat blood pressure to less than 130/80 in patients with type 2 diabetes, but pushing this to less than 120/80 does not provide added benefits.