Thursday, February 6, 2014

#DreamRCT: Anticoagulation in Hemodialysis

Back in December, I had Ed El Sayed (@iApothecary) do the first guest post on PBFluids. He wrote about Nephron D for the top nephrology stories of the year project. It was one of my most popular stories of the fourth quarter of 2013. Ed is back with his contribution to the DreamRCT project:

When should dialysis patients with non-valvular Atrial Fibrillation be anti- coagulated?


End Stage Renal Disease (ESRD) patients on dialysis have an increased risk for bleeding due to a number of factors, most notably failure of uremic platelets dysfunction (decreased degranulation and aggregation). This increases the risk of therapeutic anticoagulation in dialysis patients, they just have a significantly increased risk of bleeding.

Quantifying this risk is important because in numerous clinical situations the choice to anti coagulate or not to anti coagulate must ejudicated. Often times, clinicians are faced with an issue where the evidence base simply does not exist, or is unfortunately, ambiguous. When trying to determine if anticoagulation for atrial fibrillation is appropriate in ESRD patients, nephrologists, cardiologists, and pharmacologists cannot mine the medical literature for an answer. The evidence is insufficient.

That being said, experts recommend anti-coagulation pharmacotherapy in ESRD patients who have one or more of the following conditions: 
  • Pulmonary Embolism
  • Deep Vein Thromboembolism
  • Anti-Phospholipid Syndrome
  • Mechanical prosthetic cardiac valve
This expert recommendation is based on the hope that the anti-coagulation benefits in those conditions outweighs the risk of bleeding.

So where do we stand?

The Dialysis Outcomes And Practice Pattern Study (DOPPS) trial and the United Stats Renal Data Service (USRDS) both demonstrated an increasing rate of atrial fibrillation (AF) among dialysis patients. AF was also shown to be more prevalent in pre-dialysis CKD patients in the Chronic Renal Insufficiency Cohort (CIRC) trial. Even more worrisome is data showing that AF in ESRD patients increases all cause mortality. On the other hand, the data is inconsistent on the association between AF and stroke in ESRD patients (no association: here, and here, positive association: previous KI article).

Another dilemma clinicians often face in clinical practice is whether to use the CHAD2S2 score to assess the need for using warfarin to prevent stroke in AF patients on dialysis. While the CHAD2S2 score is a derivative of CHADS2 score, its validity was based on data from non-renal patients and experts advocate against using it on renal patents.

Several studies have been performed to determine the benefit of warfarin in AF patients on dialysis. The results however, were inconsistent. A few studies were pro-warfarin, while others were anti-warfarin.

Despite numerous studies, prospective data is both scant and contradictory. The data in patients without renal insufficiency, while compelling cannot be used to judge the safety and efficacy of anticoagulation in dialysis. This means we do not have the data to make the decisions we need.

My Dream RCT: The PHANTOM-1 Study

Placebo in Hemodialysis vs ANTicoagulation. My aim is to design a multi-center, randomized, double blinded, placebo controlled trial to study the effect of Warfarin pharmacotherapy in AF patients who require hemodialysis. PHANTOM-1 study would have the following criteria:

  • Inclusion Criteria
    • Age range 50 - 84 years
    • Sex males and females
    • CHADS2 Score greater than or equal to 2
    • History of Non-Valvular AF for 2 or more years
    • On Warfarin with INR 2-3
    • Ethnicity White, Asian, African American
    • History of ESRD requiring hemodialysis 3 or more times weekly
  • Exclusion Criteria
    • Age range younger than 50 years and older than 84 years
    • CHADS2 Score less than 2
    • AF secondary to valvular disease
    • History of Non-Valvular AF for less than 2 years
    • On Warfarin with INR below 2 or above 3
    • Renal disease without the need for hemodialysis
    • ESRD patients undergoing Peritoneal Dialysis
    • History of Neuro-endocrine disease

The study design would have 2 arms, with one group continuing to receive oral warfarin 5-10 mg once daily to maintain INR between 2-3, while the other group receive a placebo. The outcomes of the study would be as follows:
  • Primary Endpoint - Onset of Transient Ischemic Attack (TIA) or stroke (Ischemic or Hemorrhagic)
  • Secondary Endpoint - Incident of major bleeding (outside the CNS) and access survival.
All patients in the trial would receive multi-disciplinary medical counseling and monitoring throughout the study time frame. The result of the study would be welcomed and published, regardless of the outcome.

Prospectively studying this in a randomized, placebo controlled trial would definitively answer an increasingly common question that nephrologists, cardiologists and primary care doctors face.


I received this feedback:
As a long time hematologist with an interest in anticoagulation I was very interested by your post as this is something my nephrology colleagues and I discuss all the time. I would also advocate enrolling folks not currently on anticoagulation because even in the non-dialysis population a lot of patients with afib who should be on warfarin are not. The other issues is would renal dose adjusted new direct oral anticoagulants be safer (50% Risk reduction of ICH in trials) esp when the antidote become available.
if this program gets rolling let me know how I can help.
--tom Thomas DeLoughery, MD FACP FAWMInterim Associate Division HeadProfessor of Medicine, Pathology and PediatricsOregon Health & Sciences University
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