DAWN of a new era in stroke care

Thrombectomy performed within 6 hours of symptom onset has been demonstrated to significantly improve clinical outcomes after stroke. Though there is generally diminishing benefit with increased time interval from last known well to the time of intervention, some previous data suggested that patients with “salvageable” brain tissue on diffusion weighted imaging (DWI) may still benefit from reperfusion despite being beyond the 6 hour window. Recently published randomized controlled trials including the DAWN and DEFUSE-3 trials now provide further evidence supporting this practice, though to a selected population of patients.

Here’s an overview of the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial:

  • Population: multicenter study, 206 patients with ICA/MCA infarcts with a last known well of 6-24 hours prior to randomization and with a greater than expected neuro deficit compared to the infarct volume on neuroimaging
  • Intervention: thrombectomy + usual care
  • Control: usual care alone
  • Outcomes: the average disability scores (utility-weighted modified Rankin scale) and the rate of functional independence at 90 days.
    •  significantly improved UW-mRS in the intervention vs control group (5.5 vs 3.4 out of 10 point scale)
    • 49% vs 13% functionally independent at 90 days in the intervention and control groups, respectively
    • NNT to gain functional independence = 2.8
    • Trial stopped early after interim analysis showed clear benefit of thrombectomy
    • Recanalizaton achieved in 77% vs 36% of patients
    • similar symptomatic ICH and stroke-related death rates at 90 days
  • Limitations:
    • infarct volumes overall very small (median 8-9 mL) though inclusion criteria ranged from <21 mL to max 51 mL. I couldn’t find data on typical acute MCA stroke volumes, but, for comparison, in another small study, the mean final infarct volumes in MCA strokes was 195 mL. Authors predict that 1/3 of patients
    • patients with milder symptoms (NIHSS <10) were excluded, further limiting generalizability
    • Stryker-sponsored study (though authors had full access to data and no writing assistance from the sponsor)

Despite the limitations, it seems that this study demonstrates potentially significant benefit in quality of life and little harm to the carefully chosen stroke patient, and it makes sense that we are now involving neurology and calling stroke codes for patients with delayed stroke presentations and wake-up strokes.

References:
Nogueira et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. NEJM 2018.

Age adjusted D-dimer – do units matter?

The use of an age-adjusted D-dimer cutoff in ruling out venous thromboembolism for patients over the age of 50 is now largely accepted. Most commonly, the age-adjusted dimer cutoff is calculated based on the patient’s age x 10 (e.g. the age-adjusted upper limit of normal for a 70-year-old patient is 700). This makes sense when the standard reference range is 0-0.5 or 0-500, but what about when the reference range for the test is 0-230?

It turns out that, even though all quantitative D-dimer assays seem to use similar methodology (“latex enhanced immunoturbidimetric immunoassays), some assays report in units of FEU (fibrinogen equivalent units), while others report in DDU (D-dimer units). The reason for this is a difference in machine calibration.Those that report in FEU will have cutoffs of 0-0.5 ug/L or 0-500 ug/mL or some equivalent conversion. Assays that report using DDU typically have cutoffs of 0-230 or 0-250 ng/mL.

2 DDU = 1 FEU

Therefore, that 70-year-old patient has an age-adjusted d-dimer of 700ug/mL FEU or 350 ng/mL DDU. To simplify, instead of multiplying by 10, you can just multiply by 5.

And why should you even use an age-adjusted D-dimer? One meta-analysis demonstrated that, among older patients determined to be low risk for DVTor PE by Wells’ score, using an age-adjusted D-dimer improved specificity by an absolute range of 5-30%, while maintaining >97% sensitivity at all age groups. This allows you to practice good resource management by minimizing unnecessary testing without compromising safety.

References:

 

Kayexalate in Hyperkalemia – to give or not to give?

When a patient presents with hyperkalemia, in addition to the initial steps of obtaining an EKG and treating with calcium, insulin, glucose, albuterol, and furosemide if indicated, consultants will often ask us to also administer sodium polystyrene sulfonate, more commonly known as kayexalate, pending hemodialysis. Is this management strategy supported by evidence? Reviewing the (rather sparse) literature, the short answer appears to be no.

 

Kayexalate was approved for use in 1958, four years before the FDA began requiring drug manufacturers to demonstrate efficacy as well as safety. It theoretically lowers potassium by binding cations in the GI tract and increasing GI excretion of potassium. In the best case scenario, it takes on the order of hours to begin to have an effect. Moreover, it may not have any acute effect at all; some studies have demonstrated that, when taken for multiple days, kayexalate can effectively treat mild hyperkalemia in the outpatient setting, but there is almost no data supporting the use of kayexalate in moderate or severe hyperkalemia. One study found that a single dose of kayexalate + laxative (phenolphthalein or sorbitol) given to ESRD patients did not increase stool potassium output over a 12 hour period compared to administering a laxative alone. It did not lower serum potassium by a significant amount either, though these patients were not hyperkalemic to start with.

There have also been numerous case reports of intestinal ischemia/necrosis, bezoar formation, and death associated with kayexalate, particularly when administered with sorbitol. Furthermore, because it is a general cation binder, it may decrease absorption of other medications such as lithium and thyroxine.

Patiromer is another recently FDA-approved gastrointestinal cation binders that have a higher selectivity for binding potassium than kayexalate, though again there is as yet no data on its efficacy in acute hyperkalemia. It also is not currently available at Sinai. ZS-9 is another similar drug in the pipeline, but it’s not yet been FDA approved.

 

Therefore, the next time the consulting or admitting team raises the question of giving kayexalate as an adjunctive therapy for hyperkalemia, consider bringing up its potential for significant harm and the paucity of data on its efficacy in acute hyperkalemia. If the patient is unable excrete potassium effectively through lasix, perhaps it is time for hemodialysis.

 

Special thanks to Dr. Gregory Fernandez for prompting the review of this topic.

 

References:

J Am Soc Nephrol. 2010 May;21(5):733-5. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective?

J Am Soc Nephrol. 1998 Oct. Effect of Single Dose Resin-Cathartic Therapy on Serum Potassium Concentration in Patients with End-Stage Renal Disease.

Clin J Am Soc Nephrol. 2015 Dec 7;10(12):2136-42. Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD.

Pharmacy and Therapeutics. 41(1), 43–50. Potassium-Binding Agents for the Clinical Management of Hyperkalemia.

Food and Drug Administration. 2009. Kayexalate

Emcrit – Is Kayexalate Useless?