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Author: Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

With the inclusion of ivabradine (Corlanor®) in the 2016 update to the American College of Cardiology Foundation / American Heart Association (ACCF/AHA) heart failure guidelines, there’s been a lot of talk about what exactly to do with it.1 In SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), ivabradine decreased the combined endpoint of cardiovascular death or hospitalization for heart failure (24% vs. 29% with placebo, p<0.0001), an endpoint driven primarily by hospitalizations (16% vs. 21% with placebo, p<0.0001), with a number needed-to-treat (NNT) of 20.2 Incidentally, it also decreased death from heart failure (3% vs. 5% with placebo, p=0.014), although the study was not powered to detect this latter outcome. Only a quarter of patients were at target doses of beta blocker therapy, so it is unclear whether ivabradine would have conferred similar benefits if patients had been receiving optimal therapy.

But it turns out we’ve already had a drug capable of reducing heart failure hospitalizations for quite some time: digoxin. In the DIG (Digitalis Investigation Group) trial, digoxin also reduced hospitalizations for heart failure (26.8% vs. 34.7% with placebo, p<0.001), with a NNT of only 13.3 Although we often relegate its use to patients with advanced heart failure, such as those with New York Heart Association (NYHA) class IV symptoms, over half of the patients enrolled in DIG had only NYHA class II disease, and another third had NYHA class III symptoms. Notably, digoxin failed to reduce death from heart failure (p=0.06), although subsequent analyses of the DIG trial indicate that this lack of benefit (and perhaps even increased risk in some patients) may have resulted from elevated serum digoxin concentrations (SDCs). In fact, among patients with SDCs of 0.5-0.8 ng/mL, there was a 6.3% reduction in all-cause mortality compared to placebo.4 These potential benefits were corroborated in another trial comparing patients from DIG who continued digoxin at low SDCs versus those that discontinued therapy; patients who continued therapy experienced reductions in all-cause mortality, all-cause hospitalizations, and hospitalizations for heart failure.5

Certainly these trials showing improvements in mortality are limited by their retrospective nature and are at best hypothesis-generating. But they do seem to indicate one thing: digoxin remains a viable option in many patients with heart failure…  if the drug is managed appropriately. Too many times, digoxin gets added indiscriminately without full consideration of its potential risks in a specific patient (e.g., older age, lower body weight, impaired renal function), which may in part explain why it often gets such bad press (examples here and here). Worst of all is that we actually have a tool for helping ensure that digoxin therapy is appropriately managed, although it is so often underutilized: SDC monitoring.

Sometimes I’ll get a dismissive response when I bring up SDC monitoring, but if there’s potential for both benefit and risk and we know both are associated with specific SDC ranges, then why not? Here are some of my strategies:

  • Use a patient’s individual digoxin clearance to determine their daily maintenance dose.*
  • Obtain a “baseline” SDC once the patient is at steady state (about a week) to ensure it is < 1 ng/mL.
  • Obtain a SDC in the setting of acute kidney injury or worsening chronic kidney disease.
  • Obtain a SDC whenever the patient presents with signs/symptoms that may represent toxicity, as these may mask (or be masked by) worsening heart failure.
  • Use linear pharmacokinetics to make adjustments when SDC > 1 ng/mL (Concentration/ Concentration2 = Dose/ Dose2).

Finally, digoxin is not only a useful strategy for reducing heart failure hospitalizations — it also does so at a fraction of the cost of ivabradine. In this area, based on estimates from GoodRx, 30 days of digoxin 125 mcg runs anywhere from between $10 to around $30. Compare that to ivabradine, which costs approximately $400 per month. Yes, some patients may be able to obtain ivabradine through their health insurance (likely at their highest tier copay), but somebody is still paying the full cost of that medication.

Bottom line: If we can safely reduce heart failure hospitalizations by using digoxin responsibly (and at a fraction of the cost), then why make a SHIFT to ivabradine?

 

 
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed

 

References

  1. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016 May 17. pii: S0735-1097(16)33024-8. doi: 10.1016/j.jacc.2016.05.011.
  2. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376(9744):875–85.
  3. The Digitalis Investigation Group. The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure. N Engl J Med 1997;336(8):525–33.
  4. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of Serum Digoxin Concentration and Outcomes in Patients With Heart Failure. JAMA  2003;289(7):871–8.
  5. Ahmed A, Gambassi G, Weaver MT, Young JB, Wehrmacher WH, Rich MW. Effects of Discontinuation of Digoxin Versus Continuation at Low Serum Digoxin Concentrations in Chronic Heart Failure. Am J Cardiol 2007;100(2):280–4.

*A patient’s daily digoxin clearance can be determined by: ((creatinine clearance/5) + 14) / 100. Approximately 5.0 to 7.5 mcg/kg of ideal body weight (IBW) is required to achieve a total body concentration of 1 ng/mL, so the daily digoxin dose can be determined by multiplying this amount by daily digoxin clearance.

Example: A 72 year-old patient with an IBW of 65 kg requires a dose of 325-487.5 mcg of digoxin to achieve a total body concentration of 1 ng/mL (let’s use 325 mcg for this example). Let’s say this hypothetical patient has a creatinine clearance of 40 mL/min, which corresponds to a daily digoxin clearance of 0.22. Thus, to maintain a serum concentration of 1 ng/mL, take 325 mcg x 0.22 = 71.5 mcg of digoxin per day. This could be accomplished by administering 125-mcg tablets on Mondays, Wednesdays, and Fridays.

Digoxin defended: why make a SHIFT to ivabradine?

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