The Rising Costs of Isoproterenol

The most commonly used cardiac medication in the EP laboratory is isoproterenol (Isuprel). It has been used for years to increase sympathetic tone in patients who are sedated, and is titrated to mimic a broad spectrum of autonomic states, from a more awake status to that during exercise. Now likely used in a majority of EP procedures, isoproterenol has proven to be invaluable. For example, a low-dose isoproterenol infusion is often needed to allow induction of paroxysmal supraventricular tachycardia (PSVT) in a patient with documented tachycardia, but no inducible tachycardia at baseline. Many of these patients have no ventriculoatrial conduction at baseline. In patients with atrial fibrillation (AF), there is data that using high-dose isoproterenol to identify and ablate AF triggers leads to better outcomes. Isoproterenol also increases triggered activity and is used to induce idiopathic ventricular tachycardia. Outside of the EP lab, isoproterenol is still used at many hospitals as a provocative agent during head-up tilt table testing.

Isoproterenol is a nonspecific beta agonist with some alpha effects that cause an increase in heart rate and cardiac contractility. In the EP lab, it is usually started at 1-2 mcg/min and increased to achieve a 15-20% increase in the sinus rate. To provoke AF triggers, it is common for the dose to be increased up to 20 mcg/min. It can be infused through a peripheral IV line or through a central venous access sheath that was placed as part of the EP procedure. Key advantages of isoproterenol are its rapid onset and offset, potent effects on AV nodal conduction, and relative safety. Disadvantages of isoproterenol during EP procedures are that the resultant increased contractility makes catheter stability difficult and hypotension at high doses.

However, there is a major problem with isoproterenol. It is very expensive. According to a statement posted in April 2015 by the Heart Rhythm Society,¹ the increased costs are not due to a shortage of supply. “Several years ago, Marathon Pharmaceuticals bought isoproterenol from Hospira. Upon acquisition, Marathon Pharmaceuticals increased the price from $44.5/dose to $218.3/dose. Subsequently, Marathon Pharmaceuticals sold isoproterenol to Valeant Pharmaceuticals International Inc. in February 2015. Upon acquisition, Valeant Pharmaceuticals increased the price from $218.3/dose to $1,200/dose.” The United States Congress was trying to pass legislation to prohibit this type of behavior by the pharmaceutical industry, but to no avail. The cost of Isuprel continues to escalate, with its price now at $1,356 per vial.

At large medical centers, the pharmacy costs of isoproterenol now exceed half a million dollars. Compounding the price problem is the short shelf life after preparation. At most hospitals, the drug is mixed by a nurse in the EP lab for immediate administration, but some hospital policies require for sterility reasons that isoproterenol be spiked under a laminar flow hood in the pharmacy. This leads to delay. To minimize the delay between order entry and delivery of the drug to the EP lab, premade bags can be made and kept refrigerated in a nearby, automated medication dispensing system (Pyxis [CareFusion], Omnicell, etc.). A batch system can also be used to make two bags of isoproterenol, each with 500 mcg in 250 mL of saline (2 mcg/mL), from one ampule.² However, isoproterenol prepared this way expires after 48 hours and has to be thrown out if not used.

There are at least three approaches to lowering the pharmacy spend on Isuprel. The first approach is to find a substitute. This is a challenge. Many centers have already switched from isoproterenol to sublingual nitroglycerin as a provocative agent during tilt table testing. Substitution options in the EP lab include dobutamine, epinephrine, dopamine, and atropine. Unfortunately, none of these are optimal. Each has different pharmacological effects and atropine takes too long to wear off. Dobutamine is a logical substitute; it would be an interesting choice, given that dobutamine was actually derived from isoproterenol with a goal of making an inotrope that does not cause as much tachycardia as isoproterenol. One study found that dobutamine at doses from 10-40 mcg/min was comparable to isoproterenol from 1-3 mcg/min during EP procedures.³ For hospitals that do not permit preparation in the EP lab, another option is to identify a formulation with a longer shelf life. There is now a premade formulation available that comes as 200 mcg in 50 mL of D5W, has 180-day stability, and costs $682 per bag. Another option is to only use it when absolutely necessary. Hospitals that use it during every AF ablation to look for triggers might want to carefully analyze the studies that tout better outcomes.

It is likely that many EP programs are unaware that their hospital is spending hundreds of thousands of dollars on isoproterenol. This is a cost that is often not on the radar of the hospital supply chain team because it is part of a separate pharmacy budget. Unless the price of isoproterenol can be dramatically reduced, it is important to investigate alternative agents in the EP lab.

References

1. Special Notice Regarding Pricing of Isoproterenol/Isuprel. The Heart Rhythm Society. Published April 8, 2015. Available online at https://www.hrsonline.org/Policy-Payment/Health-Policy-Payments/2015/Dramatic-Increase-in-the-Price-of-Isoproterenol-Isuprel#sthash.OuRLhwfe.dpuf. Accessed February 13, 2017.  
2. Leedahl ND, Olson LM, Leedahl DD. A potential cost savings strategy for isoproterenol hydrochloride using novel stability data. J Cardiol Neuro Cardiovasc Dis. 2016;3:011.
3. Vanegas D, Perez C, Montenegro J, Orjuela A. Dobutamine use for arrhythmia induction during electrical programmed heart stimulation. Revista Colombiana de Cardiologia. 2006;38(16):479-483.