Torsemide: when, how, and why I use it in canine CHF

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Diuretics play a critical role in the management of congestive heart failure (CHF) in both veterinary and human patients. Among loop diuretics, furosemide has been the most prescribed drug in this class in both human and veterinary medicine since it became available in 1966. Loop diuretics act via inhibition of the Na+/K+/2Cl cotransporter at the thick, ascending loop of Henle to promote the excretion of sodium, chloride, and water. This diuresis leads to a reduction in intravascular volume and thus a decrease in venous and capillary pressures, leading to resolution or at least mitigation of the clinical signs of CHF. Furosemide’s potency and rapid onset (when given intravenously) make it a mainstay in the acute treatment of the CHF crisis in dogs. Furosemide is also the most commonly used diuretic in the chronic management of canine CHF, including CHF secondary to myxomatous mitral valve disease (MMVD) and dilated cardiomyopathy. In this chronic usage, furosemide plays a critical but supporting role alongside other medications, most commonly including angiotensin-converting enzyme (ACE) inhibitors, pimobendan, and spironolactone (and less commonly, thiazide diuretics, other vasodilators, digoxin, and other agents).¹

As with all diuretics, there are limitations and potential side effects associated with the use of furosemide. The most common adverse effects can include polyuria/polydipsia, urinary incontinence, decreased cardiac output (because of decreased preload), azotemia, and/or hypokalemia and hypomagnesemia (due to increased urinary loss). Furosemide is also a potent activator of the renin-angiotensin-aldosterone system, which promotes near- and long-term negative impacts, including increased aldosterone secretion, vasoconstriction, promotion of arrhythmia, and myocardial fibrosis. These effects not only are deleterious for dogs with chronic heart disease, but they also likely contribute to the gradual onset of furosemide resistance in some patients.

In addition, there are some pharmacokinetic limitations inherent to furosemide that can limit its impact. Bioavailability in dogs following oral administration has been reported as only 77%. It is worth noting that in extensive human studies, furosemide bioavailability when given orally has been shown to be highly variable (10%-90%), both among patients and even within an individual. Moreover, the half-life of furosemide after oral dosing in the dog is just 1 to 2 hours and the duration of increased natriuresis is only 5 to 6 hours. As a result, oral administration needs to be at least twice a day in most CHF cases, with advanced or long-standing CHF often requiring furosemide every 8 or even every 6 hours. This frequency can be limiting for clients who work or need a full night’s sleep, and in many cases, this can lead to a decision to euthanize.

Thankfully, for canine patients with CHF secondary to MMVD, research over many decades has yielded high-quality evidence outlining the clear survival benefits and improved quality of life associated with some cardiac medications. These include ACE inhibitors, pimobendan, and spironolactone, which have all been shown to have benefit when used with a loop diuretic in this setting. Recently, there has also been growing interest in investigating the use of alternative loop diuretics for canine CHF such as torsemide in lieu of furosemide to see if there could be any advantages.

What is torsemide?

Torsemide is a loop diuretic first approved by the US Food and Drug Administration in 1993. It acts via inhibition of the Na+/K+/2Cl cotransporter at the thick, ascending loop of Henle, but it has a chemical structure different from furosemide’s. Torsemide has received interest and greater usage in human medicine over the years as a result of its higher bioavailability and longer duration of action compared with furosemide, as well as its anti-aldosterone effects. Some studies in chronic human heart failure patients have demonstrated reductions in hospitalizations associated with heart failure as well as decreased cardiac mortality when using torsemide compared with furosemide.^2,3

Early veterinary research showed that torsemide also had different pharmacokinetic and pharmacodynamic properties compared to furosemide.^4,5 In dogs, torsemide was shown to have a longer half-life and a longer duration of action (12 hours) compared with the 5- to 6-hour natriuresis provided by furosemide. Moreover, orally administered torsemide was shown to be more bioavailable (80%-100%) than furosemide in dogs. Veterinary research has suggested that torsemide is approximately 10 to 20 times as powerful as furosemide. Some canine studies have suggested that the potency ratio between them varies on a “sliding scale” in dogs, such that at lower dose of furosemide, torsemide may be closer to 10 times as powerful. That ratio may rise to torsemide being closer to 20 times as powerful when substituted for high doses of furosemide. As a result, one of the challenges when beginning to use torsemide is determining the proper dose to use in an individual. Below I will address how we consider this in our practice.

Diuretics are the only cardiac medication I use for which I tell the client that I expect them to see at least 1 adverse effect (polyuria/polydipsia). The spectrum of potentially more serious adverse effects seen with torsemide in the dog is very similar to those listed above with furosemide. Loop diuretics provide powerful and often lifesaving impacts and their adverse effects can be equally powerful. We therefore need to be vigilant with monitoring and work to find the lowest effective dose for keeping a dog out of CHF. As with any loop diuretic, renal function and electrolytes need to be monitored very carefully both before and after adding or changing the dose of torsemide.

Torsemide in studies

There have thus far been 2 large-scale prospective veterinary studies investigating the safety and efficacy of using torsemide vs furosemide in naturally occurring canine CHF.

Published in 2017, the TEST study was a randomized, single-blinded, controlled trial in which the authors hypothesized that torsemide given once a day would be noninferior to furosemide given twice a day.⁶ They evaluated 366 dogs with CHF secondary to MMVD. All were receiving standard therapy that included furosemide at enrollment. About half the dogs then started torsemide every 24 hours in lieu of their furosemide and continued their other CHF medications. The other half of the dogs simply continued their furosemide every 12 hours as well as their other CHF therapy. When torsemide was substituted for furosemide, the daily dose of torsemide given was generally between 5% and 10% of the daily furosemide dose. This was done on a sliding-scale basis in which the higher the dose of furosemide in an individual dog, the more powerful torsemide was projected to be on a mg/kg/day basis. As a result, torsemide was dosed with the assumption that it was about 10 to 20 times as powerful.

Over the course of 3 months and multiple scheduled visits, the dogs that had been switched to torsemide were found to be at least as likely to remain clinically and radiographically stable or as improved as the dogs receiving furosemide (ie, torsemide was noninferior to furosemide). The investigators also looked at the percentage of dogs in each group that during the 3-month study period either experienced a cardiac death, had worsening of their heart failure class, or whose owners elected euthanasia due to their heart disease. They found that the dogs receiving furosemide were about twice as likely (22%) to experience one of those three serious or fatal cardiac complications as those receiving torsemide (11%).

The frequency of adverse events was also studied closely in each group. Dogs receiving torsemide were significantly more likely to have owners report urinary incontinence (20%) compared with the furosemide group (4%; P < .001). Additionally, renal adverse events, which ranged from mild increases in renal parameters compared with baseline (even if still within the normal ranges) to acute renal failure were significantly more common in the dogs receiving torsemide (18%) compared with the furosemide group (4%; P < .001). However, there was not a significant difference in the frequency of death due to renal events between the torsemide group (4%) and the furosemide group (2%) (P < .22).

The second large, multicenter prospective investigation was the CARPODIEM study published in 20207. This was also a noninferiority study comparing torsemide to furosemide in dogs with CHF caused by MMVD. Unlike the TEST study, however, the CARPODIEM investigation looked at dogs that had just developed CHF and were thus starting a loop diuretic for the first time. These 319 dogs were then randomly assigned to receive either furosemide or torsemide in a double-blinded manner, plus other standard CHF therapy. Torsemide was prescribed every 24 hours and furosemide every 12 hours in nearly all dogs. The ratio of torsemide to furosemide used for the initial dose (in mg/kg/day) varied as in the TEST study, with torsemide assumed to be even more relatively powerful than furosemide as the dose increased.

They hypothesized, and then showed, that torsemide was noninferior to furosemide in controlling pulmonary edema, dyspnea, and cough over the first 14 days of treatment.They continued to follow these dogs over 12 weeks, with the cardiac investigators free to adjust the diuretic dose as they wished within certain limits. They found that dogs receiving torsemide had a significant reduction in the risk of developing cardiac death (spontaneous or euthanasia) or removal from the study due to worsening heart failure. The most common adverse events seen in each group involved the renal system, especially blood urea nitrogen or creatinine values above the normal range. While this was the most common adverse event in each group, it was more frequently seen in the dogs receiving torsemide. Over 93% of these instances of renal insufficiency were not serious enough to warrant a change in treatment.

Torsemide in practice

In the private practice referral hospital setting where my colleagues and I work, the majority of dogs we are treating for congestive heart failure are still receiving furosemide as their loop diuretic. However, we do find ourselves using torsemide more often each year, both as an attempted rescue agent when we are seeing a poor response despite furosemide dose escalation and also sometimes as the initial loop diuretic when dogs first reach CHF.

In the cases in which I am using it as a first-line agent at the onset of CHF, I am choosing my cases with intention and carefully managing my dosing and follow-up plan. For example, part of my approach is that I am using torsemide only with clients who I know from their past behavior are absolutely committed to following through on all recommended lab value appointments and requested communications. I also am generally using torsemide preferentially with clients whose observational skills I trust to notice subtle negative changes in appetite or energy such that we might catch dogs developing adverse events before they become severe.All of these considerations are critical, of course, when starting furosemide as well, but the greater potency of torsemide and the necessary ratio estimation involved in converting from the familiar furosemide dose simply make me more particular in choosing my cases while I continue to gain a better feel for the drug.

Any time I am starting torsemide anew or using it to replace furosemide, we request an email or phone update from the owner within 48 to 72 hours with respect to patient appetite, energy, and respiratory status. We add this anticipated update to our clinic schedule and if we do not receive the update on time, someone from our staff will get in touch to retrieve it. We also recheck renal values/electrolytes and blood pressure generally within 5 to 7 days of starting torsemide or making a significant change in daily dose.

Consider a dog that has developed CHF for the first time secondary to MMVD that has been stabilized in the emergency department and is switching to oral medications to go home. I am generally dosing torsemide in such a patient at approximately 10% of the total daily dose I would be using of furosemide. In other words, for an 8-kg dog that (based on their particular individual clinical situation) I might historically choose to start on 25 mg of oral furosemide per 24 hours (perhaps as 12.5 mg every 12 hours), I might try torsemide instead at 2.5 mg every 24 hours. Such a dog in our clinic would of course also be on other medications, generally, pimobendan, spironolactone, and an ACE inhibitor.

When starting torsemide after the initial onset of CHF, I am tending to use it either once a day or at most divided every 12 hours. I have yet to have an occasion where I used torsemide more frequently than twice daily, and we frequently find ourselves using furosemide every 8 hours in the latter stages of canine CHF. The longer duration of action is a powerful advantage of torsemide, both for the sake of owner convenience and also because there is no shortage of data showing that medication compliance decreases as the frequency of dosing increases.

In a dog that is presenting with recurrent CHF despite a high furosemide dose (eg, > ~7 mg/kg/day) and appropriate use of other CHF therapies (and anti-arrhythmic medications if appropriate), I would take a different approach when estimating the torsemide dose. First, the dog would need to be stabilized and possibly hospitalized as appropriate. Once they were stable and switched to oral medications to go home is when I would consider a switch to torsemide. Rather than a 10x ratio, based on the particulars of the case, I might choose a torsemide dose that was 1/15th or 1/20th the dose of furosemide that I might otherwise choose to increase this dog to.

Most veterinarians have spent the entirety of their careers using only furosemide when reaching for a loop diuretic. Such a depth of experience has given us a comfort with how we use furosemide and its inherent risks and benefits. The goal of this article is to provide some background on torsemide and why it might confer additive benefit in some canine CHF patients, as I believe you will be hearing more about it in the coming years.

CHF in dogs is most often a terminal condition, and any new treatment strategy that can confer incremental benefit will improve countless lives. The initial large investigations of torsemide use in canine heart failure have been promising and suggest efficacy that is at least on par with furosemide, with even more favorable outcomes seen in some cases. The fact that torsemide has a duration of action twice as long as furosemide is a clear benefit that gives you and your clients more convenient dosing options and better compliance. It is also clear that powerful medication can have powerful adverse effects and we need to be vigilant with our monitoring. If you find yourself considering using torsemide for chronic treatment in one of your canine CHF patients, I would choose your first such cases carefully.I would strongly recommend starting with cases that have previously been evaluated by a cardiologist and then talking with that clinician for guidance and dosage insight particular to that dog. The 2 large prospective veterinary clinical trials I mentioned are each detailed, illustrative, and well-written papers that are available free online. They are listed below, along with other primary source material, and I would recommend reading these papers closely if you are considering trying torsemide.

References

1. Keene BW, Atkins CE, Bonagura JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019;33(3):1127-1140. doi:10.1111/jvim.15488
2. Cosin J, Diez J; TORIC Investigators. Torasemide in chronic heart failure: results of the TORIC study. Eur J Heart Fail. 2002;4(4):507-513. doi:10.1016/s1388-9842(02)00122-8
3. Shah P, Patel H, Mithawala P, Doshi R. Torsemide versus furosemide in heart failure patients: a meta-analysis of randomized controlled trials. Eur J Intern Med. 2018;57:e38-e340. doi:10.1016/j.ejim.2018.08.015
4. Uechi M, Matsuoka M, Kuwajima E, et al. The effects of the loop diuretics furosemide and torasemide on diuresis in dogs and cats. J Vet Med Sci. 2003;65(10):1057-1061. doi:10.1292/jvms.65.1057
5. Paulin A, Schneider M, Dron F, Woehrlé F. A pharmacokinetic/ pharmacodynamic model capturing the time course of torasemide-induced diuresis in the dog. J Vet Pharmacol Ther. 2016;39(6):547-559. doi:10.1111/jvp.12316
6. Chetboul V, Pouchelon JL, Menard J, et al. Short-term efficacy and safety of torasemide and furosemide in 366 dogs with degenerative mitral valve disease: the TEST study. J Vet Intern Med. 2017;31(6):1629-1642. doi:10.1111/jvim.14841