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The CARPODIEM study in veterinary medicine: How well does torasemide work in dogs? | VETgirl Veterinary Continuing Education Podcasts

In this VETgirl online veterinary continuing education podcast, we discuss the CARPODIEM study in veterinary medicine, which looks at how well oral torasemide works in dogs with degenerative mitral valve disease and new onset congestive heart failure. If you’re still ‘scipting out furosemide to your heart murmur patients, listen up.

Ok, guys, so let’s address one thing right from the beginning – for those of you who may be thinking “Torse-what?”, we need to get you up to speed on the subject of investigation of today’s study, ‘torsemide’. Torsemide (aka Torasemide) is a loop diuretic with greater potency, longer duration of action, and smoother diuretic effect than furosemide. Recent data in dogs has indicated that the dose correlation of torsemide to furosemide is nonlinear – at doses less than 0.2 mg/kg/day, torsemide is approximately 10X more potent than furosemide, but at doses greater than 0.2 mg/kg/day, that potency factor is closer to twenty. Torsemide’s duration of action is twelve hours in oral form in dogs compared with six hours for furosemide.

Torsemide has undergone extensive investigation as a treatment option for congestive heart failure (CHF) in humans and has been demonstrated to be superior to furosemide in a number of respects. Torsemide has recently garnered more attention in veterinary medicine, as well, but the studies in dogs have been observational or have utilized torsemide as a replacement for furosemide for either refractory CHF, or less severe CHF. So, Besche et al wanted to evaluate this in a study entitled Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study. The authors wanted to investigate torsemide as a first-line therapy for CHF in dogs, head-to-head with furosemide. The study intended to investigate clinical efficacy, adverse effects, and outcome. As a heads up, please be aware that the primary conflict of interest in this study is a significant one – the study was funded and conducted by Ceva Sante Animale (Ceva Animal Health). The study otherwise boasts the hallmarks of a credible study in that it was performed in a prospective, multicenter, randomized, double-blind, positive-controlled, noninferiority field manner. And, this was a huge study – 46 private veterinary practices in 7 countries throughout Europe participated.

The study population consisted of dogs with the typical echocardiographic and radiographic features of degenerative mitral valve disease who also had clinical and radiographic evidence of CHF as determined by a specific scoring system. Only dogs experiencing their first episode of clinical CHF were included, which meant that they had not previously been exposed to furosemide, torsemide, or hydrochlorothiazide, with the exception that dogs could be included if they had received furosemide for less than 48 hours prior to entry and at a dose of less than 4 mg/kg/day. Treatment with pimobendan, spironolactone, and/or angiotensin-converting enzyme inhibitors (ACEIs) was permitted – no other cardiac medications were allowed. Doses of those three medications had to have been unchanged for the four-week period prior to enrollment. Dogs with CHF severe enough to warrant hospitalization or use of injectable diuretic therapy were excluded. Also, dogs with any other form of heart disease, kidney disease, significant systemic disease and pregnant/lactating animals were excluded. A total of 315 dogs were ultimately enrolled, with no significant baseline characteristics detected between groups.

Randomization was performed in 1:1 fashion with torsemide as the tested treatment, and furosemide as the control. In short summary, dogs were prescribed initial doses of treatment on day 0 proportionate to the severity of their clinical signs based on a predetermined clinical severity scale (to allow for rapid stabilization prior to maintenance CHF therapy). The dosing regimen was based on the potency relationships between furosemide and torsemide, as I previously reviewed earlier in this podcast, with the premise that these doses would provide equivalent diuresis. The lower dose target for torsemide was 0.13 mg/kg orally once daily, and for furosemide 1.3 mg/kg/day orally divided into twice daily dosing. Maximum dose allowed in this group was 0.25 mg/kg/day for torsemide and 2.5 mg/kg/day for furosemide. In dogs with higher clinical CHF scores, a torsemide dose of 0.26 mg/kg orally once daily was used, with comparable furosemide dose of 3.5 mg/kg/day divided into twice daily dosing. Maximum doses for this group were 0.5 mg/kg/day of torsemide and 7.5 mg/kg/day of furosemide. For this group with higher clinical severity score, the doses of treatment were then ideally tapered into the lower dose range once the patient was deemed stable. (In full disclosure, we criticalists typically reach for higher doses initially while in fulminant failure!).

In this study, dogs underwent evaluation on days 0, 4, 14, 42, and 84, receiving some combination of clinical examination, quality of life, cardiac imaging, and blood/urine testing (including chemistry profile and NT-proBNP) on each visit. The primary endpoint was treatment success at day 14, determined by reduction in the radiographic and clinical scores supportive of CHF at the time of study entry. Secondary criteria evaluated treatment response at days 14 and 84 defined as a radiographic pulmonary score of 0 (no pulmonary edema) or 1 (mild pulmonary edema) without any worsening of other clinical parameters of CHF. Owner compliance and clinician satisfaction with treatment were also evaluated. A time to clinical event outcome was tabulated for each patient when applicable, defined as time to cardiac-related death, euthanasia, or worsening of CHF such that treatment doses needed to be increased above the target ranges or additional cardiac therapies became necessary. Twenty-one dogs per group were removed at day 14. 32 additional torsemide dogs and 26 additional furosemide dogs were removed by day 84. Thus, per protocol 1 (PP1, 275 dogs) and per protocol 2 (PP2, 217 dogs) analysis groups existed corresponding to days 14 and 84, respectively.

So which drug won – or was it a draw? There were no differences between groups in the primary efficacy point at day 14, as well as the primary and secondary clinical endpoints at days 14 and 84 – this was the demonstration of non-inferiority of torsemide to furosemide in short-term treatment of CHF. Overall, approximately one-third of dogs in each group required cardiac therapy adjustment during the study period. Treatment compliance in the initial 14 days was higher for torsemide, which was a significant difference, but this did not differ by day 84. This may speak to the relative ease of once-daily administration of CHF therapy, especially early in the course of treatment for a new canine heart failure patient. No difference in clinician-perceived efficacy or owner-perceived quality of life were noted.

The big news from this study came from the time to event outcome evaluation. No difference was observed between groups in the percentage of dogs who reached cardiac death or euthanasia (6-7% overall) outcome, but more than twice the percentage of dogs receiving furosemide (15.8%) vs torsemide (7.5%) reached the endpoint of the need for additional cardiac therapy – either “forbidden therapies” or diuretic doses above the allowable range. Time to endpoint was significantly different between groups, in favor of torsemide, and this parameter was driven by withdrawal due to need to stabilize recurrent CHF as opposed to cardiac death or euthanasia.

In this study, there were 5 parameters that correlated with survival. Four of them – dyspnea score, echocardiographic left atrial:aortic root ratio (LA:Ao), heart rate, and NTproBNP concentration – are well established, direct markers of disease severity. What was the fifth variable? – torsemide! After adjusting for the other four variables, torsemide was associated with a 64% reduction in risk of event outcome. No difference was noted in all-cause mortality between the two groups. Now there is a little bit of a “catch” here: A significantly greater percentage of dogs receiving torsemide (60.2%) had non-serious (as in, not debilitating or life-threatening) adverse events compared with furosemide (48.1%), which were predominantly related to laboratory evidence of worsened kidney function. The vast majority of these events did not require treatment or dosage adjustment, however. No significant difference in serious adverse events was noted between groups.

So, what do we take away from this VETgirl podcast? At any given time point – a literal snapshot – in the first nearly 3 months of treatment of first-time CHF, torsemide was equivalent to furosemide at improving clinical and radiographic signs of CHF at dogs who remained in the study. But when evaluating the time to when dogs had to be withdrawn from the study at some point due to worsening signs of CHF (and were therefore not available for side-by-side comparison at the next time point), torsemide was in fact superior over the course of the nearly 3-month duration of the study. This did come with a not-so-surprising tradeoff: greater negative impact on kidney function. This is almost always the tradeoff with improved control of CHF using more or greater diuretic therapy. In this study, this impact on kidney function was not clinically significant, but 84 days is not a long period of time. It’s possible this impact is cumulative over a dog’s entire CHF treatment period, which could then adversely affect quality of life and/or survival time. This is an important subject of future investigation, particularly given that none of the dogs included in this study had preexisting kidney disease, by design.

This study tells us that perhaps we should be considering torsemide as a first-line therapy for CHF in dogs with degenerative mitral valve disease. This is doubly good news given that it can be administered as a once daily therapy. Like many decisions we make, we have to keep the patient’s total body health in mind, and we do not have enough information yet to determine whether this treatment choice would be appropriate for dogs with known kidney disease or other systemic diseases. Whatever treatment choices you make for CHF, the basic principles are the same – titrate your diuretic doses to effectively control clinical signs while trying to limit the footprint you make on kidney function along the way!

References:
1. Besche B, Blondel T, Guillot E et al. Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study. J Vet Intern Med 2020;34:1746–1758.

Today’s VETgirl online veterinary CE podcast is sponsored by IndeVets, who’s on a mission to make veterinary medicine better. IndeVets is hiring qualified vets to become a part of their team. Skip the off-hour call and office politics and get back to the medicine as an associate with great benefits! This isn’t a relief gig. IndeVets wants to rid the vet industry of burnout and over-working and empower vets to take control of when and where they want to work, so they can enjoy life outside of the clinic and be a better vet inside it. Go to IndeVets.com to learn more and apply.

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