20 Apr 2022
Image: © themost / Adobe Stock
In their first article, the authors outlined the mechanism of action of aldosterone and illustrated how spironolactone can be used for its mineralocorticoid antagonist properties to counteract these effects.
This article looks at how the theory behind the use of spironolactone is translated into improving the quality of life of dogs suffering from heart disease.
We have seen that a number of good theoretical reasons exist as to why spironolactone might help dogs with heart disease – in particular, in congestive heart failure (CHF). However, to justify the use of any drug in practice we need evidence to show its efficacy, in terms of increased survival and/or improved quality of life.
Where evidence for improved outcome isn’t available due to lack of clinical trials, we have to rely on anecdotal, theoretical or laboratory-based data to inform our decisions.
Evidenced-based medicine (EBM) for the use of spironolactone in canine patients with CHF is largely based on one study1 (the “Bernay trial”). Single studies are a common weakness of veterinary EBM (compared to many human drugs, which often have multiple trials) and is not restricted just to spironolactone.
The “Bernay trial” showed a striking 55% reduction in the risk of cardiac morbidity and mortality in dogs with myxomatous mitral valve disease (MMVD) when compared with conventional therapy alone (angiotensin-converting enzyme inhibitor [ACEi] plus furosemide, and digoxin, if needed). An even greater reduction (69%) in the risk of mortality was found when only cardiac mortality was analysed. While a lack of rigor of identifying dogs with CHF was a potential weakness of this study, for the benefit to be apparent in a group of dogs that showed a range of severity of disease is potentially an even more potent reason for its use.
The potential benefit of spironolactone is also supported by the results of a small pilot study with more rigorous CHF identification2. While, in a much smaller group than the Bernay trial, this showed no benefit in outcome, it did show a reduction in left atrial to aortic root ratio (LA:Ao) and left ventricular end diastolic diameter (LVDd), which are consistently strong indicators of severity and prognosis in this condition. It also showed a trend for reduction in a biomarker reflecting ventricular stretch (NTproBNP) in the treatment group2.
To investigate these issues further, the “DELAY trial”3 looked at the role of spironolactone and benazepril in dogs, which would fit the more subsequent American College of Veterinary Internal Medicine (ACVIM) class B2 classification4. This prospective, randomised, single-blinded, placebo-controlled, multicentre trial failed to demonstrate that combined administration of spironolactone and benazepril delays onset of HF in dogs with preclinical MMVD compared to the control group receiving placebo.
The authors concluded that treatment induced beneficial effects on cardiac remodelling and, therefore, these results could be of clinical relevance.
While hyperkalaemia is a commonly reported side effect in people, and the rise in death due to hyperkalaemia between 1994 and 2001 was attributed to rise in prescriptions for spironolactone5, research in dogs with CHF receiving spironolactone in addition to conventional treatment has shown that they are not at a higher risk of hyperkalaemia6. This remains the case even when they are also receiving ACEi.
Vets should know that some data sheets still warn against the drug combination, despite the evidence documenting a lack of problems in combining the two drugs. Indeed, as discussed previously, aldosterone escape from the actions of ACEi alone means that a sound rationale exists to combine the two products.
Facial dermatitis in cats receiving spironolactone has been reported in one study of a group of Maine coons7, but not in another study with a mixture of cat breeds8, potentially due to the use of different formulation tablets, or a different genetic predisposition. However, dermatitis has not been reported as a side effect of spironolactone in dogs.
Spironolactone should not be given to patients with:
While an increased risk of nephrotoxicity exists in some patients, it is important to accept that a degree of prerenal azotaemia will exist in many patients with CHF managed with furosemide and this does not mean that spironolactone or ACEi should be withdrawn. Spironolactone can decrease digoxin elimination. As the therapeutic index for digoxin is very narrow, it is advisable to monitor closely dogs receiving both digoxin and spironolactone.
The currently recommended dose of spironolactone is 2mg/kg by mouth every 24 hours, and the drug is best absorbed when given with food. It is significantly (50%) better absorbed when given with food.
Spironolactone is only licensed in Europe in 10mg, 50mg and 100mg divisible tablets and as part of a combination product with benazepril. Spironolactone is not licensed for use in dogs in the US. Generic human preparations do not hold a veterinary licence and cannot typically be justified under the cascade system in the UK.
The combination product contains both the ACEi benazepril and spironolactone in one tablet, flavoured to aid compliance. While fixed ratio drug combinations can have some limitations in terms of dosing, the added advantage for compliance means the authors frequently choose this product.
In safety trials, no benefit or problems were identified when spironolactone was used at a higher dose of 4mg/kg9, so when used as a combination tablet the dose of benazepril may dictate tablet size selection. The tablet should be given with food and the once-daily dosing recommendation makes correct administration considerably easier for some pet owners.
It is really important that vets are up to date on advice regarding MMVD: it is found in around 10% of dogs and represents 75% of canine cardiac disease. The past few years have seen significant changes – particularly following the QUEST10, Bernay1 and EPIC11 studies.
Consensus exists on the large part of use of drugs for treatment of CHF, although room exists for variable opinion in other aspects of management. These are summarised in the 2009 ACVIM consensus statement12 and recently updated in the 2019 ACVIM4 consensus statement on treatment of MMVD.
Consensus exists that dogs in stages A (predisposed) and B1 (MMVD, but no cardiomegaly) do not warrant medication.
The updated ACVIM recommendations4 showed consensus that strong evidence exists that dogs in B2 (asymptomatic MVD with cardiomegaly) require pimobendan. The 2019 update further defined B2 cardiomegaly to be when echocardiographic evidence exists of an LA:Ao of greater than 1.6 and bodyweight normalised left ventricular dimension13 of greater than 1.7.
Some cardiologists on the ACVIM panel also use ACEi in B2 dogs. Some cardiologists see a rationale for spironolactone based on a pilot study2, with the results of the DELAY study3 not being published at the time of the last ACVIM consensus statement.
Dogs are defined as reaching stage C at the onset of CHF. This can be defined by a raised sleeping respiratory rate (SRR)13 and a radiographic evidence of a hilar interstitial or alveolar pattern. Consensus existed on the ACVIM panel4 for the need for furosemide, pimobendan, ACEi and spironolactone for chronic treatment at this stage of disease.
Subsequent evidence of favour of spironolactone for dogs in CHF has come from the larger scale Benazepril Spironolactone Study14. Published after the past ACVIM guidelines, this trial looked at the potential benefit to dogs in CHF of adding spironolactone to “standard” treatment of furosemide and an ACEi (benazepril, although “standard therapy” in this study excluded pimobendan).
In the 569 dogs initially enrolled, a 44% reduction occurred in the odds of reaching the primary endpoint of cardiac death euthanasia or treatment failure in the group receiving spironolactone as opposed to placebo (OR = 0.56; 95% CI, 0.32 to 0.98; P = .04).
The ACVIM panel recommended furosemide, pimobendan, ACEi and spironolactone for stage D dogs. For these severe refractory cases, some panellists add a range of additional treatments depending on the details of the individual case, such as sildenafil for pulmonary hypertension or digoxin to slow persistent sinus tachycardia.
The authors routinely use spironolactone in MMVD stage C and D. Usually they use the combination tablet because compliance is so important in ensuring the patient receives the correct medication and it is a once-daily palatable tablet given with food.
Cost is always part of the balance to be struck when managing our patients. However, we should always offer what we regarded as optimum treatment and allow owners to choose.
In smaller-breed dogs, often it is not just the drugs that are the large part of the cost – but reduced revisits make treatment less expensive and this is usually preferred by owners (and their dogs).
Owners who are educated about their pets’ disease by their vets are often more favourable towards the use of the “quadruple therapy” – the combination of spironolactone, pimobendan, ACEi and furosemide (shortened to “SPAF” by some cardiologists).
Postponing ACEi or spironolactone serves little purpose: these drugs have long-term benefit and so starting them at the onset of CHF (the time of maximal neurohormonal activation) is the most rational approach. It is important to note that these drugs work over months and years, and so benefits will not be seen immediately.
Successful management of patients with MMVD relies on good owner compliance. It is easy for clinicians to spend a lot of time on diagnostic testing and formulating a treatment plan without fully explaining to a client why this plan has been adopted. This can lead to problems with medication compliance.
Compliance can be divided into adherence (which means following dose and timing instructions) and persistence (which is continuing to give the medication over time).
Vets often assume that their clients follow instructions to the letter. However, many owners find medicating their pet difficult and stressful, and may struggle to be able to dose as recommended. Some owners assume that the quantity they have been given is a “full course”, not a pragmatic choice of quantity to dispense.
It is important to explain that dogs with CHF due to MMVD are going to require twice-daily treatment every day for the rest of their lives. Sometimes, vets choose too low a drug dose to save the client money. Some fail to explain how the timing of dosing in relation to feeding can be important, or why a drug should be give once, twice or more times daily.
Appropriate consulting time should be given to explain these issues to worried owners who will be dosing and monitoring their pet often for years. Improving a client’s understanding of their pet’s condition is one of the cornerstones of successful CHF management.
Combined drugs can aid compliance. The combination product contains benazepril and spironolactone in one tablet, acting as “dual blockade” of the renin angiotensin aldosterone system (RAAS) and is flavoured to aid compliance. If an animal is to have both spironolactone and ACEi – which is entirely logical – the combination drug is cheaper and improves compliance; a “win-win”.
Both a pragmatic and a psychological effect exists for some owners, who may feel that their dog is receiving “too many tablets”. Some owners even elect euthanasia because they are overcome with the stress of multiple medications for an animal that may be reluctant to take them. Failure to medicate an uncooperative pet can be extremely stressful for even the most dedicated owners.
Vets also need to allow pragmatic choices and discuss the issues of dosing. For example, when choosing the timing of dosing of diuretics, consider the household effect of lost sleep to let a dog out to urinate in the middle of the night or finding that their pet has urinated in the house – sometimes night after night.
Drug absorption is affected by feeding, with some drugs having improved absorption and others reduced absorption. Owners need to be coached on when to deliver drugs in relation to meal times.
We sometimes find vets have held a drug back when it is indicated to “have something up their sleeve”. This is a matter of owner management not clinical indication – clear evidence exists of using spironolactone in all MMVD class C cases, for example.
When patients with CHF become refractory to standard therapy, increasing the dose of loop diuretic or changing loop diuretic is usually the best strategy. Adding in drugs that primarily counteract the effects of RAAS activation (ACEi, spironolactone) at this late stage is probably a case of “too little, too late”.
Teaching clients to monitor resting respiratory rate is the best way to monitor patients’ heart disease outside the clinic. Successful therapy results in stable SRR (mean) of less than 30 breaths per minute at home13.
Owners can be advised to monitor their dogs’ SRR at regular intervals using the combination product’s app. Clinicians can use this data to help determine control of CHF. SRR is more sensitive for detection of CHF than radiography (that is, SRR increases before radiographic changes are evident) although it is less specific (other reasons exist for a raised respiratory rate, so further assessment as to the cause may be required).
Ongoing management of stage C and D dogs largely depends on a blend of SRR and blood results looking for azotaemia and electrolyte disorders. Many of these C/D patients do not need extensive imaging to manage them, just good observation of SRR and other clinical signs such as exercise tolerance, appetite and thirst. A persistently raised SRR will likely prompt an increase in loop diuretic dose.
Strong EBM support exists for the use of furosemide, pimobendan, an ACEi and spironolactone for dogs with CHF due to MMVD (ACVIM stage C and D disease). Identification of these dogs relies on noting evidence of MMVD and clinical signs of CHF.
Strong EBM support exists for the use of pimobendan in dogs with cardiomegaly due to MMVD before the development of CHF (ACVIM B2 disease). Identification of these dogs relies on proactive echocardiographic screening in dogs with a grade 3/6 or louder murmur before they develop any clinical signs – usually before the owner seeks treatment.
A theoretical basis exists for the benefit of ACEis in stage B2 disease, which has not been supported in clinical trials. However, some clinicians on the ACVIM consensus statement panel still recommend their use at this stage.
A sound theoretical basis exists for the benefit of spironolactone in stage B2 disease, but, as yet, no clinical trial results support this. Some clinicians on the ACVIM consensus statement panel recommend spironolactone in stage B2 disease, although the DELAY trial was published after the ACVIM consensus.
Compliance remains one of the key hurdles to successful CHF management. Vets should spend appropriate time to explain to owners why drugs are chosen and the rationale for the dose and administration recommendations. Clients who have been trained in observing SRR and in giving medication are more likely to be compliant and persistent in following recommendations – to the benefit of their patient.
Vets should understand the practical limitations including cost, timing of medication and the hazards of pets that refuse to take tablets. Combination drugs can have some benefit in reducing cost and aiding compliance and persistence.
Anna Beber
Job TitleMark Patteson
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