This article reviews medications to consider when standard therapy is not enough to control signs of congestive heart failure in dogs. Some of these medications are currently used in conjunction with diuretics, pimobendan, angiotensin-converting enzyme inhibitors, and spironolactone for dogs with refractory heart failure, either in the emergent setting or for chronic heart failure control. Others are relatively new to veterinary medicine and, with more research, have the potential to be incorporated into canine heart failure management in the future.
Take-Home Points
- Several medical approaches exist to address refractory congestive heart failure (CHF) in dogs.
- The diuretic regimen can be modified by replacing furosemide with torsemide or by adding hydrochlorothiazide or acetazolamide to achieve sequential nephron blockade.
- Afterload-reducing medications can help improve forward flow (especially in dogs with degenerative mitral valve disease), which can improve CHF control and reduce diuretic requirements.
- Other neurohormone-modulating medications such as angiotensin receptor blockers and sacubitril/valsartan are less commonly used for CHF control than angiotensin-converting enzyme inhibitors; however, these drugs have the potential to become part of standard CHF therapy in the future.
- Some medication classes (e.g., sodium–glucose cotransporter-2 inhibitors) might be used in dogs in the future when more data become available.
Despite appropriate medical therapy, the underlying pathologic process of degenerative mitral valve disease (DMVD) and dilated cardiomyopathy (DCM) often continues unchecked, leading to worsening congestive heart failure (CHF), worsening renal function, or sudden death. Innovative approaches such as gene therapy, transcatheter edge-to-edge repair, or surgical mitral valve repair offer a more definitive approach to addressing the underlying disease. However, these new treatments are not widely available; therefore, understanding the role of adjunct medications in treating recurrent or refractory CHF in the general practice setting is important.
An individualized approach to medically managing CHF patients that are already receiving standard-of-care medications (e.g., loop diuretic, pimobendan, angiotensin-converting enzyme inhibitor [ACEI], spironolactone) can extend quality and quantity of life by tailoring additional medications to clinical need.1 This article presents less commonly used medications to treat heart disease and introduces emerging therapies that hold promise for treating refractory CHF in dogs. It is worth noting that none of these therapies have been approved by the U.S. Food and Drug Administration (FDA) for the discussed clinical indications.
For more information on standard-of-care medications to treat CHF in dogs, see “Standard Medical Therapies for Preclinical Heart Disease and Congestive Heart Failure in Dogs” in the September/October 2023 issue of Today’s Veterinary Practice.
Oral Medications
Torsemide
Manufacturer: Various
Mechanism of action: Torsemide binds to the Na+–K+–2Cl– cotransporter in the loop of Henle, preventing electrolyte resorption and subsequently water resorption, thereby causing natriuresis and diuresis. It is more potent (10 to 20 times) and longer-lasting (12 to 24 hours) than furosemide. Unlike furosemide, torsemide has consistently high bioavailability (90%).2
Cardiac indications and clinical use: Torsemide is most commonly used to treat refractory CHF (stage D) when furosemide is no longer efficacious at controlling the patient’s CHF signs.1 The authors use torsemide instead of furosemide as first-intention therapy for dogs with right-sided CHF due to its more consistent bioavailability than furosemide, even when systemic congestion with gastrointestinal edema might interfere with drug absorption.3
Administration: Dosing and dosage adjustments are challenging for small patients because the smallest tablet size is 5 mg. Compounding torsemide into suspension allows for fine dosage adjustments, which is essential to minimize the risk of dehydration and electrolyte derangements. Compounding should follow published recommendations to ensure drug stability.4
The dosage for first-intention administration is 0.15 to 0.2 mg/kg PO q12h. A conversion ratio of 1:15 is reasonable when transitioning a patient from furosemide to torsemide; however, if the patient is receiving high doses (e.g., >8 mg/kg/day) of furosemide at the time of transition, a 1:20 conversion ratio is preferred.2 Dosage adjustments are commonly needed with any diuretic, but especially with torsemide.
Key clinical data: Two clinical studies demonstrated noninferiority of torsemide compared with furosemide for short-term (3-month) cardiac outcomes.5,6
Monitoring: As with most diuretics, and because torsemide is highly potent, it is important to recheck serum biochemistry values (blood urea nitrogen, creatinine, sodium, potassium, chloride), blood pressure, and CHF control 1 to 2 weeks after dose initiation and then regularly thereafter.
Side effects: Dehydration, azotemia, and electrolyte imbalances can occur with torsemide. Volume and electrolyte depletion can manifest as lethargy, weakness, and anorexia.
Amlodipine (Norvasc)
Manufacturer: Pfizer (pfizer.com)
Mechanism of action: Amlodipine decreases blood pressure by inducing smooth muscle relaxation and vasodilation. It achieves this by blocking voltage-dependent L-type calcium channels, thereby inhibiting influx of calcium, decreasing vascular smooth muscle contractility, and increasing smooth muscle relaxation.
Cardiac indications and clinical use: Amlodipine is commonly used for management of systemic hypertension in dogs. In patients with advanced DMVD or DCM and high-normal or elevated systemic blood pressure, the authors commonly consider afterload reduction with amlodipine. Amlodipine has a relatively slow onset of action; therefore, for patients with acute CHF in need of rapid afterload reduction, other agents such as nitroprusside could be used.
Administration: The authors start at 0.1 mg/kg PO q24h titrated to effect. Twice-daily dosing is often necessary for dogs with severe hypertension (>180 mm Hg). A 10– to 20–mm Hg drop in blood pressure is targeted when amlodipine is used for afterload reduction in a normotensive patient with severe mitral regurgitation.
Key clinical data: Amlodipine was shown to decrease mitral regurgitation fraction and left atrial size in 2 different clinical studies.7,8 Amlodipine activates the renin-angiotensin-aldosterone system (RAAS) in healthy dogs (albeit at higher doses than used clinically); hence, concurrent therapy with an ACEI could be indicated.9 Supportive of this was a study showing that cats with systemic hypertension exhibited RAAS activation when treated with amlodipine but not in the untreated, hypertensive state.10
Monitoring: Systemic blood pressure measurement 10 to 14 days after starting amlodipine is recommended.
Side effects: Amlodipine can cause gastrointestinal signs as well as hypotension. Reversible gingival hyperplasia can occur with long-term use.
Angiotensin II Receptor Blockers
Manufacturer: Various
Mechanism of action: Angiotensin II receptor blockers (ARBs), such as telmisartan, competitively inhibit the angiotensin receptor type that interacts with angiotensin II (Ang II). By blocking the action of Ang II, they reduce vasoconstriction, sodium retention, aldosterone production, and inflammation.
Cardiac indications and clinical use: ARBs could be used instead of ACEIs for the treatment of canine CHF, but they are not widely used for this purpose. ARBs are used for the adjunctive treatment of systemic hypertension and proteinuria in both dogs and cats.
Administration: The authors most commonly use telmisartan at a dose of 1 mg/kg PO q24h.
Key clinical data: A small clinical study found higher concentrations of angiotensin-(1–7) (which has vasodilatory, natriuretic, and cardioprotective effects) in dogs with DMVD treated with ARBs compared to those treated with ACEIs, but there are no large studies evaluating ARB efficacy in dogs with CHF.11
Monitoring: Select serum biochemical variables (blood urea nitrogen, creatinine, sodium, potassium, chloride) should be evaluated before treatment, 1 to 2 weeks after initiation of therapy, and periodically thereafter or as dictated clinically. ARBs can cause hyperkalemia, although this occurs infrequently, especially with concurrent diuretic use. Blood pressure monitoring should ideally be performed at each recheck.
Side effects: Adverse effects are uncommon but can include gastrointestinal upset, weakness, or lethargy. ARBs are generally well tolerated, but bloodwork and blood pressure monitoring are indicated to monitor for azotemia, hyperkalemia, and hypotension. ARB administration in patients that are highly dependent on Ang II for maintenance of renal function (e.g., dogs with hypotension, hyponatremia, volume depletion) risks functional azotemia, which is why these drugs are not used for treatment of acute CHF.
Hydrochlorothiazide
Mechanism of action: Hydrochlorothiazide inhibits sodium resorption at the Na+–Cl– exchanger in the distal renal tubule to cause natriuresis and subsequent diuresis. It is a less effective diuretic than loop diuretics because a smaller percentage of sodium is resorbed at this location. However, it appears to restore diuresis in some dogs with refractory CHF when used in combination with loop diuretics (sequential nephron blockade).
Cardiac indications and clinical use: Hydrochlorothiazide is used in addition to standard therapy, including loop diuretics, to treat refractory CHF.
Administration: The authors use a very low dosage of 0.5 mg/kg PO q24h when adding hydrochlorothiazide to standard CHF medication due to the risk of dehydration. The dose can be titrated up to 2 mg/kg q12h if needed.
Key clinical data: No prospective studies of hydrochlorothiazide in dogs with CHF have been published. One retrospective study documented reductions in echocardiographic dimensions and worsening renal function in a small number of dogs when hydrochlorothiazide was added to other CHF medications.12
Monitoring: As with most diuretics, it is important to recheck serum biochemistry values (blood urea nitrogen, creatinine, sodium, potassium, chloride), blood pressure, and CHF control 1 to 2 weeks after dose initiation and then regularly thereafter.
Side effects: Dehydration, azotemia, and electrolyte imbalances can occur with hydrochlorothiazide use. Volume and electrolyte depletion can manifest as lethargy, weakness, and anorexia.
Acetazolamide
Manufacturer: Various
Mechanism of action: Acetazolamide is a carbonic anhydrase inhibitor that increases urinary sodium and bicarbonate excretion and facilitates hydrogen ion and chloride reabsorption in the proximal convoluted tubule. Water follows sodium loss in the urine, resulting in diuresis. Hydrogen ion reabsorption promotes acidosis. Acetazolamide may also have antidiuretic hormone–antagonizing properties, but this has not been studied in dogs.13
Cardiac indications and clinical use: The authors consider adding acetazolamide to standard therapy for refractory CHF, especially when hypochloremic metabolic alkalosis is present. Acetazolamide is not commonly used to treat CHF in dogs because it is a weak diuretic due to its proximal tubular site of action; however, efficacy in humans with acute CHF has recently been reported.14 Efficacy might be greater when combined with a loop diuretic because it provides more sodium in tubular fluid for water to follow. Acetazolamide can correct hypochloremic metabolic alkalosis associated with loop diuretic treatment of CHF, which might restore diuretic responsiveness.
Administration: The authors use acetazolamide at a dosage of 5 to 7 mg/kg PO q12h, but dosing studies have not been reported.
Key clinical data: No studies of acetazolamide use for CHF in dogs are available. One case report describes its use for refractory CHF.15
Side effects: The adverse effect profile of acetazolamide is similar to that of other diuretics in that it can cause dehydration and azotemia. Acetazolamide can also cause gastrointestinal upset. Because it promotes bicarbonate excretion, it has the potential to cause metabolic acidosis, which can manifest as deep, labored respirations (Kussmaul respiration).
Sacubitril/Valsartan (Entresto)
Manufacturer: Novartis (entresto.com)
Mechanism of action: Entresto is a combination of an ARB (valsartan) and neutral endopeptidase (NEP) inhibitor (sacubitril). The NEP enzyme cleaves natriuretic peptides that are released by the atrial and ventricular myocytes in response to increased stretch, thereby promoting diuresis and natriuresis and counteracting maladaptive RAAS effects. Inhibition of NEP reduces natriuretic peptide degradation. (See Angiotensin II Receptor Blockers for further information on valsartan’s mechanism of action.)
Cardiac indications and clinical use: Sacubitril/valsartan is used by some cardiologists instead of ACEIs for management of refractory CHF.
Administration: A dosage of 20 mg/kg PO q12h has been used in clinical studies,16,17 but the authors recommend a starting dosage in the range of 5 to 10 mg/kg PO q12h.
Key clinical data: One study showed lower urine aldosterone concentrations and no adverse effects in dogs with preclinical DMVD (stage B2) that received sacubitril/valsartan for 30 days.16 Another study found significant reverse myocardial remodeling in dogs with DMVD/CHF that received sacubitril/valsartan concurrently with pimobendan and furosemide compared with dogs receiving pimobendan, furosemide, and ramipril for a 4-week period.17
Monitoring: Monitoring serum chemistry and blood pressure is recommended in patients receiving sacubitril/valsartan.
Side effects: No adverse effects were found during the aforementioned clinical studies; however, as with other RAAS inhibitors, periodic blood analysis should be performed to monitor for side effects such as azotemia and electrolyte disturbances (specifically hyperkalemia).
Sodium–Glucose Cotransporter-2 Inhibitors
Mechanism of action: Sodium–glucose cotransporter-2 (SGLT2) inhibitors (e.g., dapagliflozin) block glucose and sodium resorption in the proximal convoluted tubule of the nephron. They were developed as antidiabetic medications but were later found to have significant cardioprotective effects through poorly understood mechanisms.18 They cause natriuresis, which results in modest diuresis.19
Cardiac indications and clinical use: Bexagliflozin (Bexacat; Elanco, elanco.com) is FDA approved for treatment of diabetes in cats,20 but there are no clinical reports of the use of SGLT2 inhibitors for CHF treatment in dogs or cats.
Key clinical data: No studies of SGLT2 inhibitors in dogs have been reported. In humans, SGLT2 inhibitors are strongly recommended for the treatment of heart failure with reduced ejection fraction, even in patients who are not diabetic; however, their clinical benefits at higher ejection fractions are less well established, and the mechanisms of benefit are not well understood.
Side effects: Excess glucose excretion into the urine might predispose to urinary tract infections. Increased urine output should be expected.19
Vaptans
Manufacturer: Various
Mechanism of action: Vaptans (e.g., tolvaptan) block the action of vasopressin (also known as antidiuretic hormone) at the vasopressin 2 receptor in the collecting duct of the nephron. Inhibition of this receptor causes aquaresis without electrolyte loss.
Cardiac indications and clinical use: Vaptans might be indicated for clinical situations in which relative free water excess is present (e.g., hyponatremia associated with CHF or with syndrome of inappropriate antidiuretic hormone secretion).
Administration: The authors have used 2 to 3 mg/kg PO q12h in dogs based on 2 studies.21,22 Long-term use of vaptans is prohibitively expensive in dogs.
Key clinical data: No clinical studies of vaptan use have been published in dogs.
Monitoring and side effects: Serum sodium concentrations must be closely monitored after starting vaptans to avoid neurologic abnormalities (e.g., obtundation, seizures) associated with a rapid rise in serum sodium.23 In the authors’ limited experience, the increase in serum sodium has occurred slowly over days.
Non-Oral Medications
Dobutamine
Manufacturer: Pfizer (pfizer.com)
Mechanism of action: Dobutamine stimulates the β1 adrenergic receptors within the myocardium, which results in increased levels of cyclic adenosine monophosphate, increased intracellular calcium concentrations, and subsequent increased cardiac contractility and stroke volume. In addition to positive inotropy, dobutamine has unwanted side effects, such as increases in heart rate and peripheral vasoconstriction, when used at higher doses. The peripheral vasoconstriction is mediated by activation of α1 receptors.
Cardiac indications and clinical use: Dobutamine is indicated for acute management of severe or refractory CHF, especially in hypotensive patients.1 Dopamine could be used in the treatment of acute CHF; however, undesirable tachycardia and vasoconstriction can be more pronounced than with dobutamine, and dopamine is used more commonly in the treatment of hypotension.24
Administration: The authors administer dobutamine as a constant-rate infusion starting at 2.5 µg/kg/min and titrating up to achieve a systemic blood pressure greater than 90 mm Hg with improved perfusion parameters. Because downregulation of β receptors occurs rapidly, the authors limit use of dobutamine to less than 48 hours.25
Key clinical data: Dobutamine has been shown to improve systolic function and cardiac output in multiple studies.26,27
Monitoring: Blood pressure, heart rate, and heart rhythm should be closely monitored.
Side effects: Adverse effects include facial twitching and arrhythmias, especially at higher dosages (>10 µg/kg/min). Patients with concurrent atrial fibrillation could experience higher heart rates with dobutamine.
Sodium Nitroprusside (Nitropress)
Manufacturer: Pfizer (pfizer.com)
Mechanism of action: Nitroprusside is a potent arteriolar and venous vasodilator and is considered both a preload and afterload reducer. Nitroprusside produces nitric oxide, which activates guanylate cyclase, causing an increase in cyclic guanosine monophosphate concentrations and resulting in vascular relaxation. Nitroprusside has a rapid onset and duration of action.
Cardiac indications and clinical use: Nitroprusside is used in patients with acute, severe, or refractory left-sided CHF. Nitroprusside can also be used for treatment of systemic hypertension.
Administration: The authors use a constant-rate infusion starting at 0.5 to 1 µg/kg/min and titrating up every 15 minutes to achieve a desired systemic arterial systolic blood pressure (typically a 20–mm Hg drop without going below 90 to 100 mm Hg). The authors use a maximum dose of 5 to 10 µg/kg/min and usually limit infusions to less than 24 to 48 hours to avoid cyanide toxicity.28 Nitroprusside needs to be diluted and protected from light.
Key clinical data: In a study using a canine model of CHF, nitroprusside at 3 µg/kg/min significantly decreased pulmonary wedge pressure and systemic vascular resistance with no effect on cardiac output.27 A recent study evaluated the efficacy of nitroprusside as monotherapy in dogs with left-sided CHF.29 Dogs treated solely with nitroprusside had a significant reduction in respiratory rate within 24 hours of treatment. Although the authors do not use nitroprusside as sole therapy for CHF, these results emphasize the importance of preload and afterload reduction in CHF management.29
Monitoring: Arterial blood pressure monitoring is recommended to guide appropriate dosing. Although direct monitoring through an arterial line is preferable, this is not always practical in dyspneic patients, and indirect monitoring is acceptable. Additionally, serum electrolytes, acid–base status, and oxygen levels should be monitored, particularly if high doses are used.
Side effects: Nitroprusside can cause hypotension if titrated too quickly. Prolonged use at high doses can lead to cyanide or thiocyanate toxicity, especially in patients with renal dysfunction, liver dysfunction, or hyponatremia.28
Nitroglycerin 2% Ointment (Nitro-Bid)
Manufacturer: Fougera Pharmaceuticals (us.sandoz.com/fougera)
Mechanism of action: Nitroglycerin’s mechanism of action is similar to that of nitroprusside. However, although high doses can induce arterial vasodilation and afterload reduction, nitroglycerin is considered primarily a preload reducer due to the predominant effect of venodilation.
Cardiac indications and clinical use: Nitroglycerin is used to treat acute CHF. Venodilation causes pooling of blood in the splanchnic vasculature and away from the lungs, thus reducing pulmonary venous pressure.
Administration: A dose of 0.5 inch of ointment per 10 kg of patient body weight is applied every 6 to 12 hours in the inner pinnae, rotating application sites.1 Wearing gloves while applying the medication and thereafter when handling the patient is imperative to avoid inadvertent absorption. The site of application can be covered and labeled with a self-adhesive bandage wrap. The authors do not continue treatment after 24 hours from the initial application given the rapid development of tolerance to nitroglycerin in dogs.
Key clinical data: Transdermal nitroglycerin caused splenic dilation (as a surrogate for peripheral venous blood pooling) without increasing splenic venous pressures in a study of anesthetized healthy dogs.30 Rapid tolerance to nitrates limits use to a few days. Although the clinical efficacy of nitroglycerin ointment has been questioned, transdermal administration makes it simple to use.
Monitoring and side effects: Although nitroglycerin ointment primarily causes venodilation, it is still prudent to monitor blood pressure. The skin at the application site should also be monitored.
Summary
Even though many dogs with CHF respond well to standard medical therapy, additional therapies are often needed as disease progresses. Therapies discussed in this article target contractility, preload, afterload, or RAAS inhibition, with the goal of either increasing forward stroke volume or decreasing left atrial pressures. Some are implemented for decongestion during acute CHF; others are added to standard therapy for chronic CHF management. Newer therapies may become standard of care for dogs with CHF as more data become available.
References
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30. Parameswaran N, Hamlin RL, Nakayama T, Rao SS. Increased splenic capacity in response to transdermal application of nitroglycerine in the dog. J Vet Intern Med. 1999;13(1):44-46.