April 17, 2014


CLINICAL CARDIOLOGY CONCEPTS
for the dog and cat

Michael R. O'Grady, DVM, MSc, Diplomate ACVIM (Cardiology)
M. Lynne O'Sullivan, DVM, DVSc, Diplomate ACVIM (Cardiology)

General Therapeutic Concepts

Therapy of Heart Failure


1 What Are Some General Considerations in the Therapy of Heart Failure?

The Goals of all Therapy should be:

  • Reverse the cause of heart failure
  • Identify and correct any precipitating cause of heart failure
  • Extend the quality of life (ameliorate distressing clinical signs and reduce the risk of morbid events)
  • Extend survival
  • When owners present their pets with congestive heart failure, they want to know:

  • Is this a fatal disorder?
  • If it is fatal how long will their pet live?
  • Will he/she suffer?
  • How will they know he/she is suffering?
  • If they have to consider euthanasia, how will they know when it is time to euthanize their pet?
  • The answers to these questions begin with an accurate diagnosis. Congestive heart failure is not a diagnosis, just like diarrhea is not a diagnosis – they are but clinical signs. The prognosis and response to therapy for both quality of life and length of life depend on an accurate diagnosis; just as with diarrhea the prognosis and response to therapy depend on the diagnosis of the cause of the diarrhea. Thus, we need to determine the cause of congestive heart failure.

    The ideal approach to improving quality of life and survival is to repair the primary abnormality such as make the heart stronger if weak, or fill better if indistensible, or repair the leak if mitral or aortic valve insufficiency is present. Since we cannot usually accomplish these goals, we rely on two approaches to management:

  • Apply therapies to improve hemodynamic performance
  • Modify vascular volume
  • The subsequent sections will address specific efforts to identify therapies that attempt to improve the performance of the heart and circulatory system.

    I wish to address the issue of therapy to modify vascular volume. The management of most cases of congestive heart failure, regardless of cause, involves an attempt to plot a management path between excessive fluid in the vasculature and reduced fluid in the vasculature. Excessive fluid in the vasculature, on the positive side, promotes an increase in cardiac output with enhancement of renal, GI, and skeletal muscle function. On the negative side, excessive fluid in the vasculature promotes pulmonary congestion with respiratory difficulties. Reduced fluid in the vasculature has a positive impact when it promotes a reduction in pulmonary congestion and the accompanying respiratory problems. However, reduced fluid in the vasculature also causes a reduction in cardiac output that will result in reduced renal, GI, and skeletal muscle function. Thus our therapeutic path attempts to find the ideal level of vascular fluid that falls between our two objectives, to promote an increase in cardiac output and to reduce pulmonary vascular volume. To remain on this path one needs to frequently “tweak” the level of medication. Our approach to these patients is to assess pulmonary congestion, via history, auscultation, and chest radiographs, and renal function and electrolyte status, especially potassium, with every examination. Our goal is to find the least dose of total diuretic that will maintain ease of breathing. This least dose will usually not result in completely clearing the lungs of congestion but should maximize the cardiac output. To use more diuretic than that required to maintain ease of breathing, such as to “really” clear the lungs, will cause an unnecessary and potentially harmful reduction of renal function.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    2 How is the Response to Heart Failure like that of Shock?

    The body responds to all situations that cause a fall in blood pressure (BP) as if there was one and only one cause for this reduction in BP. This response is as if all causes for a fall in BP are due to a loss in preload (as if due to loss of blood due to trauma).

    Response to Shock:

  • Activation of the Sympathetic Nervous System:
    • Increase in contractility: causing an increase in stroke volume and thereby BP.
    • Increase in heart rate: causing an increase in cardiac output and thereby BP.
    • Increase in arterial vasomotor tone: causing an increase in arterial resistance (afterload) and thereby BP.
    • Increase in venomotor tone: causing an increase in preload and thereby stroke volume.

  • Activation of the Renin Angiotensin Aldosterone System:
    • Increase in angiotensin II: causing arterial vasoconstriction resulting in an increase in arterial resistance and thereby BP.
    • Increase in aldosterone: causing water retention and thereby preload.

  • Activation of Arginine Vasopressin (ADH):
    • Increase in arterial vasoconstriction resulting in an in increase arterial resistance and thereby BP.
    • Increase in water retention and thereby preload.

    Comment: This response to a reduction in preload serves to raise BP. Note that the duration of shock is generally measured in hours. Shock is a disorder that is not intended to last days, months, and years.

    Response to Heart Failure: (BP falls as with shock but is persistently reduced for days to years, thus the shock response is active for days to years).

  • Activation of the Sympathetic Nervous System:
    • Increase in contractility: In people all therapies that function to increase contractility (positive inotropes) have failed to increase survival and quality of life. This occurs likely due to the increase in myocardial oxygen demand (MVO2) that exceeds the increase in coronary blood supply.
    • Increase in heart rate: A sustained increase in heart rate has been demonstrated to exacerbate heart failure. The increase in heart rate causes an increase in MVO2, reduces the time for ventricular filling (diastole), and reduces the time of coronary blood flow (diastole).
    • Increase in arterial vasomotor tone: causing an increase in arterial resistance (afterload). Increases in afterload reduce stroke volume and increase MVO2.
    • Increase in venomotor tone: causing an increase in preload. The increase in preload exacerbates existing pulmonary edema.
    • Promotes arrhythmias, both supraventricular and ventricular.
    • Promotes coronary vasospasm.
    • Induces myocardial necrosis.

  • Activation of the Renin Angiotensin Aldosterone System:
    • Increase in angiotensin II:
      • Increases arterial vasoconstriction resulting in an increase in arterial resistance (afterload). Increases in afterload reduce stroke volume and increase MVO2.
      • Induces myocardial necrosis.
    • Increase in aldosterone: causing water retention and thereby preload. The increase in preload exacerbates existing pulmonary edema.

  • Activation of Arginine Vasopressin (ADH):
    • Increase in arterial vasoconstriction resulting in an in increase arterial resistance. Increases in afterload reduce stroke volume and increase MVO2.
    • Increase in water retention and thereby preload. The increase in preload exacerbates existing pulmonary edema

    Comment: In the setting of heart failure these responses serve to exacerbate heart failure and are responsible for the relentless progression of the heart failure state. In people the only therapies (except for cardiac transplantation) that have been demonstrated to increase survival are therapies that blunt the "Shock" response. Specifically only beta blockers, ACE inhibitors, and aldosterone receptor blockers have increased survival.

  • top      General Therapeutic Concepts: Therapy of Heart Failure
    3 Outline the classes of drugs used to treat heart failure.

    The classes of drugs used to treat heart failure include:

    • diuretics
    • vasodilators
    • angiotensin converting enzyme inhibitors
    • positive inotropes
    • negative inotropes
    • negative chronotropes
    • antidysrhythmics (antiarrhythmics)
    • beta blockers
    • calcium channel blockers
    • aldosterone receptor blockers
    • angiotensin II receptor blockers
    • other investigational therapies: brain natriuretic peptide analogs, endothelin antagonists, vasopressin/ADH antagonists, anti-cytokine therapy

    Some of these classes are overlapping. It is important to consider the class of drug therapy most beneficial with each pathophysiologic state. Do not memorize the present day drugs but consider only the classes of drugs and then review the most current veterinary literature (i.e. Current Veterinary Therapy XXII if appropriate) and find the best representative drug of that class at the time.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    4 List common diuretics used to treat heart failure and list their advantages and disadvantages.

    Diuretic therapy:

    • Functions to reduce the fluid overload that occurs with heart failure. This will resolve pulmonary edema by reducing preload.
  • By reducing preload, diuretics also reduce ventricular volume (afterload).
  • Furosemide, the thiazides, and spironolactone are the most commonly employed diuretics in veterinary medicine.
  • Indications: Used only in the congestive heart failure stage of disease, that is, to reduce pulmonary edema, ascites, and/or pleural effusion.
  • Contraindications: Cardiac patients before the onset of CHF, cardiac tamponade.
  • Used with caution: In disorders with reduced renal function, prerenal azotemia, or forms of obstruction to blood flow (e.g. stenotic valve disease).
    • Furosemide blocks water resorption in the thick segment of the ascending loop of Henle
      • Potent diuretic
      • Although furosemide is known to cause significant hypokalemia in humans, hypokalemia is less common and less profound in dogs that are still eating.
      • Cats are prone to develop hypokalemia and metabolic alkalosis, particularly when given i.v.
      • Resistance / tolerance to furosemide has been described. It is the authors’ experience that doses of oral furosemide greater than 5 mg/kg TID PO have failed to increase diuresis.
      • Furosemide appears to also have venodilator properties that will also enhance its ability to reduce pulmonary edema.
      • Furosemide also appears to reduce cough presumably via some bronchodilating properties.

    • Thiazides block water resorption in the early distal convoluted tubules.
      • Potent diuretics
      • Mainly used to augment diuresis when added to furosemide
      • The authors add hydrochlorothiazide to furosemide when 5 mg/kg TID PO of the latter fails to increase diuresis and resolve respiratory signs
        • The combination induces profound diuresis
        • The authors recommend reducing the furosemide dose by 50% when hydrochlorothiazide is initiated
        • The authors recommend monitoring renal function at least twice weekly for the first 2 weeks to ensure renal function is not significantly adversely affected with the addition of hydrochlorothiazide.

    • Spironolactone (an aldosterone antagonist) functions in the late distal convoluted tubule and collecting ducts to promote the loss of Na+ and water into the nephron and conservation of K+.
      • Has received attention as a useful agent to add to patients already on furosemide in that this agent may offset the potassium losing potential of the furosemide.
      • In addition, the elevation of aldosterone is one of the key mechanisms in the progression of heart failure (causes myocardial fibrosis and remodeling, vascular fibrosis and endothelial dysfunction, and baroreceptor dysfunction), thus this class of drug may serve to direct therapy to the "heart" of one of the problems.
        • Spironolactone has been demonstrated in people with systolic heart failure (systolic dysfunction) to improve survival (RALES Trial). Veterinary clinical trials evaluating the effect of spironolactone on quality of life and survival in heart failure have been performed in Europe, however conclusions regarding efficacy await the publication of these results, which are expected in the near future.
      • A very weak diuretic
        • The authors have been disappointed with the efficacy of the addition of spironolactone to furosemide with respect to increasing total diuresis.

    The disadvantages to diuretic therapy are:

    • As preload falls, stroke volume falls; however, since the failing heart function curve is shifted to the right and downward, a sizeable reduction in preload (and therefore resolution of pulmonary edema) will cause only a small reduction in stroke volume. However, if stroke volume does fall to any extent, hypotension can occur (given that stroke volume is already very low in most cases of heart failure).
    • Diuretic therapy can cause hypovolemia, electrolyte imbalance (especially hypokalemia) and acid-base imbalance (particularly metabolic alkalosis). These effects may reduce the contractile performance of the heart and contribute to arrhythmias.
    • Diuretics now appear to be the most important cause of elevation of the renin-angiotensin-aldosterone system in patients in heart failure.

    Dosages:

    • Furosemide:
      • dog: 2-5 mg/kg BID-TID (IV, IM, SQ, PO); 1-2 mg/kg q 1h (IV) or 1-2 mg/kg/hour IV as a constant rate infusion in severe pulmonary edema
      • cat: 1-2 mg/kg BID-TID (PO, IM, IV) do not exceed 2 mg/kg (IV) as a bolus dose; 0.25-1 mg/kg/hour IV as a constant rate infusion in severe pulmonary edema
    • Hydrochlorthiazide
      • dog: 2-4 mg/kg BID (PO) when used alone; 1-2 mg/kg BID (PO) when used in combination with furosemide (along with reduction in furosemide by 50%)
      • cat: same as dog
    • Spironolactone
      • dog: 1-2 mg/kg BID (PO)
      • cat: same as dog

    Comment: The combined use of diuretics can have a profound effect on diuresis (such as use of furosemide and hydrochlorothiazide). Reduced doses of each diuretic are required when starting the combined drugs. The doses can be titrated on a daily basis, particularly while monitoring renal function, which can fall dramatically in a short period of time.

    Diuretics are an important class of drug in the management of heart failure. However they can cause considerable debilitation. One must strive to find the least dose required to achieve your goal. Frequent monitoring is required to ensure the least dose is achieved.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    5 List common venodilators used to treat heart failure and outline their advantages and disadvantages.

    Venodilator therapy reduces preload by trapping blood in the venous circulation

    • 70% of blood volume is contained in the venous circulation.
    • This effectively shifts blood from the central circulation (heart and lungs) into the peripheral circulation, reducing pulmonary edema.

    Advantages - rapidly reduces pulmonary edema. Also decreases myocardial oxygen consumption by reducing ventricular volume.

    Disadvantages - as preload is reduced, stroke volume falls. However, because the cardiac function curve for the failing heart is relatively flat (shifted downward and to the right), significant reductions in preload may produce only mild reductions in stroke volume. A marked reduction in preload with the subsequent reduction in stroke volume can cause severe hypotension, particularly in patients with an already reduced stroke volume.

  • Indications: Treatment of acute pulmonary edema due to congestive heart failure
  • Contraindications: Hypotension, cardiac tamponade

    Common venodilators are:

    • Nitroglycerin ointment
    • Isosorbide dinitrate
    • Isosorbide mononitrate

    Dosages:

    • Nitroglycerin Ointment 2%:
      • dog: small = 1/4-1/2 inch TID-QID (topically)
      • dog: large = 1/4-2 inch TID-QID (topically)
      • cat: 1/8-1/4 inch TID (topically)
    • Isosorbide dinitrate:
      • dog: 0.5-2.0 mg/kg BID (PO)
      • cat: undetermined
    • Isosorbide mononitrate:
      • dog: 0.25-2mg/kg BID (PO)
      • cat: undetermined

    Comment: Vasodilators are classified as:

    • purely venodilators
    • purely arterial vasodilators
    • mixed vasodilators

    While classified as so-called pure veno- or arterial vasodilators, all of these agents have some mixed vasodilator features while affecting primarily the venous or arterial tree, respectively.

    Comment: In people, tolerance develops to sustained nitrate therapy. Presumably, this may also occur in animals. To minimize this effect, use pulsed therapy with drug use for 12 hours, then none for the next 12 hours, then start again for 12 hours, and so on.

    Comment: Whenever vasodilator therapy is added to diuretic therapy the potential for hypotension is greatly increased.

  • top      General Therapeutic Concepts: Therapy of Heart Failure
    6 List common arteriolar dilators used to treat heart failure and outline their advantages and disadvantages.

    Arteriolar dilator therapy reduces afterload by reducing arterial vasomotor tone. This results in an increase in stroke volume and a reduction in MVO2 (myocardial oxygen consumption)(link). As stroke volume increases and more blood is moved forward, preload falls (resolves pulmonary edema). In addition, when cardiac output is increased, the compensatory measures that are detrimental in the long term are blunted (blunt or abolition of increased sympathetic tone), and by increasing coronary perfusion, hypoxia-induced dysrhythmias may be abolished.

    Advantages: Reduce afterload causing an increase in stroke volume, decrease in MVO2, and decrease in preload

    Disadvantages: May significantly reduce blood pressure causing hypotension; may cause a reflex tachycardia

    Indications: Symptomatic chronic mitral valve insufficiency (CMVI) or dilated cardiomyopathy (DCM), systemic hypertension.

    Contraindicated in: Valvular stenosis, hypertrophic cardiomyopathy, cardiac tamponade, hypotension

    Common arterial vasodilators:

    • Calcium channel blocker
      • amlodipine
    • Arterial smooth muscle relaxant
      • hydralazine
    • Alpha receptor blocker
      • acepromazine
      • prazosin
    • ACE inhibitor
      • enalapril
      • benazepril
      • ramipril
      • imidapril

    Dosages:

    • Amlodipine
      • dog: 0.05 - 0.2 mg/kg SID (PO)
      • cat: 0.625 mg per cat SID (PO)
    • Hydralazine
      • dog: 0.5-3 mg/kg BID (PO)
      • cat: 2.5 mg per cat SID-BID (PO)
    • Enalapril
      • dog: 0.5 mg/kg SID-BID (PO), usually BID
      • cat: 0.5 mg/kg SID (PO)
    • Benazepril
      • dog: 0.5 mg/kg SID-BID(PO), usually BID
      • cat: 0.25-0.5 mg/kg SID (PO)

      Note: Prazosin and ACE inhibitors are more balanced than pure arterial vasodilators.

    • ACE inhibitors are very weak arterial vasodilators. Because they are weak vasodilators, problems such as hypotension are uncommon with the initiation of ACE inhibitor therapy.
    • ACE inhibitor therapy has been demonstrated to be effective in the management of CMVI and DCM in dogs. It appears this benefit is not primarily due to arterial vasodilation but due to blockade of the RAAS system. Two distinct RAAS systems have been identified: A circulating RAAS system and a local tissue system. Benefit from ACE inhibition may occur due to blockade of both systems.
    • Hydralazine and amlodipine are potent arterial vasodilators.
      • These agents are not likely to be of benefit in the setting of CHF due to DCM. We believe ACE inhibition (blocking the Shock Response [Neurohumoral Response]) is the mechanism of benefit with ACE inhibitors and not arterial vasodilation itself.
      • These potent arterial vasodilators may be very useful to treat CHF due to CMVI.

    • Commencement of arterial vasodilator therapy:
      • Individuals may experience hypotension when vasodilator therapy is commenced.
        • This is particularly true of the potent arterial vasodilators, such as hydralazine and amlodipine, and much less likely with the weak arterial vasodilators, like ACE inhibitors. This may also be a concern when two or more arterial vasodilators are used concurrently or an arterial vasodilator is used with a diuretic.
      • Therefore we recommend a gradual increase in the dosage to maintenance levels with potent arterial vasodilators and intermittent monitoring of blood pressure to avoid hypotension. Start at about 1/3 maintenance dose for 4-5 days, then increase to about 2/3 maintenance dose for 4-5 days, and finally institute maintenance therapeutic dosage levels. Renal function should also be monitored in these situations.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    7 List common angiotensin converting enzyme inhibitors and outline their advantages and disadvantages.

    The 1990's were the decade of the ACE inhibitors in the area of cardiovascular therapeutics in people with heart failure. ACE inhibitors are important for their role in blocking the deleterious results of the maladaptive neurohumoral response that occurs in heart failure, that is the activation of the RAAS. ACE inhibitors block production of angiotensin II (potent arterial constrictor) and block production of aldosterone (which contributes to fluid overload), thereby causing vasodilation and reduction of fluid retention. Through both of these actions ACE inhibitors appear to delay the progression of heart failure. These agents have been demonstrated in people to reduce mortality in patients with CHF due to systolic dysfunction. In dogs with CHF due to chronic mitral valve insufficiency (CMVI), ACE inhibitors reduced mortality. In dogs with CHF due to DCM, several small studies have been less clear, whereas there is abundant evidence of efficacy in people with DCM (see below). There is evidence in dogs with pre-clinical (pre-CHF) DCM that ACE-inhibitors delay the onset of CHF.

    Disadvantages:

    Like all arterial vasodilators these drugs can induce arterial hypotension. Renal arterial hypotension may be the most common consequence causing a reduction in GFR (BUN/creatinine become elevated). ACE inhibitors can cause cough in people. Cough is rare in domestic animals.

    Indications: Symptomatic CMVI, symptomatic or asymptomatic DCM, systemic hypertension, CHF due to hypertrophic cardiomyopathy

    Contraindicated in: valvular stenosis, cardiac tamponade, hypotension

    ACE inhibitors:

    • enalapril
    • benazepril
    • imidapril
    • rampiril

    Dosages:

    • Enalapril
      • dog: 0.5 mg/kg SID-BID (PO), usually BID
      • cat: 0.5 mg/kg SID (PO)
    • Benazapril
      • dog: 0.5 mg/kg SID-BID(PO), usually BID
      • cat: 0.25-0.5 mg/kg SID (PO)
    • Imidapril
      • Follow package guidelines for dosing of reconstituted oral liquid

    Comment: Of the ACE inhibitors, enalapril, benazepril and imidapril have been approved to treat dogs with heart failure in Canada. Only enalapril is approved in the United States. Although the manufacturer for benazepril recommends once daily dosing, we believe a dose of 0.5 mg/kg BID is better. In addition, we dose enalapril at 0.5 mg/kg BID for our patients with heart failure.

    Comment: Benazepril undergoes less renal excretion than enalapril. In the setting of renal insufficiency, a common by-product of heart failure, less of the active compound will accumulate in the blood stream. At this time it is unclear that this represents a real advantage for benazepril.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    8 List combined vasodilators used to treat heart failure and outline their advantages and disadvantages.

    Mixed or combined vasodilators cause both venous and arterial vasodilation.

    Combined (mixed) vasodilators:

    • Prazosin (alpha receptor blocker)
    • ACE inhibitors

    Advantages:

    • Combined reductions of preload and afterload

    Disadvantages:

    • May reduce stroke volume/blood pressure excessively resulting in hypotension
    • This tends to occur if:
    • A large dosage is used.
    • A gradual increase in dosage to maintenance levels is not followed.
    • Combined with diuretics (vasodilator dosage must be monitored more carefully).
    • Patient is volume depleted.

    Indications: pulmonary edema, pleural or abdominal effusions, systemic hypertension

    Contraindications: valvular stenosis, cardiac tamponade, hypotension

    top      General Therapeutic Concepts: Therapy of Heart Failure
    9 How can drug induced hypotension be detected?

    When mean blood pressure is 60 mmHg or less, blood flow to renal, myocardial, and cerebral vascular beds is compromised. This refers to a critical level of hypotension. Any circumstance wherein blood pressure is reduced to less than a mean of 70 to 80 mmHg is hypotension that warrants attention.

    Clearly the best method to assess hypotension is to measure the arterial blood pressure. In that blood pressure is not always obtainable in small animals, we also resort to measuring the consequences of arterial hypotension. This involves assessing renal function (urea, creatinine) and attempting to determine if there is any reduction in renal function.

    Thus, when potent vasodilators such as hydralazine or amlodipine are used, either alone or in combination with other vasodilators or diuretics, urea and creatinine should be monitored 5 to 10 days after drug initiation, and then periodically thereafter, particularly prior to an increase in the dosage of the vasodilator or the diuretic.

    If urea and creatinine are elevated, the diuretic dose may be reduced first, as opposed to the ACE inhibitor or vasodilator dose. Recheck renal function in 5 days.

    Moderate to severe hypotension will require intravenous fluid therapy.

    Mild hypotension may be treated by merely reducing the dose of the diuretic agent and augmenting oral water intake.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    10 List positive inotropes used to treat heart failure and outline their advantages and disadvantages.

    Positive inotropic therapy functions to enhance contractility. These agents have been thought to be indicated when contractility is reduced (systolic dysfunction).

    Advantages: Increase in contractility shifts the cardiac function curve upward and to the left causing an increase in stroke volume for the same level of preload (link)

    Disadvantages:

    • Increase MVO2; pimobendan may be an exception
    • All of these agents are arrhythmogenic (especially catecholamines); whether pimobendan is an exception to this rule remains to be determined
    • Will exacerbate hypertrophic cardiomyopathy

    Indications: CHF secondary to CMVI (particularly when systolic dysfunction is present) or DCM

    Contraindicated in: hypertrophic cardiomyopathy, valvular stenosis, cardiac tamponade

    Modes of inducing positive inotropy:

    • Increasing intracellular cyclic AMP:
      • beta adrenergic receptor agonists
        • catecholamines, dopamine & dobutamine
      • phosphodiesterase inhibitors
        • theophylline
        • milrinone & amrinone (historic)
    • Increasing intracellular sodium:
      • digitalis
      • sodium channel enhancers (under investigation)
    • Drugs that enhance the sensitivity of the contractile proteins to calcium.
      • pimobendan
      • levosimendan
      • investigational agents

    Comments: Pimobendan is the only positive inotrope has been evaluated clinically in the dog. Pimobendan is approved for the treatment of congestive heart failure due to dilated cardiomyopathy and chronic mitral valve insufficiency in the dog.

    Agents:

    1. Pimobendan:

    • Mode of action: Positive inotrope and arterial vasodilator. Agents with this dual function have been termed inodilators.
      • Positive inotropic activity occurs due to:
        • Calcium sensitization
          • Positive inotrope response without the need to increase cytosolic calcium
          • Increased affinity of Tn-C for intracellular Ca
        • Phosphodiesterase III inhibition
          • Increase cAMP by reducing its breakdown
          • Increase cAMP increases Ca influx during phase 2 of the action potential, increases intracellular Ca
      • Arterial vasodilation:
        • Phosphodiesterase III and phosphodiesterase V inhibition
      • Phosphodiesterase V inhibition may be particularly useful to treat pulmonary artery hypertension
        • Other actions:
          • Increases appetite and other indices of well-being

        Dosages:

        • dog: 0.25 mg/kg BID on an empty stomach
        • cat: unknown

        Comment:

      • Whereas all the other positive inotropes are suspected to increase MVO2 in excess of the increase in O2 supply and thereby mediate the deleterious actions of these agents, pimobendan appears to be the exception. Thus pimobendan does not adversely affect MVO2.
      • As of 2009, the evidence in support of the ability of pimobendan to increase survival and quality of life for patients with CHF due to:
        • DCM is overwhelmingly supportive. See the University of Guelph DCM trial results below.
        • Chronic mitral valve insufficiency is also strongly supportive. See the QUEST trial results below.
        • Studies investigating the use of pimobendan in asymptomatic (occult) CMVI or DCM are currently ongoing or being planned. Thus there is currently no data to support the use of pimobendan in occult (pre-CHF) CMVI or DCM.

    2. Digitalis (digoxin)

    • Mode of action:
      • Inhibits the Na/K ATPase pump. This inhibits Na from leaving the cell via this pump. Na utilizes the Na/Ca exchange mechanism to enable Na to exit the cell however in return Ca enters the cell. The increase in cytosolic Ca promotes a positive inotropic response.
      • Digoxin is a weak positive inotrope
    • Also effective to slow HR associated with sinus tachycardia, atrial fibrillation, or supraventricular arrhythmias
    • Digitalis may promote all forms of dysrhythmias and potentiate ventricular dysrhythmias in particular
    • Digoxin has a very long half-life, about 30 hours in the dog and 20 hours in the cat. Therefore it takes a long time to reach steady state plasma levels and it takes a long time to remove digoxin from the body in states of toxicity
    • Digitalis toxicity:
      • Can be monitored clinically
        • Causes vomiting, diarrhea, anorexia
      • Can be monitored by blood sample
        • a serum level of > 2.5 ng/ml or 2.0 nmol/l taken 8 hours after a treatment is in the toxic range
        • although the above statement follows conventional dogma, some dogs can be toxic at less than 1.0 nmol/l.
      • Digitalis toxicity is potentiated in the following conditions and therefore the dosage should be lowered:
        • renal failure
        • hypothyroidism
        • hypokalemia
        • older animals
        • Dobermans
        • in the presence of other drugs esp. quinidine

        ECG is not useful to detect digitalis intoxication

      Dosages:

      • dog: 0.22 mg/m2 BID (PO)
      • cat: 1/4 of 0.125 mg q 24-48h (PO)
      • I.V.: rarely used. Only used in an emergency situation.

      Comment: There has been considerable controversy as to the efficacy of digitalis in the setting of heart failure in patients with a normal sinus rhythm. Emerging evidence suggests that digoxin may have a beneficial effect not as a result of its modest positive inotropic properties but digoxin may reduce the enhanced sympathetic activity characteristic of heart failure. In that this enhanced sympathetic activity may contribute to the vicious cycle of heart failure begets more heart failure, digoxin may be beneficial.

    • In 1997 long term survival studies were reported evaluating the efficacy of digoxin to improve survival in people with congestive heart failure.
      • Digoxin failed to improve survival, an effect similar to all other positive inotropes. Unlike other positive inotropes at least digoxin did not enhance mortality!
      • In light of this evidence in people, digoxin may have little use in our cases except in the setting off supraventricular arrhythmias (to slow heart rate).
    • It is possible that the previous recommendations with respect to the dose of digoxin produced serum levels of drug that were too high. There is support in people for using a dose of digoxin that produces serum levels not greater than 0.9 ng/ml. Perhaps lower doses of digoxin would benefit dogs as well. This hypothesis remains to be confirmed.

    3. Dobutamine:

    • Potent positive inotrope (catecholamine)
    • Administered IV (constant rate infusion [CRI])
    • A 72 hour infusion may show sustained hemodynamic benefit in people
    • May promote ventricular dysrhythmias
    • May cause tachycardia
    • Tolerance appears to develop in people
    • Should only be used in an ICU setting where cardiac rate and rhythm can be monitored (for tachycardia and VPCs)

    Dosages:

    • dog: 5-15 ug/kg/min (CRI)
    • cat: 1-2 ug/kg/min (CRI); but NOT for use in HCM

    Comment: Dobutamine has a role only in the acute management of severe heart failure due to systolic dysfunction. A three-day infusion of dobutamine has been very useful in people to revert cases of refractory heart failure with pulmonary edema into a state of stable heart failure.

    Comments: All positive inotropes (both oral catecholamines and phosphodiesterase inhibitors) have failed to improve survival in people with chronic heart failure due to systolic dysfunction. In fact, this group of agents has reduced survival in these patients. Dogs may be quite different from people in their potential to respond to positive inotropes. Only pimobendan has been shown to improve survival and quality of life for dogs with CHF.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    11 List negative inotropes used to treat heart failure and outline their advantages and disadvantages.

    Negative inotropes are divided into two general categories:

    • beta-adrenergic blockers
    • calcium channel blockers

    These agents are also potent negative chronotropes. They may mediate most of their benefit via their negative chronotropic properties.

    Indications:

    • Primary therapeutic agents to treat hypertrophic cardiomyopathy (they improve ventricular filling)
    • They reduce myocardial oxygen demand
    • Treat supraventricular arrhythmias (including atrial fibrillation) and supraventricular tachycardia (a negative chronotropic function)
    • Long term beta blocker therapy improves survival in people with congestive heart failure due to reduced contractility (systolic dysfunction)
    • Beta blockers may improve the outcome for dogs and cats with aortic, subaortic, pulmonic stenosis.

    Disadvantages:

    • As both agents slow the heart rate, they may cause sufficient bradycardia as to promote weakness. In heart failure, many patients require a critical heart rate (often between 130 and 160 bpm) and if the rate falls below this level they show evidence of worsening failure.
    • These agents will reduce contractility in the short term. If contractility is already low, they could exacerbate failure when initiated. This can sometimes be avoided by a treatment regimen that very gradually increases the level of the drug. With the advent of pimobendan, we may be able use higher doses of these agents than previous, particularly for cases requiring heart rate control.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    12 List beta-blockers used to treat heart failure and outline their advantages and disadvantages.

    There has been a great deal of attention in human heart failure medicine concerning the role of beta-blockers. On the surface the use of beta-blockers appears counter-intuitive. However, catecholamines have been shown to cause myocardial necrosis, coronary vasospasm, and dysrhythmias, increase afterload, increase heart rate, and increase MVO2. The use of beta-blockers therefore can counteract the excess catecholamines typical of heart failure, actually resulting in improved systolic function in the long term and increased survival time.

    Common Beta-Blockers:

    • Selective beta-blockers:
      • Metoprolol
      • Atenolol
    • Non selective beta-blockers:
      • Propranolol
    • Third generation beta-blockers (non-selective beta-blocker and alpha-blocker)
      • Carvedilol

    Advantages:

    • Beta-blockers increase survival in people with heart failure.
    • They can protect against arrhythmic death (sudden death).

    Disadvantages:

    • Hypotension
    • Bronchospasm (less of a problem with selective beta1-blockers)
    • Bradycardia
    • Negative inotropy in the immediate and short term

    Indications:

    • Primary therapeutic agents to treat hypertrophic cardiomyopathy (they improve ventricular filling by slowing heart rate and reduce dynamic outflow obstruction)
    • Treatment of supraventricular arrhythmias including atrial fibrillation and supraventricular tachycardia (a negative chronotropic function)
    • Treatment of some ventricular arrhythmias
    • Beta blockers improve survival in people with congestive heart failure due to reduced contractility (systolic dysfunction)
    • May be useful in the treatment of congenital subaortic stenosis or pulmonic stenosis (reduce myocardial oxygen demand, improve coronary flow)

    Contraindications: Active and significant pulmonary edema, hypotension, bradycardia

    Dosages:

    • Propranolol
      • dog: 0.2-1.0 mg/kg TID (PO); 0.02-0.06 mg/kg (IV) slowly
      • cat: 0.2-1.0 mg/kg BID-TID (PO); 0.04 mg/kg (IV) slowly
    • Metoprolol
      • dog: 0.25-1 mg/kg BID-TID (PO)
      • cat: 0.25-1 mg/kg BID-TID (PO)
    • Atenolol
      • dog: 5-12.5 mg SID-BID (PO) or 0.25-1 mg/kg SID-BID (PO)
      • cat: 5-12.5 mg SID-BID (PO)
    • Carvedilol
      • dog: 0.2-1.5mg/kg BID (PO) (Note that the high end of the dose comes from dosing studies in healthy dogs. Dogs with cardiac disease may not tolerate doses that high.)
      • cat: unknown

    Comments:

    • Beta-blockers must be initiated at low doses and up-titrated slowly.
    • Also, they should not be discontinued abruptly, rather gradually weaned down.
    • Recent evidence suggests that atenolol in the cat may be better suited to a BID regimen. Also the response of dogs to beta-blockers (particularly atenolol) can be very unpredictable with a marked reduction in heart rate developing that requires support. We recommend starting atenolol in a hospital environment to monitor heart rate.
    • Non-selective beta-blockers appear to confer greater benefit for patients in heart failure than selective beta-blockers. Of these agents, the novel beta-blockers with combined alpha blocking and non-selective beta-blocking properties appear to be the most promising agents yet. An example of the latter group is carvedilol.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    13 What have we learned from the veterinary clinical heart failure trials?

    Treating congestive heart failure in dogs due to CMVI or DCM:

    ACE-inhibitor Trials:

    1. COVE Trial (COVE Study Group. JVIM 1995;9(4):243-252)

    • Objective: to determine whether ACE inhibitor therapy improves quality of life in dogs with CHF due to CMVI or DCM
    • Study Design:
      • Dogs were randomized in a double-blind study to receive enalapril or placebo in addition to furosemide +/- digoxin
      • 28-day quality of life study, 14 variables were assessed
      • Involved dogs with CHF due to CMVI (141 dogs) and DCM (70 dogs)
    • Result:
      • Quality of Life parameters (mobility, activity, cough score, and "overall" evaluation) were significantly improved in the enalapril group compared with the placebo group for the CMVI dogs.
      • All 14 Quality of Life parameters were significantly improved in the enalapril group compared with the placebo group for the DCM dogs
    • Limitation:
      • Assessment and scoring of quality of life parameters is very subjective.
      • Only a 28 day study
      • Not a survival study
    • Our Conclusion: This study provides reasonably strong evidence that ACE inhibitors improve quality of life for dogs with CHF due to CMVI and DCM

    2. LIVE Trial (LIVE Study Group. JAVMA 1998;213(11):1573-1577)

    • Objective: To demonstrate that ACE inhibitor therapy improves survival in dogs with CHF due to CMVI or DCM
    • Study Design:
      • Randomized, double-blind, placebo-controlled multicenter study
      • Survival/treatment failure (of sorts) study
      • 110 dogs with CHF due to CMVI (67 dogs) and DCM (43 dogs) enrolled
      • Dogs were randomized to receive enalapril or placebo in addition to furosemide +/- digoxin
      • Of the 67 CMVI dogs: 34 received enalapril; 33 received placebo
      • Of the 43 DCM dogs: 21 received enalapril; 22 received placebo
      • Excluded dogs that were not expected to survive for at least 1 month
      • Endpoints:
        • Not really a survival trial, somewhat of a treatment failure study
        • The endpoint was death due to heart disease for some dogs, but for other dogs the endpoint was withdrawal from the study due to failure to improve
    • Result:
      • CMVI Dogs: Mean time to endpoint
        • Enalapril dogs: 159.5 days
        • Placebo dogs: 86.6 days
        • P = 0.041
      • DCM Dogs: Mean time to endpoint
        • Enalapril dogs: 143 days
        • Placebo dogs: 57 days
        • P = 0.06
    • Limitations:
      • The withdrawal criteria as an endpoint makes it difficult to assess survival
      • Fewer dogs were enrolled in the DCM part of the study making it more difficult to find a significant difference.
        • There is a plethora of evidence in people with CHF due to DCM demonstrating that ACE inhibitors improve survival
    • Our Conclusions:
      • For the CMVI dogs: the evidence is supportive of an increase in survival with ACE inhibitor therapy.
      • For the DCM dogs: this study definitely does not indicate that ACE inhibitors will fail to increase survival. The study was underpowered to show a difference.

    3. BENCH Trial (BENCH Study Group. J Vet Cardiol 1999;1(1):7-18)

    • Objective: To demonstrate that ACE inhibitor therapy improves survival in dogs with CHF due to CMVI or DCM
    • Study Design:
      • Randomized, double-blind, placebo-controlled multicenter study
      • Survival/treatment failure (of sorts) study
      • 162 dogs with CHF due to CMVI (125 dogs) and DCM (37 dogs)
      • Dogs were randomized to receive benazepril or placebo in addition to furosemide +/- digoxin
      • Of the 125 CMVI dogs: 70 received benazepril; 55 received placebo
      • Of the 37 DCM dogs: 17 received benazepril; 20 received placebo
      • Endpoints:
        • Not really a survival trial, somewhat of a treatment failure study
        • The endpoint was death due to heart disease for some dogs, but for other dogs the endpoint was withdrawal from the study due to failure to improve
    • Result:
      • CMVI Dogs: Mean time to endpoint
        • Benazepril dogs: 436 days
        • Placebo dogs: 151 days
        • P = 0.015
      • DCM Dogs: Mean time to endpoint
        • Benazepril dogs: 394 days
        • Placebo dogs: 164 days
        • P = 0.66
    • Limitations:
      • The withdrawal criteria as an endpoint makes it difficult to assess survival
      • A number of dogs were enrolled that were not receiving furosemide, hence were not in congestive heart failure. These dogs should not have been enrolled into the study. Including them in the analysis confounds the results.
      • Fewer dogs were enrolled in the DCM part of the study making it more difficult to find a significant difference
        • There is a plethora of evidence in people with CHF due to DCM demonstrating that ACE inhibitors improve survival
    • Our Conclusions:
      • For the CMVI dogs: the evidence is supportive of an increase in survival with ACE inhibitor therapy
      • For the DCM dogs: again, this study definitely does not indicate that ACE inhibitors will fail to increase survival. The overwhelming human data suggests a similar benefit must occur in dogs.

    Pimobendan Trials

    1. The Fuentes Study (Fuentes et al: JVIM 2002;16(3):255-261)

    • Objective: To show that pimobendan will increase survival and quality of life for dogs with DCM when added to conventional therapy consisting of diuretics, ACE inhibitors, and digoxin
    • Study Design:
      • Two populations of dogs were studied: Doberman Pinschers and Cocker Spaniels with DCM and CHF
      • Each group was randomized separately into dogs to receive pimobendan or placebo in addition to conventional therapy consisting of furosemide, enalapril, and digoxin
      • This was a prospective, randomized, placebo-controlled, double-blinded trial
      • 10 Doberman Pinschers (5 receiving pimobendan, and 5 receiving placebo) were enrolled
      • 10 Cocker Spaniels (5 receiving pimobendan, and 5 receiving placebo) were enrolled
    • Results:
      • The Doberman Pinschers:
        • Average time to death:
          • Pimobendan dogs: 329 days
          • Placebo dogs: 50 days
        • Difference between treatment groups: P < 0.02
        • There was a significant improvement in NYHA Class (quality of life score) with the addition of pimobendan
      • The Cocker Spaniels:
        • Average time to death:
          • Pimobendan dogs: 1037 days
          • Placebo dogs: 537 days
        • Difference between treatment groups: P = 0.77
        • There was a significant improvement in NYHA Class (quality of life score) with the addition of pimobendan
    • Limitations:
      • Doberman Pinschers:
        • 3 of the placebo Dobermans had atrial fibrillation at the time of enrollment, whereas only 1 of the pimobendan Dobermans had atrial fibrillation at the time of enrollment
        • Atrial fibrillation carries a profound negative impact on survival hence significantly disadvantaging the placebo group
      • The Cocker Spaniels:
        • 9 of the Cocker Spaniels failed to reach the endpoint of cardiac death (6 dogs were still alive at the end of the study and 3 dogs died of non-cardiac causes)
        • Thus the study was not designed to find a difference between the Cocker Spaniel treatment groups
    • Our Conclusions:
      • Although the study has a strong bias in favour of pimobendan due to the higher prevalence of atrial fibrillation in the non-pimobendan group, the duration of survival in the pimobendan Dobermans is so much greater than we historically observe in our non-pimobendan Dobermans that we feel there must have been a favourable impact of pimobendan.
      • Although it is profoundly difficult to assign NYHA Class scores in dogs with heart failure (this classification scheme is much better suited to people than dogs), this data suggests an improvement in quality of life based on NYHA Class score reduction with pimobendan.
      • This study sheds no light on the role of pimobendan for survival in Cocker Spaniels with DCM and CHF.

    2. University of Guelph Pimobendan in DCM Trial (O’Grady MR, Minors SL, O’Sullivan ML and Horne R. JVIM 2008:22:897-904).

    • Objectives: To determine whether pimobendan, when compared with placebo, will increase survival and quality of life for dogs with CHF due to DCM when added to conventional therapy consisting of diuretics and ACE inhibitors
    • Study Design:
      • Prospective, double-blinded, placebo-controlled, randomized trial involving Doberman Pinschers with CHF due to DCM
      • 16 Dobermans enrolled:
        • 8 received pimobendan;
        • 8 received placebo
      • Excluded dogs with atrial fibrillation
      • Endpoints:
        • Treatment failure - defined as a failure of 5 mg/kg TID of furosemide to control respiratory distress, or death due to cardiac reasons prior to this dose of furosemide
        • Death
      • Dogs that met the furosemide treatment failure criteria were offered both therapies (placebo and pimobendan)
    • Results:
      • Quality of life assessment: Both groups were to be compared at the one month and two month time points. At one month, 8 pimobendan and 3 placebo dogs were available for analysis. There was no difference in any of the quality of life variables between groups at this time. At two months, there were 6 pimobendan and 1 placebo dogs available for analysis. Thus there were too few placebo dogs available to compare groups. One could argue that since there were so few placebo dogs at both time points due to treatment failure, this of itself indicates a favourable effect of pimobendan.
      • Average time to treatment failure: dogs were censored for failure to meet the treatment failure criteria
        • Pimobendan dogs (7 dogs): 130.5 days
        • Placebo dogs (8 dogs): 14 days
        • P = 0.0002
    • Limitations:
      • Small numbers
      • Dobermans only
    • Our Conclusions: This is the first study to definitively demonstrate the benefit of pimobendan on both quality of life and survival in DCM dogs

    3. QUEST Trial (Haggstrom J, Boswood A, O’Grady M, et al for the Quest Investigators JVIM 2008;22(5):1124-35)

    • Objective: In dogs with congestive heart failure due to chronic mitral valve disease, to determine whether pimobendan when added to conventional therapy of a diuretic will extend time to sudden death, euthanasia for cardiac reasons, or treatment failure when compared with benazepril when added to the same conventional therapy.
    • Study Design:
      • Randomized, single-blinded (investigator was blinded), multicenter (28 centers) study of dogs with CHF due to CMVI .
      • A mixed population of small breed dogs, middle age or older (> 5 years, from 5 to 20 kg)
      • 260 dogs enrolled; 8 dogs excluded
        • 124 randomized to pimobendan (0.4-0.6 mg/kg/day)
        • 126 randomized to benazepril (0.25-1.0 mg/kg/day)
    • Results:
      • The median time to the primary endpoint of sudden death, euthanasia for cardiac reasons, or treatment failure:
        • For all dogs: 188 days
        • For Pimobendan dogs: 267 days
        • For Benazepril dogs: 140 days
        • P = 0.0099
        • Significant persisted in a multivariate analysis
      • All 3 endpoints were required in combination to find significant difference
        • With each endpoint taken individually, the time to endpoint was not significantly between treatment groups however the pimobendan group had a longer time to each endpoint – thus no one endpoint was entirely responsible for the overall significance.
      • 62 dogs were censored (25%)
        • 36 in the pimobendan dogs
        • 26 in the benazepril dogs
      • Median treatment dose
        • For pimobendan – 0.47 mg/kg/day divided BID
        • For benazepril – 0.38 mg/kg/day
    • Limitations:
      • This is a single-blinded study
      • All 3 endpoints were required to reach significance
      • There was a high percentage of Cavalier King Charles Spaniels and Dachshunds in this trial
      • This study did not address the important question of whether one should treat such patients with the combination of pimobendan and benazepril (or another ACE inhibitor) and diuretics as is the case in most practices.
    • Strengths of this Study:
      • Multicenter
      • Dogs enrolled from 3 continents
      • The largest clinical cardiovascular trial
      • The most aggressive/rigorous statistical analysis
    • Our conclusions:
      • This study provides the most compelling evidence that pimobendan has an important role in the management of CHF due to CMVI.
      • This study does not answer the question of the benefit or lack of benefit of triple therapy (pimobendan, an ACE inhibitor, and furosemide) – our current practice in the management of these cases.

    Treating pre-clinical heart disease due to CMVI or DCM in dogs (absence of clinical signs):

    The goal of therapy at this stage of heart disease is not to improve clinical signs as none exist. The goal of therapy is to delay the inevitable progress to overt heart failure (onset of clinical signs).

    Treatment of symptom-free (free of clinical signs) CMVI:

    Two studies investigated the role of ACE inhibitors to delay the progression of CMVI to the onset of clinical signs of heart failure:

    1. SVEP Trial (Kvart et al: JVIM 2002;16:80-88)

    • Objective: To show that starting an ACE inhibitor before the onset of clinical signs of heart failure for dogs with CMVI would delay the onset of clinical signs of CHF
    • Study Design:
      • Randomized, double-blinded, placebo-controlled multicenter study of dogs with CMVI but not yet in CHF
      • Only CKCS included: 229 dogs enrolled
        • 116 received enalapril
        • 113 received placebo
    • Results:
      • Time to onset of CHF - average
        • Enalapril dogs: 1,150 days +/- 50 days
        • Placebo dogs: 1,130 days +/- 50 days
        • Difference between treatment groups: P = 0.85
      • Average enalapril dose used: 0.37 +/- 0.08 mg/kg/day
      • Follow-up period: 4.5 years
      • Dogs with bigger hearts achieved the endpoint of CHF faster than dogs with smaller hearts
      • There was no difference in the effect of enalapril therapy whether dogs had cardiomegaly at enrolment (thus more advanced within the occult stage of CMVI) vs dogs without cardiomegaly at enrolment (thus less advanced within the occult stage of CMVI) as to outcome
    • Limitations:
      • About half the dogs reached the end point of CHF
      • Only Cavaliers studied, will this apply to all small breed dogs with CMVI?
    • Our Conclusions:
      • This study is the most exhaustive cardiovascular clinical study conducted in veterinary medicine to date.
      • The study is underpowered to detect a small difference between the enalapril and placebo treatment groups. This strongly suggests that if enalapril has any benefit it must be small.
      • This study also suggests that dogs both early in the phase of occult CMVI and late in the phase of occult CMVI fail to benefit from ACE inhibition.
      • As for whether a study in Cavaliers can serve as an accurate model of CMVI in all small breed dogs, we believe Cavaliers are likely very representative of all small breed dogs with respect to a response to enalapril at this stage of heart disease.

    2. VETPROOF Trial: Atkins et al: JAVMA 2007;231(7):1061-1069

    • Objective: To show that starting an ACE inhibitor before the onset of clinical signs of heart failure for dogs with CMVI would delay the onset of clinical signs of CHF
    • Study Design:
      • Randomized, double blinded, placebo controlled multicenter study of dogs with CMVI but not yet in CHF
      • A mixed population of small breed dogs were enrolled (139 dogs)
      • 70 dogs were randomized to enalapril
      • 69 dogs were randomized to placebo
      • 15 dogs left the study within a run-in period of 60 days and were not included in final analyses, leaving 124 dogs for study (59 in enalapril group, 65 in placebo group)
      • Primary endpoint: days to CHF
      • Secondary endpoints: combined endpoint of time to CHF or all-cause death; number of dogs free of CHF at 500, 1000, and 1500 days; and days from entry to CHF, dropout, or death
    • Results:
      • Time to onset of CHF - median
        • Enalapril dogs: 895 days
        • Placebo dogs: 778 days
        • Difference between treatment groups: P = 0.06 (not significant)
      • Average enalapril dose used: 0.46 mg/kg/d
      • Follow-up period: 5 years
    • Limitations:
      • Only about half the dogs reached the primary end point of CHF just as the SVEP Study (thus half were censored)
      • While some of the secondary endpoints were significantly in favor of the enalapril treated group, these data allow the inclusion of dogs that never reached CHF, the a priori primary endpoint of the study
    • Our Conclusions:
      • This study fails to provide definitive evidence in support of the benefit of starting ACE inhibitors during the occult stage of CMVI.
      • The study is also underpowered to detect a small difference between the enalapril and placebo treatment groups. This strongly suggests that if enalapril has any benefit it must be small.
      • The dogs in this study reached the endpoint of overt heart failure in half the time it took Cavaliers in the SVEP Trial. This suggests that the dogs in the VETPROOF Trial were more advanced within the occult phase of their disease.

    Treatment of symptom-free (free of clinical signs) DCM:

    One published study from the University of Guelph has investigated the role of ACE-inhibitors to delay the progression of DCM to the onset of clinical signs of heart failure:

    1. Benazepril in Occult Doberman DCM (O’Grady MR, O’Sullivan ML, Minors SL, Horne R. JVIM 2009;23:977-983)

    • Objective: To determine whether the initiation of benazepril during the occult (preclinical) phase of DCM delays the progression to overt (clinical or symptomatic) DCM in Dobermans
    • Study Design:
      • Retrospective study of Doberman Pinschers that met criteria for occult DCM comparing those that received an ACE inhibitor vs those that did not receive an ACE inhibitor
        • Two separate echocardiographic criteria for cardiac enlargement for the diagnosis of occult DCM were considered, one body weight-independent and one body weight-dependent
      • 91 dogs met the criteria for occult DCM
        • 57 dogs received benazepril
        • 34 dogs did not receive an ACE inhibitor
      • Endpoints included the onset of overt clinical DCM defined as congestive heart failure, sudden death, or syncope
      • Dogs were censored if they were euthanized or died before the onset of overt DCM, lost to follow-up, or still alive and occult at the end of the study
    • Results:
      • 73 dogs reached the cardiac endpoint while 18 dogs were censored
      • Dogs receiving benazepril experienced a significantly longer time to overt DCM (by about 100 days) and a 43% decreased likelihood of developing overt DCM. This effect persisted when adjustments were made for other covariates that could be measured (such as age, cardiac size, other drugs used, etc).
    • Limitations: Retrospective studies are limited by a lack of randomization and blinding.
    • Our conclusions:
      • This study provides evidence that ACE-inhibitors, specifically benazepril, can slow the progression of occult (preclinical DCM), which is substantiated in the human literature. This effect likely translates to other ACE-inhibitors and other breeds as well. As such, we do recommend the use of ACE-inhibitors in dogs with preclinical DCM.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    14 How should I treat congestive heart failure?

    RECALL: CONGESTIVE HEART FAILURE IS NOT A DIAGNOSIS, JUST LIKE DIARRHEA IS NOT A DIAGNOSIS – THEY ARE BUT CLINICAL SIGNS.

    In addition to establishing a diagnosis, there are other factors to consider when selecting a therapeutic plan:

    • Is acute fulminant pulmonary edema present? This patient would be dyspneic, non-ambulatory and anorectic.
    • Is this patient ambulatory and still eating?
    • Does this patient have refractory congestive heart failure?
    • Does this patient have refractory ascites?

    top      General Therapeutic Concepts: Therapy of Heart Failure
    15 How should I treat the patient with fulminant pulmonary edema?

    These patients have profound respiratory distress, are non-ambulatory, and are usually anorectic. Therefore oral medications will be inadequate; use of an ICU and intravenous medications are mandatory.

    The goals of therapy are to relieve the severe pulmonary edema. One requires at least a presumptive diagnosis as to the cause of pulmonary edema in order to develop a therapeutic plan. For patients with pulmonary edema due to systolic dysfunction, pulmonary edema is reduced by:

    • Marked reduction of the circulating blood volume:
      • potent diuretic therapy, such as furosemide IV or CRI
      • phlebotomy 10 cc/kg (dog, cat)
    • Trap blood in the peripheral venous system and away from the heart and lungs:
      • nitrate therapy: as topical 2% nitroglycerin cream
      • intravenous morphine (morphine is a strong venodilator)
      • intravenous sodium nitroprusside: CAUTION this agent is our most potent hypotensive agent; therefore, it must only be used in patients with continuous blood pressure monitoring. This agent is both an arterial and venodilator. Therefore, it will both trap blood away from the heart and lungs and also dilate small arteries (reduce systemic vascular resistance [afterload]) which will result in an increase in stroke volume.
    • Supplement with oxygen: an oxygen tent or nasal oxygen
    • Strengthen the heart: for those with reduced contractility
      • intravenous dobutamine: CAUTION this agent can increase the heart rate and/or induce arrhythmias particularly ventricular tachycardia. Therefore, it must only be used in patients that are receiving continuous cardiac rhythm monitoring.

    What about oral therapies? There is no place for oral therapy in these cases. As they are anorectic, they likely have little to no gastric motility so that the medication may just sit in the stomach. In addition, intestinal absorption is likely markedly reduced as blood is usually shunted away from the bowel.

    What about intravenous fluids? In general, no intravenous fluids should be used. Fluids are only used if they are required as a vehicle to administer drugs requiring constant rate infusion such as sodium nitroprusside, dobutamine, or antiarrhythmic drugs. In these situations, only use 25% of the maintenance fluid rate and use fluids low in sodium such as 5% dextrose in water or half strength saline and dextrose. Also monitor that the combined fluid of all CRIs does not inadvertently result in further fluid overload.

    What about inducing azotemia? Expect that some degree of azotemia will develop since aggressive volume depletion is sometimes necessary to relieve severe life threatening pulmonary edema. In two to three days after the onset of therapy, we may be required to provide fluid support for renal function at which time cardiovascular status should be substantively improved and the patient should be able to handle the fluid load. In addition, as cardiac performance improves the renal blood flow will improve.

    So how would the authors treat this patient with systolic dysfunction and fulminant pulmonary edema? We must consider whether we have the ability to provide continuous monitoring. We recommend attempting to use a facility that has continuous monitoring.

  • Using a facility that has continuous blood pressure and electrocardiographic monitoring:
    • Furosemide:
      • 4 mg/kg IV followed by repeat injections every 4 hours until respiratory rate has fallen by 50%;.
      • Or 4 mg/kg IV followed a CRI of furosemide (0.2 – 1 mg/kg/hr for 8-12 hours or until respiratory rate has fallen by 50%.
    • Sodium nitroprusside (SNP):
      • Start infusion at 2 ug/kg/min.
      • Increase the infusion dose by increments of 1 ug/kg/minute every 30 minutes up to a total of 6 ug/kg/min as long as mean blood pressure remains above 75 mmHg and systolic blood pressure remains above 90 mmHg.
      • Maintain the target CRI for 24 to 72 hours.
      • If the mean blood pressure falls below 75 mmHg, reduce the infusion rate to the previous CRI dose level.
      • If the mean blood pressure falls below 75 mmHg with the lowest dose, stop the SNP and start an infusion of dobutamine, then start the SNP after one hour of the dobutamine infusion.
      • The dog should demonstrate a marked improvement in respiratory function in 24 hours.
      • Tolerance can develop to the SNP after 24 to 48 hours.
      • Cyanide toxicity may develop with a high dose or long duration of treatment (> 72 hours).
    • Dobutamine: only for dogs with reduced systolic function.
      • If DCM is suspected, start dobutamine prior to starting the SNP infusion
      • Start the infusion at 5 ug/kg/min.
      • Increase the infusion rate every 4 hours by 2.5 ug/kg/min to a maximal dose of 15 ug/kg/min.
      • If the heart rate increases by 10% or rises over 180 bpm reduce the infusion rate of the dobutamine.
      • If ventricular tachycardia develops then reduce the infusion rate of dobutamine.
    • Note: The above regimen applies only to dogs. Cats are very sensitive to dobutamine. We would not recommend a dose of dobutamine greater than 2 ug/kg/min. We have no experience with sodium nitroprusside in the cat. We would consider substituting nitroglycerine cream for the SNP. Cats are also very sensitive to furosemide. Relative to dogs they are prone to develop severe dehydration, hypokalemia, and metabolic alkalosis. For cats, we recommend a dose of furosemide of 1-2 mg/kg IV to be repeated as often as every 2 hours for several doses or a CRI of 0.2-0.5 mg/kg/hour with repeated evaluation of electrolytes, acid-base status and renal parameters.
  • Using a facility that will not allow the opportunity to continuously monitor blood pressure and cardiac rhythm:
    • Furosemide (in the dog):
      • 2-4 mg/kg IV followed by hourly injections of 2-4 mg/kg IV every hour until the respiratory rate falls by 50%;
    • Nitroglycerin (in the dog):
      • Using the 2% cream: apply 1/4 inch per 2.5 kg of body weight to a maximum of 2 inches.
      • Apply three times in 12 hours then none for 12 hours, then re-apply three times in 12 hours.
      • Using the transdermal patches: use 1/2 of a 2.5 mg patch (2.5 mg of nitroglycerin/24hours) per 5 kg body weight. Leave the patch on for 12 hours then remove for the next 12 hours, then re-apply etc.
    • Comments:
      • In the cat, due to their increased sensitivity to furosemide, we recommend an initial dose of 2 mg/kg IV and observe the response. If and as more furosemide is required then repeated additional doses of 1-2 mg/kg as required. Frequent monitoring of electrolytes, acid-base status and renal status is necessary.
      • Nitroglycerin cream is used in the cat at 1/8 to 1/4 of an inch three times over 12 hours, then none for 12 hours, and repeat as per the dog.
    • Start on oral medications as soon as possible.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    16 How would the authors treat the patient with severe congestive heart failure on an outpatient basis?

    Here we are referring to that patient that is ambulatory, still eating at least partially, and has congestive heart failure due to DCM or mitral valve insufficiency.

    The goals of therapy are:

    • Reverse the cause of heart failure
    • Identify and reverse any precipitating causes of heart failure
    • Extend the quality of life (ameliorate distressing symptoms and reduce the risk of morbid events)
    • Extend survival

    Usually the cause of heart failure cannot be identified as in dilated cardiomyopathy or cannot be altered as in the case of chronic mitral valve disease.

    However, it can be very productive to identify and arrest any precipitating causes of heart failure such as:

    • the development of an arrhythmia
    • the development of valvular vegetative endocarditis
    • a large sodium load ingested
    • excessive exercise
    • the development of another disorder such as anemia or inflammation/infection

    In addition to addressing the precipitating causes of heart failure, we want to introduce therapies that can extend both the quality and length of life. Today, only the ACE inhibitors and pimobendan have been demonstrated to extend survival for dogs.

    So how would the authors treat this patient?

    • 1. Furosemide:
      • Find the least dose that controls the respiratory embarrassment.
      • Most dogs with respiratory distress need 2 to 4 mg/kg PO BID to TID. After 3 to 7 days attempt to reduce the dose to find the least dose that promotes ease of breathing. Some dogs may tolerate alternate day furosemide dosing. Others may need up to 5 mg/kg TID to remain free of respiratory distress.
    • 2. ACE Inhibitor:
      • The manufacturers recommend starting at one dose then increase if the response is inadequate. We believe one should begin at the highest dose:
        • Enalapril
          • dog: 0.5 mg/kg BID (PO)
          • cat: 0.5 mg/kg SID (PO)
        • Benazepril
          • dog: 0.5 mg/kg BID(PO)
          • cat: 0.25-0.5 mg/kg SID (PO)
      • We believe the effect of these drugs is a class effect. Therefore they should be equally effective to improve survival.
      • They will take 7 to 10 days to start producing their beneficial effects.
      • Renal function should be assessed in 3-7 days. If the renal function is reduced, then consider first dropping the dose of the diuretic, not the ACE inhibitor.
    • 3. Pimobendan:
      • Pimobendan has demonstrated the most profound effect of all therapies on both length and quality of life for these patients.
      • As soon as the dog can take oral medications, begin pimobendan at 0.25 mg/kg PO BID.
      • Benefit is often observed within 24 hours.
    • 4. Arterial Vasodilators:
      • For dogs with chronic mitral valve insufficiency.
        • Hydralazine
          • dog: 0.5-3 mg/kg BID (PO)
        • Amlodipine
          • dog: 0.05-0.2 mg/kg SID (PO).
        • Start at a low dose and slowly up titrate to the recommended maintenance dose by monitoring blood pressure and renal function
      • There is likely no role for non-ACE inhibitor vasodilators in the treatment of dilated cardiomyopathy.
    • 5. Treating complicating arrhythmias
      • See the electrocardiography section for indications and selection of the most appropriate anti-arrhythmics to treat ventricular and supraventricular arrhythmias
  • 6. Low sodium diet and severe exercise restriction:
    • These measures continue to be important in providing quality of life.
    • With respect to a low sodium diet, they might be poorly palatable and so result in the dog receiving inadequate caloric intake. Heart failure is a calorie reducing state, and so we feel it is very important that we attempt to keep the caloric intake up. Therefore, we are prepared to feed the dog a normal or even relatively high sodium diet in exchange for a normal to slightly increased caloric intake. If this diet promotes water retention this can be addressed with an increase in the diuretic load.
    • Note also that starting a low sodium diet before the onset of heart failure may only serve to activate the RAAS system and speed the onset of overt heart failure.

    Management of congestive heart failure involves controlling vascular volume by finding a balance between meeting renal blood flow needs through enhancing vascular volume (preload) and reducing pulmonary edema by reducing vascular volume (preload).

    Surveillance: The following should be monitored at least once weekly initially:

    • Degree of pulmonary edema via thoracic radiographs
    • Renal function with a BUN/creatinine
    • Presence of arrhythmias via ECG
    • Systolic blood pressure.
  • top      General Therapeutic Concepts: Therapy of Heart Failure
    17 How should the patient with refractory heart failure or refractory ascites due to systolic dysfunction be treated?

  • Attempt to maximize the dose of pimobendan and ACE inhibitor therapies.
    • For ACE inhibitors we recommend:
      • Benazepril – 0.5 mg/kg PO BID
      • Enalapril – 0.5 mg/kg PO BID
    • We have used pimobendan at a dose higher than recommended >0.25 mg/kg PO BID. It remains to be determined whether this is safe and effective.
  • For patients with mitral valve insufficiency (canine) as the underlying cause of heart failure, add amlodipine to the treatment regimen. Start amlodipine at 0.05 mg/kg PO SID and increase to a maintenance dose of 0.1 mg/kg SID. Monitor renal function, evidence of weakness, and heart rate.
    • There is very little data addressing the appropriate dose of amlodipine in the dog. It is likely that doses 2 to 5 times these may be tolerated in the dog. We recommend following systolic blood pressure as one increases the dose to these levels.
    • Alternatively, hydralazine can be used in lieu of amlodipine. Begin hydralazine at 0.5 mg/kg PO BID. Slowly increase the dose as permitted by systolic blood pressure monitoring.
  • Add a second diuretic such as hydrochlorothiazide. Start at 0.5 mg/kg BID and increase each week by 0.5 mg/kg to a maintenance dose of 2 mg/kg BID. The dose of furosemide should be reduced in half as hydrochlorothiazide is started.
  • Comment:

    • Adding the second diuretic usually results in marked diuresis. Renal function often can fall dramatically and quickly. Renal function should be rechecked within 5 days of starting a second diuretic. Reduce the diuretic load if renal function falls.
  • Some of these patients need intermittent paracentesis to relieve discomfort.
  • It may be necessary to place the dog on an infusion of dobutamine for 1-2 days to strengthen the heart, then continue with routine therapy as above.
  • top      General Therapeutic Concepts: Therapy of Heart Failure
    18 Should I treat the patient that has heart disease without heart failure with the goal of improving survival?

    Evidence in people (the Prevention Limb of the SOLVD Trial and the SAVE Trial) indicates that in asymptomatic patients with DCM (early cardiac enlargement and reduced contractility), the early introduction of an angiotensin converting enzyme inhibitor will:

    • reduce the progression of left ventricular enlargement
    • prolong the time to onset of symptoms of heart failure
    • improve survival once signs of heart failure begin
    • reduce the chance of myocardial infarction.

    Recent work in the Doberman shows us that dogs with left ventricular enlargement and reduced contractility but free of symptoms of heart failure (occult dilated cardiomyopathy) benefited from the use of ACE inhibitors. ACE inhibitors delayed the onset of overt signs of heart failure (see above). Other breeds of dogs with occult dilated cardiomyopathy should also benefit from the early use of ACE inhibitors.

    However, the situation in dogs with chronic mitral valve insufficiency (such as small breed dogs with a mitral valve murmur but free of symptoms) and in the absence of heart failure is unclear. Only ACE inhibitors have been assessed in this setting in naturally-occurring disease, and they have failed to delay the onset of congestive heart failure in dogs with mitral valve insufficiency and no clinical signs. Work with experimentally induced mitral valve insufficiency in dogs suggests that ACE inhibitor therapy may not improve the outcome for patients with pre-clinical CMVI due to its negative impact on protein metabolism and myocardial function. Beta blocker therapy, however, shows promise in this experimental model for its ability to reverse myocardial remodeling and restore contractile function of myocytes in early mitral valve disease. Further work is required to clarify this picture.

    top      General Therapeutic Concepts: Therapy of Heart Failure
    19 What is the prognosis with therapy for heart failure?

    Unless the etiology for the heart failure can be reversed (hyperthyroidism, taurine deficiency-induced dilated cardiomyopathy, tachycardia-induced heart failure, carnitine deficiency-induced cardiomyopathy), patients usually die of heart failure. The average survival time from the onset of CHF due to dilated cardiomyopathy is 6 months in Dobermans and about 1 year in other large breed dogs. Small breed dogs with chronic mitral valve insufficiency induced heart failure usually die within 2 years after the onset of congestive heart failure.

    Severe chronic mitral valve insufficiency can result in episodes of severe fulminate pulmonary edema associated with chordal rupture. It is the authors’ experience that if these dogs are supported through this period of respiratory difficulty they often can revert back to a compensated form of heart failure.

    Atrial fibrillation appears to markedly reduce the prognosis for Dobermans with DCM and heart failure (median survival is 9 days). Atrial fibrillation carries a far less ominous impact in other breeds with DCM and in dogs with other forms of heart failure.