WHAT'S NEW IN MANAGEMENT OF CHF ?
An Internist's favorite cardiac medications

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Gary P. Oswald DVM, DACVIM (Internal Medicine)
Tampa Bay Veterinary Specialists, Clearwater FL

WHAT'S NEW IN MANAGEMENT OF CHF ? An Internist's favorite cardiac medications

The current standard of care for canine patients with CHF due to mitral valve degeneration or non-obstructive forms of cardiomyopathy begins with a combination therapy of a diuretic, balanced vasodilator (ACE-inhibition) and pimobendan (Vetmedin).  Drug therapy must then be individualized to meet the ongoing needs of each CHF patient.  As there is no medical or surgical cure for these diseases at the present time, the goal of therapy is to provide a compensated CHF status and maintain or improve the patient’s quality of life.

How Should I use Pimobendan in my cardiac patients? Pimobendan (Vetmedin®) is a novel cardiac medication with properties that are highly desirable in the clinical management of CHF.  It is best classified as an inodilator.  Its interaction with calcium metabolism (phosphodiestrase III inhibition) allows for increased strength of myocardial contraction (positive inotrope) along with coronary, pulmonary, peripheral arterial and venous vasodilation.  The net effect is a significantly increased cardiac output and improved circulation. 
Pimobendan is safe and well tolerated alone and in combination therapy with diuretics and ACE-I vasodilators.  Early concerns about ventricular arrhythmia promotion and progressive mitral valve damage have not been seen with wide spread clinical use.
The drug has demonstrated remarkable ability to quickly reduce CHF symptoms and restore and maintain life quality for most CHF patients.  Its positive inotropic and vasodilating effects are beneficial in maintaining (or improving) renal blood flow and renal function in patients with concurrent CRF issues.
The combined use with diuretic and angiotensin-converting enzyme inhibition therapies is the recommended treatment for all canine CHF patients (both dilated CM and mitral valve degeneration).  The drug should be initiated immediately at the time congestive heart failure is recognized and not delayed for use in more advanced stages of disease.

            Canine dose 0.25 mg/kg PO q12h.                                                                                       

            (frequency of administration can be increased to q8h in advanced CHF patients).

The use of pimobendan in feline congestive heart failure caused by DCM, RCM, FUCM and non-obstructive HCM also appears to be safe, well tolerated and efficacious.        

            Feline dose 0.25 mg/kg PO q12h.

            Pimobendan (Vetmedin®) 1.25mg, 5.0mg chewable tablets.

ACE Inhibitor Use and Controversies
When should I initiate balanced vasodilator therapy?
Balanced vasodilator (angiotensin converting enzyme-inhibitor [ACE-I]) treatment has been well documented to provide a survival advantage and improved quality of life in dogs in heart failure.  Based on clinical and experimental information from other species these drugs had been proposed to be of benefit in slowing the progression of cardiac disease in both DMVD and DCM.
However, several controlled studies (Europe, USA) are in conflict regarding early initiation of ACE-I medication prior to CHF in dogs with DMVD.  This conflict elicits varied opinions and a non-consensus regarding their early (non-CHF) use from veterinary cardiologists at this time.  There is agreement that DCM patients do benefit from early (pre-CHF) vasodilator use and it should be initiated at the time of diagnosis.
Practical implications –
ACE-I vasodilator therapy is indicated in every canine patient in CHF.  Their use in asymptomatic DMVD cardiac patients is questioned.  However, if there is left-sided cardiac enlargement (especially left atrial enlargement) on radiographs I would suggest that this is the time to begin treatment with an ACE-I medication.
ACE-I vasodilators have not been extensively studied in cats.  Their use is thought to have some benefit in managing cats that have progressed to CHF.  Pre-CHF use is questionable but has shown no benefits in asymptomatic HCM cats.

Which Dug is Better – Enalapril or Benazepril ?
Benazepril is hydrolyzed in the liver to benazeprilat.  Enalapril is converted in the liver to enalaprilat.  Both benazeprilit and enalaprilit inhibit angiotensin-converting enzyme (ACE) activity thereby reducing conversion of angiotensin-I to angiotensin-II.  Reducing the angiotensin-II end product produces balanced vasodilation and reduces aldosterone production in the adrenal gland. The overall effect of ACE inhibitors include reduced systemic blood pressure and reduced vascular resistance which is of benefit in increasing cardiac output and reducing congestion (edema, effusion) in patients with congestive heart failure.
ACE inhibitors' also have beneficial effects in renal compromised patients (CRF).  ACE inhibition reduces intraglomerular hypertension due to vasodilating effect on postglomerular arterioles.  This results in glomerular preservation and reduced urinary protein loss.   Studies in cats with chronic renal failure, benazepril has been shown to reduce systemic arterial pressure and glomerular capillary pressure while increasing renal plasma flow and glomerular filtration rates.
Benazeprilat is cleared equally via both renal and hepatic routes.  Enalaprilat is cleared primarily (95%) via renal routes and reduced renal function may impact elimination rates.
In cats, inhibition of ACE is longer lasting due to high affinity of benazeprilat and enalaprilit to ACE. 
Potential drug interactions include the potential for increased hypotensive effects when combined with diuretics; hyperkalemia with patients on increased potassium content diets (renal diets), oral potassium supplementation and spironolactone; concurrent NSAID use may reduce the anti-hypertensive or positive hemodynamic effects of ACE-I and may increase the risk for reduced renal function.
Adverse effects may include anorexia, vomiting, diarrhea, weakness, hypotension, renal dysfunction and hyperkalemia could occur.   ACE inhibitors rarely cause a dry cough as commonly seen in people.
Practical implications -- Both drugs are of equal efficacy in CHF patients.  In dogs, both drugs equally suppress ACE activity for slightly > 12 hours so BID administration is necessary.  Both drugs have a longer half-life in cats so QD dosing may be appropriate.                                                                                                                     

There is no evidence that ACE inhibitors reduce abnormal cardiac hypertrophy in cats.
Benazepril is less reliant on renal elimination but it has an equal effect when compared with enalapril on renal hemodynamics so it really has no safety advantage when used in renal compromised patients. 
Both drugs are generally safe with few side-effects.                                                                            

Studies on enalapril treatment in dogs with CHF revealed its safety margin with no significant renal toxicity (J Am Vet Med Assoc 2002 Sept 1. Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation.  Atkins CE, et al.  North Carolina State University).
Cats: 0.25–0.5 mg/kg PO once to twice daily.
Dogs: 0.5 mg/kg PO twice daily.

Both drugs are available in generic human tablet formulation.                                                        

Benazepril HCl tablets: 5 mg, 10 mg, 20 mg, & 40 mg                                                          

Enalapril Maleate tablets: 2.5 mg, 5 mg, 10 mg & 20 mg

 

How to use diuretics to maintain compensated CHF status and manage pulmonary edema and/or pleural effusion ?
Diuretic therapy should only be initiated when a patient has proven fluid retention relating to congestive heart failure (ie pulmonary edema, peritoneal or pleural effusion, peripheral edema).  You cannot prove a patient has pulmonary edema or pleural effusion with your stethoscope.  You need imaging confirmation (radiograph).

A loop (of Henle) diuretic is always the first choice for control of edema or effusion as the activity of these drugs will provide maximal initial diuresis.  The goal of diuretic therapy is to provide enough diuretic activity to resolve/minimize edema or effusion and improve/maintain respiratory effort but at the same time to avoid use of high dosages that creates other issues such as reduced cardiac output, dehydration, electrolyte imbalances, etc. These drugs must be used cautiously in patients with pre-existing renal disease and electrolyte or water balance abnormalities.  Close monitoring of hydration status, renal and electrolyte values is necessary.  Drug dose reduction or discontinuation is indicated if progressive azotemia is documented during therapy. 
There are two loop diuretic that can be considered at this time in veterinary medicine – furosemide and torsemide.

Furosemide (Lasix)
Furosemide is an ascending loop of Henle diuretic. It reduces the absorption of electrolytes in the distal renal tubule causing renal excretion of water, sodium, potassium, chloride, calcium, magnesium, hydrogen, ammonium, and bicarbonate.   The excretion of sodium is more significant compared to potassium in dogs so hyponatremia may be more of a clinical concern than hypokalemia.  In cats significant potassium loss also occurs so hypokalemia can be a concern.
Oral bioavailability is approximately (77%) with peak activity within 1-2 hours after oral dosing.  IV administration results in diuretic effects within 5 minutes after IV administration with peak effects occurring approximately 30 minutes after IV dosing.  IM administration provides diuretic effect within 30 minutes.
Important drug interactions may include hypotension when combined with ACE-inhibitors, increased serum digoxin levels (digoxin) and increased theophylline effects (theophylline).
Furosemide is available in a number of different pill strengths, an oral solution and injectable concentrations.
Management of acute CHF & pulmonary edema.
Dogs: 4 - 8 mg/kg IV or IM every 1–2 hours until respiratory rate and effort improves; an alternate CRI treatment of 0.66 mg/kg/hr may be used with reported greater diuresis, natriuresis and less potassium loss.
Management of chronic heart failure (in combination with ACE-I & pimobendan).
Dose range 1-4 mg/kg PO.  Dosing interval range from once daily for milder cases to q 8h for more severe heart failure patients.  Doses and intervals should be titrated to effect in each patient.  Attempt to use lowest possible dose of furosemide that controls edema or effusion.
Furosemide resistance can develop in patients but is difficult to distinguish from progress CHF.  Resistance may be caused by poor owner compliance (pseudoresistance), reduced gastrointestinal drug absorption or reduced renal efficacy (nephron hypertrophy).  The end result is reduced diuretic effect.  Consider trial treatment with SQ furosemide administration to avoid poor absorption or switch to different diuretic to maximize renal effects.
Torsemide (Demadex®.)
Torsemide is a newer loop diuretic.  When compared to furosemide it is approximately 10 times more potent and its diuretic effects persist for a longer period.  It does not cause as much urinary potassium excretion.  It has been used in dogs (published studies) and appears to be a useful treatment for congestive heart failure, especially in patients that appear to have become refractory to the diuretic effects of furosemide.  Studies suggest that diuretic resistance does not appear to occur with this drug when compared to furosemide which is known to suffer from diuretic resistance over time in some dogs.
Oral bioavailability is between 80–100% in dogs.   Diuretic activity begins within one hour of dosing, peaks at about 2 hours and persists for approximately 12 hours.
A starting dose of 10% of the furosemide dose is recommended (furosemide 2 mg/kg PO twice daily, torsemide 0.2 mg/kg PO twice daily).  As torsemide has a longer acting diuretic effect (approximately 12 hours) the dosing frequency may also be reduced to q 12-24 hours in some patients.
As with any diuretic, monitoring for hydration status, azotemia development and electrolyte imbalances is recommended.
Suggested starting dose 0.2 mg/kg PO q 8-24h.  Titrate to desired effect in each patient.
Torsemide tablets available as human generic 5 mg, 10 mg, 20 mg, & 100 mg tablets; Demadex®.
Hydrochlorothiazide & Spironolactone (“sequential nephron blockade”).
Hydrochlorothiazide
Thiazide diuretics are weaker in action when compared to loop diuretics.  Activity is in the cortical diluting segment of the nephron via interference with sodium reabsorption.  This activity provides increased urinary excretion of sodium, chloride, and water. Thiazides also increase urinary excretion of potassium, magnesium and phosphate and decrease the glomerular filtration rate (GFR). 
Onset of diuretic activity occurs within 2 hours of oral administration; peaks at 4-6 hours with a 6-12 hours duration of activity.
All diuretics should be used with caution in patients with renal disease or water balance abnormalities.  Mild hypokalemia may occur so monitoring of potassium is recommended with chronic therapy especially in cats.  Thiazides can cause or exacerbate hyperglycemia in diabetic patients or induce diabetes mellitus in prediabetic patients.
Hydrochlorothiazide tablets are available as human generic Rx in 25mg, 50mg, & 100mg sizes. Hydrochlorothiazide + Spironolactone tablets are available as human generic Rx in 25mg/25mg & 50mg/50mg.
Diuretic dose for congestive heart failure patients -- 
2–4 mg/kg PO q12h in dogs.
1-2 mg/kg PO q 12h in cats. 
Doses should be titrated to effect in each patient.
Practical application –
Used in combination with furosemide/torsemide in patients who have become refractory to furosemide alone and require additional diuretic effect to control effusions or edema.  Works particularly well in cats with resistant pleural effusion and dogs with resistant ascites.
Monitor renal and electrolyte values in patients receiving diuretic therapy.
Spironolactone
Spironolactone competitively inhibits aldosterone activity in the distal renal tubules.  The result is increased urinary excretion of sodium, chloride and water but decreased urinary excretion of potassium.  When given to healthy dogs this drug does not cause any significant diuresis.  Spironolactone has its greatest effect in patients with hyperaldosteronism thus it has therapeutic use in congestive heart failure patients.  However to be an effective diuretic it must be combined with a thiazide and/or loop diuretic to produce maximum diuretic effect.
Spironolactone has an antifibrotic effect on cardiac muscle in humans.  This effect is controversial and debated currently in our heart failure patients.  A recent study in dogs with moderate to severe mitral valvular disease, concluded that the addition of spironolactone to conventional therapy, was of benefit in decreasing the risk for death (or euthanasia) and severe worsening of signs. This study conclusion is debated by veterinary cardiologists.
Oral bioavailability is approximately 50%, but increases up to 90% when given with food.
A suggested dose of 2 mg/kg PO once daily would hopefully obtain concentrations effective at inhibiting aldosterone levels associated with heart failure.
Spironolactone should be used with caution in patients with renal disease or water balance abnormalities.  Caution must also be exercise in patients prone to hyperkalemia (Addison's disease, renal failure) as serum potassium levels may increase when receiving this drug. 
Cats may experience severe facial pruritus as a side effect of this drug.
Suggested dose –
Refractory CHF patients: 1–2 mg/kg PO q12h (dogs and cats).
Spironolactone tablets are available as human generic Rx: 25 mg, 50 mg & 100 mg.
Spironolactone/Hydrochlorothiazide tablets: 25mg/25mg & 50mg/50mg
Spironolactone/Hydrochlorothiazide combination

Practical application –
The combination of hydrochlorothiazide and spironolactone can be used with a loop diuretic (furosemide, torsemide) to provide enhanced diuresis in patients with refractory edema or effusion.  Each drug acts at a different location within the nephron unit thus providing for maximal diuresis (“sequential nephron blockade”).

Diuretic dose for refractory congestive heart failure patients -- 
2–4 mg/kg PO q12h in dogs.
1-2 mg/kg PO q 12h in cats. 
Doses should be titrated to effect in each patient.
Spironolactone/Hydrochlorothiazide available generic in 25mg/25mg & 50mg/50mg tablets.