Treatment of Heart Failure Triple Therapy Please

Transcription

1 Treatment of Heart Failure Triple Therapy Please Terri DeFrancesco, DVM, DACVIM (Cardiology), DACVECC Associate Professor in Cardiology and Critical Care NC State University College of Veterinary Medicine Raleigh, NC The most important recent advancement in heart failure management is the addition of an ino-dilator, pimobendan. Over the past several years, NCSU cardiology has treated over 2000 dogs and 200 cats with pimobendan. The use of pimobendan has evolved over the years from being a salvage, last-ditch medication to one that we use early in the management of heart failure, essentially first-time heart failure. Several clinical trials have shown improved quantity and quality of life in canine heart failure patients, due to both mitral valve disease and dilated cardiomyopathy. 1-3 Pimobendan, together with furosemide and an angiotensin converting enzyme inhibitor (ACE-I), has become standard of care for all cause canine heart failure. The role of pimobendan in feline heart failure is still evolving. No clinical trials exist in cats. Prior to reviewing the medications listed above, an important reminder for anyone treating the cardiac patient is that the goals for treating the cardiac patients vary depending on the stage and severity of their disease. Moreover, the goals for chronic management of heart failure are somewhat different than your goals for acutely decompensated heart disease. For acute heart failure, you are focused on restoring comfortable breathing, relieving life-threatening fluid accumulations and optimizing cardiac output. For chronic heart failure, you want to maintain the acute hemodynamic gains in addition to individualizing your management with the following issues in mind in order to improve survival and quality of life: Co-morbid conditions (concurrent airway disease, organ failure, or endocrine disease) Improving or maintaining quality of life maintaining appetite, weight and exercise capacity Minimizing hospitalizations, especially expensive ER admissions Minimizing complications of cardiac medications Optimizing owner and patient compliance (can they do TID medications?) Evaluating the financial impact of recheck visits, monitoring and medications The human literature as well as my 15 years of experience as a cardiology specialist, would support the notion that long term success of treating the cardiac patient requires constant vigilance, communication and an understanding of the pathophysiology of heart failure as well as an understanding of the cardiac medications. Treating the acutely decompensated heart failure patient, especially on their first episode of heart failure, is usually successful. A recent study showed about a 90% survival rate to discharge for dogs with acute heart failure that were admitted to an university emergency department in an urban setting. The real challenge is usually in keeping the cardiac patient stable on medications for the long term. Treatment of Acute Decompensated Heart Failure (ADHF): The medical treatments of ADHF are designed to improve/optimize cardiac output and relieve clinical signs. The immediate goal of emergency therapy is to reduce abnormal fluid accumulations and provide adequate cardiac output by either increasing contractility, decreasing afterload (reducing resistance to ejection of blood) and/or normalizing a cardiac dysrhythmia. For acute fulminant cardiogenic pulmonary edema, some of the initial database may be postponed and administration of parenteral furosemide and an oxygen rich environment (40%) is recommended. Strict cage rest and minimizing stress are of the utmost importance. Most patients with ADHF can be initially managed with off-loading therapy, i.e., drugs that reduce preload and afterload. Furosemide (Lasix or Salix ) 2 4 mg/kg IV or IM q 2-12 hrs as needed. Not to exceed 12 mg/kg/day. Can also use a furosemide CRI 2-4 mg/kg over 4-8 hrs after initial bolus. Long term the lowest effective dose is ideal. The initial furosemide dose is usually higher than the long-term dose. Supplemental oxygen therapy (40 %) Nitroglycerin 2 % paste : ¼ inch for small dogs/cats up to 1 inch for large dogs transdermal (inner ear pinnae, groin or axilla) as needed q 8 hrs for the first 24 hours. Wear gloves to apply. Not commonly used in

2 the chronic management of heart failure because of drug tolerance. I usually don t use nitroglycerin in an outpatient heart failure patient. Sedation if very anxious and dyspneic Acepromazine (dog only if not hypotensive, especially in CVD) mg/kg IV Butorphenol (dog and cat) mg/kg IV or SQ Buprenorphine (dog and cat) (could use instead of Butorphenol) mg/kg IV or SQ Pimobendan is a useful and safe drug for acute and chronic management of heart failure. Onset of action and peak blood levels of pimobendan and its metabolites are reached within one hour of administration. Our primary experience is in dogs with HF due to chronic valvular disease or dilated cardiomyopathy.( 0.5 mg/kg/day PO divided BID) If the pleural or abdominal effusion is of significant quantity, the most effective, immediate therapeutic maneuver is the removal of the fluid, in addition to diuretic therapy. Sometimes, both sides of the chest will need to be tapped. The author prefers a gauge over the needle catheter with multiple small side holes when performing a therapeutic thoracocentesis. Improvement in dyspnea should occur within 30 minutes to one hour. However if no improvement is seen, repeat dose of furosemide is advised or start a CRI. Most acute canine HF patients should improve with diuretic therapy alone. However, if your patient continues to be refractory to therapy despite repeated doses of the diuretics, you should consider an alternate diagnosis (this animal does not have CHF) or more aggressive CHF management. Now, a review of the commonly used cardiac medications in more detail, their indications and their adverse effects. Unfortunately time and space constraints do not allow for a full discussion of all medications. Additionally for specific doses, please refer to the drug chart at the end of the lecture notes: Pimobendan has a dual mechanism of action, that is an inodilator. Specifically, it is a calcium-sensitizing drug that improves contractility (positive inotrope) with minimal effects on myocardial oxygen consumption. The other mechanism of action is that of phosphodiesterase inhibition leading to a balanced vasodilation (arterial and venous) and as well as improving myocardial performance. Indications: o Labeled for use to treat class II, III, IV heart failure in dogs secondary to degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). o Several studies show improved quality of life and survival in both MR and DCM when compared to ACE-inhibitor. o In general, quite helpful in animals with heart failure and renal insufficiency. Allows lower doses of furosemide and enalapril, if needed. o Add in with ACE-I and furosemide at first onset of HF. o May still add in digoxin especially if pet has supraventricular tachyarrhythmia (eg, atrial fibrillation) and no evidence of renal insufficiency. o Severe pulmonary hypertension idiopathic or secondary to heartworm disease. Improves typical signs of either syncope or right heart failure in these dogs. o Miscellaneous causes of severe heart failure such as congenital heart diseases or infectious endocarditis. o Helpful in feline heart failure due to cardiomyopathy with systolic myocardial dysfunction, especially with concurrent renal insufficiency. Adverse Effects: o Minimal side effects in general o Concerns for tachycardia and pro-arrhythmia tendencies o Possible excessive vasodilation and hypotension o Very early use (prior to heart failure) has been associated with worsening of valvular insufficiency Dosing Considerations:

3 o o o o Has rapid onset of action (within one hour) VERY USEFUL in acute severe heart failure as soon as patient can swallow a pill or crush in water via syringe. Highly protein bound. Rapid oral absorption. Requires conversion to active metabolite in liver. Eliminated in feces via bile. Only 5 % renal excreted. Safe to use with concurrent renal disease and heart failure. Moderately expensive in big dog. Labeled dose: 0.5 mg/kg per day divided BID. Dosing and frequency escalation is common with recurrent or refractory heart failure. NCSU cardiology has used higher than labeled doses with good clinical response. ACE-Inhibitors, most commonly Enalapril and Benazepril, block the conversion of angiotensin I to angiogensin II. Ag II has several negative effects in the setting of heart failure leading to vasoconstriction, resorption of sodium and water as well as direct myocardial toxic effects. Previous studies in dogs have shown that ACE-I improves survival and quality of life in dogs with congestive heart failure secondary to both dilated cardiomyopathy and chronic valvuar heart disease. The benefit of the ACE-I seems to involve more than just it s vasodilator effects. It may possibly inhibit local RAAS which may reverse some of the deleterious remodeling effects. ACE-I usually improves intra- renal blood flow and GFR, however in the setting of pre-existing renal disease, could lower renal perfusion pressures excessively and cause azotemia. For the average HF with a creatinine < 2.0 g/dl, ace-inhibition is recommended as soon as the patient is able to take oral medications. If patient is severely hypotensive or azotemic, cautious use of the vasodilators and diuretics is recommended. Dose reduction and close blood pressure/renal blood work monitoring are recommended. If the dog is already on an ACE- I and not azotemic, increase to maximal dose of 0.5 mg/kg twice daily. The main controversy with the ACE-I is whether or not, it is indicated in preclinical heart disease, that Is, prior to the onset of congestive heart failure. We will discuss that in another lecture. Furosemide is a loop diuretic that removes excess fluid accumulation however does not improve cardiac output or reverse the impairment in cardiac function. The dose of furosemide is usually the most challenging issue with this drug because it needs to be tailored to the individual patient and because we all know that too high of a dose can have deleterious effects on renal perfusion and electrolytes. That said, too low of a dose can lead to unnecessary hospitalization, expense and potential euthanasia. For an inpatient heart failure, the dose is typically ~ 2 4 mg/kg IV or IM q 2-12 hrs as needed. Not to exceed 12 mg/kg/day. We commonly use a furosemide CRI 2-4 mg/kg over 4-8 hrs after initial bolus. For an outpatient heart failure patient, the dose is usually 1-2 mg/kg once to twice daily. The initial furosemide dose is usually higher than the long-term dose. The best dose chronically is the lowest effective dose as overzealous furosemide therapy can lead to low effective circulating volume, hypokalemia (hypomagnesemia) and activation of the RAAS. These electrolyte abnormalities in humans have been shown to predispose to serious arrhythmias. The lowest effective dose is achieved with the aid of the patient s owner. After the first episode of HF, I will teach the owner to take resting respiratory rate and to keep a cough diary. Together we will try (if possible) to lower the furosemide dose gradually over time. I will also give the owner a flex dose of furosemide based on the dog s clinical status and food/water intake. I always remind the owner if the dog is not eating or drinking, the diuretic need may be greatly reduced. Periodic chest radiographs are also helpful to determine the best dose of furosemide. Frank-Starlings Law Furosemide Not congested congested Cardiac Output Preload Spironolactone is a potassium sparing diuretic that works by blocking aldosterone at the collecting ducts. Spironolactone is used together with furosemide as a diuretic and for its anti-aldosterone effects in most causes of chronic CHF. It is not

4 considered an ER drug, as its onset of action is slow. In humans with severe CHF, spironolactone improved survival as compared to placebo when added to conventional CHF treatment (furosemide, ACE-inhibitor, Digoxin). It s improved survival benefit is thought to be primarily due to reduced hypokalemia and arrhythmic death. A clinical trial in dogs with mild to moderate heart failure due to mitral valve disease was recently performed in Europe which suggests survival benefit in dogs receiving the spironolactone vs. placebo. The most common adverse effect is hyperkalemia, which is rare and dose dependent. Like all other diuretics, it has the potential to cause effective hypovolemia and azotemia, albeit less likely than furosemide or hydrochlorthiazide. I am using more spironolactone than in the past since the European study suggesting a survival benefit. That said, I am most commonly using it in refractory or recurrent heart failure especially with right heart failure (ascites). Hydrochlorthiazide is a potassium wasting diuretic that works by blocking sodium and water resorption at the distal tubule. It is occasionally used in end stage heart failure for its additional diuretic effect. At NCSU, we often use a combination diuretic tablet (Spironolactone and hydrochlorothiazide). These oral diuretics can be useful to-go-home medications in a non-azotemic refractory or recurrent heart failure cases who are already on high dose furosemide. By adding a diuretic with a different and more distal site of action (hydrochlorothiazide distal tubule, spironolactone collecting ducts), the diuretics will have a synergistic diuretic effect.

5 NCSU CARDIOLOGY DRUG FORMULARY (updated 2011) DRUG SPECIES ROUTE DOSE ACE INHIBITORS Enalapril Dog PO 0.5 mg/kg q hr (start even lower if azotemic,maybe avoid if creat >3 ) Enalapril Cat PO 0.5mg/kg q hr (start even lower if azotemic,maybe avoid if creat >3 ) Benazapril Dog PO 0.5mg/kg q hr (start even lower if azotemic,maybe avoid if creat >3 ) Benazapril Cat PO 0.5 mg/kg q 24 hr (start even lower if azotemic,maybe avoid if creat >3 ) DIURETICS Furosemide Dog IV/SQ 1-4 mg/kg q 6-12hr PRN (MAX 12 mg/kg/day) Furosemide Dog PO 1-4 mg/kg q 8-24hr PRN (MAX 12 mg/kg/day) Furosemide Dog CRI mg/kg/hr x 4-8hr post bolus Furosemide Cat IV/SQ 1-4mg/kg q 8-24hr Furosemide Cat PO 1-4mg/kg q12-48 hr Spironolactone Dog PO 1-2mg/kg q 12-24hr Aldactazide (HTCZ + Spironolocactone) Dog PO mg/kg dosed based on spironolactone q 12-48hr VASODILATORS Nitroglycerine 2% oint. Both skin 0.25" /5-10 kg q 8 hr (for first 24 hrs typically) Nitroprusside Dog IV mcg/kg/min CRI (Direct BP monitoring ideal) Amlodipine Cat PO 0.625mg q 24 hr, titrate up PRN w/ BP monitor Amlodipine Dog PO 0.1 mg/kg q hr initially.prn titrate- 0.25mg/kg q hr monitor BP Hydralazine Dog PO,IV 0.5mg/kg q hr initially, PRN titrate -1-3mg/kg q 12 hr monitor ABP Pentoxyfylline Dog PO 200 or 400mg q 24 hr Sildenafil (viagra) Dog PO mg/kg q 8-12 (smallest tablet size is 25 mg) $$$ ANTIARRHYTHMIC Lidocaine Dog IV 2-mg/kg bolus, repeat up to 8 mg/kg or adv.eff, 30-80ug/kg/min CRI Lidocaine Cat IV mg/kg slow bolus 1-2x MAX Procainamide Dog IV 2-4 mg/kg slow bolus up to MAX 16 mg/kg, CRI mcg/kg/min Procainamide Dog PO mg/kg q 6-8hr Tocainide Dog PO 4-20mg/kg q 8hr Mexilitine Dog PO 6-8mg/kg q 8 hr Carvedilol Dog PO mg/kg q 12 hr. Start low titrate up once stable CHF Carvedilol Cat PO Q 12 hr, start low titrate up once stable CHF Esmolol Both IV 0.1mg/kg can titrate up to 0.5mg/kg, max effect 2-4min Propanolol(Inderal) Dog PO 0.1-2mg/kg q 8hr - start low, titrate up Propanolol Cat PO 2.5-5mg total q8 hr - start low Atenolol (Tenormin) Dog PO 0.25 mg/kg q12-24hr and titrate up to mg/kg if no HF - start low, titrate up IF STABLE HF, start at 0.1 mg/kg, titrate upward to mg/kg PO BID wk Atenolol Cat PO mg q12-24 hr Sotalol (Betapace) Dog PO 1-3 mg/kg q 12hr (Lower if concurrent renal disease) Sotalol Cat PO 1-2mg/kg q 12 hr (lower if concurrent renal disease) Amiodarone Dog PO mg/kg q12hr x7 d, then mg/kg q 12 hr x 14 d, then mg/kg q24hr Amiodarone Dog IV 0.5mg/kg in ml NaCl over 30 min Diltiazem Dog PO mg/kg q8hr - start low, titrate up Diltiazem Dog IV mg/kg over 3 minutes. Dilacor (Diltiazem SR) Dog PO 1-4 mg/kg q 12 hr. (60 mg tablets inside capsule) Diltiazem Cat PO 7.5mg/cat q 8 hr Dilacor (Dilt SR) Cat PO 30mg/cat q hr (1/2 of 60 mg tablet inside a capsule) Cardizem CD(sustain release) Cat PO 10mg/kg q 24 hr (human capsules = 120mg with spinkles inside) Magnesium sulfate Dog IV 30mg/kg slow IV (15-20 min), then 30mg/kg over 12-24hr Magnesium chloride Dog IV meq/kg slow over 15 min Magnesium oxide Dog PO 1-2 meq/kg/day INOTROPES Digoxin (Cardoxin) Dog PO 0.003mg/kg q 12 h (not to exceed 0.25mg BID) (Th.levels ng/ml) Digoxin Dog IV mg/kg q1hr x 4 hr (total 0.01mg/kg) Digoxin Cat PO 0.01mg/kg q 48hr (1/4 of a 0.125tab q 48 hr) Pimobendan Both PO 0.25 mg/kg q 12 hr (can increase dose and to q 8 hr in refractory cases) Dobutamine Dog IV 1-10 mcg/kg/min CRI Dobutamine Cat IV 1-3 mcg/kg/min CRI VAGOLYTICS Atropine Both IV/SQ 0.04mg/kg

6 Glycopyrollate Both IV/SQ mg/kg (generally 0.011mg/kg) Probantheline Dog PO mg/kg q 8 hr BRONCHODILATOR Terbutaline Dog PO 2.5-5mg total dose q 8-12 hr Terbutaline Cat PO 1.25mg total dose q 8-12 hr Terbutaline Both SQ 0.01mg/kg q 4 hr Theophylline ER Both PO 10 mg/kg q 12 hr Aminophylline Dog IV/SQ 10mg/kg q 8hr dilute and slow IV SEDATION/ANALGESIA Morphine sulfate Dog IV/SQ 0.05mg/kg IV q3 min to effect ( mg/kg tot) (can vomit) Butorphanol Both IV/SQ mg/kg, repeat as needed Buprenorphine Both IV mg/kg q 6-8 hr Hydromorphone Cat IV/im mg/kg Acepromazine Both IV/SQ 0.01 to 0.03 mg/kg Midazolam Both IV/im 0.25mg/kg Hydromorphone Dog IV/im mg/kg Fentanyl Both IV 2-3 mcg/kg, then 1-5 mcg/kg/hr CRI Ketamine Cat IV/IM 5-10 mg total dose Ketamine Cat IV CRI mg/kg/hr ANTITHROMBOTIC Dalteparin (Fragmin) Cat SQ 100 IU/kg q hr Dalteparin (Fragmin) Dog SQ IU/kg q hr Enoxaparin Both SQ 1mg/kg q 12 hr for acute tx Enoxaparin Both SQ 1.5 mg/kg q 24 hr for prophylaxis UF Heparin Dog SQ 100 u/kg q 8hr UF Heparin Cat SQ 100 u/kg IV once then 200u/kg SQ q 8 hr (APTT 1.5-2x) UF Heparin Cat IV 100 u/kg once then 600 u/kg/day CRI (APTT 1.5-2x) Aspirin Dog PO 5 mg/kg q 24 hr with food; Mini dose 0.5 mg/kg q 24 hrs Aspirin Cat PO 81mg q 72 hr with food Warfarin Cat PO 0.25 mg q 24 hr initial dose, titrate up based on INR/PT Tissue Plasminogen Act Cat IV 0.75 mg IV bolus, 2.5 mg IV over 30 min, 1.75 mg IV over 1 hr (5 mg total) Tissue Plasminogen Act Dog IV 0.2 mg/kg IV bolus, 0.7 mg/kg IV over 30 min, 0.5 mg/kg IV over 1 hr (1.4 mg/kg total) Clodiprogel (Plavix) Cat PO mg / cat (1/4 of 75 mg tablet) Clodiprogel Dog PO 1 mg/kg q 24 hr (start low), 10 mg/kg loading dose - 1 d if active clot NUTRACEUTICALS Taurine Dog PO mg q 8-12 hr Taurine Cat PO 250mg q 12 hr L-carnitine Dog PO 50mg/kg q 8 hr w/food or 1-2 gm/dog q 8-12 hr Fish Oils Dog PO EPA 40mg/kg, DHA 25mg/kg q24 hr (w/o vitamin D) (2 gm/day for Boxers) CoQ10 Dog PO 30-90mg/dog q 24 hr Vitamin C Dog PO mg q 24 hr Vitamin E Dog PO 30 IU q 24 hr HEARTWORM PREV. Ivermectin Dog PO 6 12 ug/kg every 30 day for prevention Ivermectin Cat PO 24 ug/kg every 30 day for prevention Dilution of lg animal ivomec: 0.1 ml ivomec ml water = 1000mcg/ml