Presents: With: CANINE AND FELINE CARDIOLOGY CLARKE E. ATKINS DVM, DACVIM

Transcription

1 Presents: CANINE AND FELINE CARDIOLOGY With: CLARKE E. ATKINS DVM, DACVIM December 14, 2011

2 AN APPROACH TO ASYMPTOMATIC ACQUIRED HEART DISEASE IN DOGS AND CATS Clarke E. Atkins, DVM, Diplomate, ACVIM (Internal Medicine & Cardiology) Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine Cardiovascular diseases in dogs and cats produce devastating consequences in those severely affected. Newer diagnostic methods allow earlier and more comprehensive evaluations of patients with heart disease. Frequently the diagnosis is made before clinical signs are evident, obviously the best time for medical or surgical intervention, when possible. Acquired diseases for which early intervention has been proven or would seem likely to be beneficial include dirofilariasis, mitral regurgitation (endocardiosis; MR) dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), hypertension, endocarditis, and some cases of pericardial effusion. This brief manuscript will include a discussion of only the most commonly encountered canine and feline diseases, MR, DCM and HCM. This author does not generally employ diuretics and salt-restriction prior to the onset of (CHF). Potential exceptions to this stance might include diuretics in the management of coexistent hypertension and the use of spironolactone as an aldosterone receptor blocker. Similarly salt restriction, which is useful after the onset of CHF, is not employed prior to its appearance. Again, an exception is in the hypertensive patient. In addition, mild salt restriction, in the form of avoidance of salty treats is probably never contraindicated and the pet s palate may likewise be retrained by mild restriction in anticipation of the need for future sodium restriction. With the exception of patients in atrial fibrillation, digoxin is likewise reserved for patients in heart failure. The role of exercise restriction is not well established. It is known that controlled exercise improves muscle strength and cardiac function in humans in CHF, but may also induce or aggravate arrhythmias. I do not restrict exercise in heart patients prior to the advent of CHF unless the precipitation of life-threatening arrhythmias or syncope is of concern. Mitral Regurgitation Mitral regurgitation, often recognized during mid-life, affords the veterinarian with the somewhat unique opportunity of a long symptom-free window for potential intervention. Since the ideal treatment, surgical correction, is available to a limited number of clients, medical intervention remains the only hope for most clients with dogs suffering from MR. Potential and readily available interventions include angiotensin-converting enzyme (ACE) inhibitors, betablockers, and afterload reducing agents. Each is aimed at blunting the remodeling that occurs with chronic volume loading and/or reduction in the regurgitant volume. There are not data on beta-blockers in naturally-acquired canine MR, though there are data in experimental MR, indicating hemodynamic and remodeling benefit. Additionally, there are clear data indicating quality of life and survival benefit in humans with CHF, treated with beta-blockers. Unfortunately, dosing these agents is somewhat difficult in small dogs and this author has yet to routinely embrace this group of agents (carvedilol, atenolol, and metoprolol) in this setting, either before or after the onset of CHF. ACE inhibitors have received the majority of attention in asymptomatic MR. There are studies which support and refute the activation of the RAAS prior to CHF in MR, leaving the question to be answered by clinical trials. Two studies have prospectively evaluated enalapril in dogs with MR, prior to the onset of heart failure. The first (SVEP) was carried out in Northern Europe in cavalier king Charles spaniels. This well-designed double-blind, placebocontrolled (DBPC) study was unable to demonstrate a benefit in time to onset of CHF when the drug was compared to placebo in mildly to moderately affected Cavalier King Charles Spaniels. The second (VETPROOF), a DBPC trial carried out in the U.S., has recently been completed (to both CHF and death as end-points). This study showed benefits in time remaining in study, number of dogs CHF-free at 500 days and study termination. The Kaplan-Meier Survival Curves demonstrate a strong, but not statistically significant, trend toward a modest increase in time to onset of heart failure. Both studies demonstrated the safety of enalapril in aged dogs with compensated heart disease. A recent survey of 100 ACVIM-board-certified cardiologists showed that 70% believed that ACE-Inhibitors Clarke E. Atkins DVM, DACVIM 1 Canine & Feline Cardiology

3 were useful in asymptomatic MR and while the ACVIM Consensus Panel on MR failed to reach 100% consensus on its use in this arena, the majority of panelists believed it to be useful. This author offers ACE-I therapy to dogs with asymptomatic MR and radiographic and/or echocardiographic evidence of remodeling (VHS > 11). Reasons for this approach include the proven hemodynamic improvement in human MR, the results of the VETPROOF, the strong safety record, and potential for benefit in reducing mitral regurgitation and in blunting remodeling initiated by the RAAS. Careful scrutiny of renal function, blood pressure, and serum potassium concentration is provided initially and periodically during therapy. In addition, the owner is advised as to cost, the potential for life-time administration, the risk of hypotension, and the varied results of clinical trials. Aldosterone-receptor-blockers, such as spironolactone (0.5 mg/kg bid) or eplerinone have theoretical benefit in this setting as an adjunct to ACE inhibition as aldosterone escape has been recognized in humans receiving chronic ACE inhibition. Interestingly, 2 publications have failed to show diuretic efficacy with spironolactone alone and in conjunction with furosemide in normal dogs. However, a recent publication has shown benefits of spironolactone at 2 mg/kg daily in dogs with heart failure. Conventional vasodilator therapy has been largely replaced with the advent of ACE inhibitors but venodilators play a role in emergency management of CHF and afterload-reducing arteriolar dilators agents are often employed to unload the heart, reducing mitral regurgitation. There is certainly evidence to show that arteriolar vasodilators, such as hydralazine and amlodipine, can reduce mitral regurgitation. Unfortunately, these drugs activate the RAAS and may increase resting heart rate as well. If used chronically prior to the onset of CHF, their use should be accompanied by concurrent ACE inhibition or angiotensin receptor blockade. While pimobendan, the inodilator, has been proven to be useful in the treatment of dogs with CHF due to MR, there has been controversy regarding its use prior to the onset of heart failure. Currently, this use is being investigated in a double-blind, placebo-controlled trial. In summary, while each of these drug groups has theoretical utility in this setting, there is not strong evidence for any. While a combination of 2 or even 3 of these drugs has appeal, the risk is hypotension and its attendant undesirable sequelae. This author has employed the combination of enalapril and amlodipine in hypertensive dogs with severe MR, prior to the onset of CHF. In most cases, however, I begin an ACE-inhibitor after there is radiographic or echocardiographic evidence of remodeling. The owner is involved in the decision and is educated as to the limited proof of efficacy, cost, risks, and that the drugs will likely be given for life. Enalapril is initiated at mg/kg after renal function, blood pressure, and serum electrolytes are evaluated. In approximately one week the dosage is increased to the target dosage of.5-1 mg/kg either QD or divided BID. Renal parameters, serum electrolytes, and ideally systemic blood pressure are rechecked in 2-3 weeks and then as often as clinically indicated thereafter. For the motivated client, after the ACE-inhibitor is prescribed and tolerated, beta-blockade with carvedilol is instituted with up-titration to.8-1 mg/kg BID over Dilated Cardiomyopathy DCM in dogs is a much more devastating disease than MR and is more often diagnosed after the onset of CHF. Nevertheless, DCM may be diagnosed prior to CHF, via echocardiography, after detection of a cardiac gallop or murmur or through routine screening in certain breeds. It seems clear that beta-blockers, administered early, are beneficial in this disease in humans; anecdotal reports suggest a similar benefit in dogs. ACE-inhibitors have been shown to provide benefit in humans with DCM or ischemic cardiomyopathy prior to heart failure. O Grady, in a retrospective study, showed that Doberman pinschers with occult DCM lived longer (substantially so) when they received ACE-I, as compared to the control population which did not. Aldosterone-receptor-blockers, such as spironolactone (0.5 mg/kg bid) or eplerinone have the same theoretical benefit in DCM as in MR. Pimobendan, not yet available in this country, has improved survival and quality of life in Doberman pinschers with DCM and CHF and may have a future role prior to CHF. Carnitine and taurine have potential benefits in dogs deficient in these nutrients and may be instituted either alone or together, with or without having measured serum concentrations. Carnitine is provided as a treatment option for asymptomatic DCM, particularly in boxers, while taurine and Clarke E. Atkins DVM, DACVIM 2 Canine & Feline Cardiology

4 carnitine are administered to all American cocker spaniels with DCM. Digoxin, in the author s opinion, has no role in asymptomatic DCM unless atrial fibrillation is present. In this setting, digoxin is administered, with the addition of diltiazem or a beta-blocker, as needed to control the ventricular response. While pimobendan, the inodilator, has been proven to be useful in the treatment of dogs with CHF due to DCM, there has been controversy regarding its use prior to the onset of heart failure. Currently, this use is being investigated in a double-blind, placebocontrolled trial. In the clinic at NCSU, asymptomatic DCM would most typically be treated with avoidance of heavily-salted foods, possibly taurine and/or carnitine (depending on the breed and input from the owner), and an ACE-Inhibitor (Enalapril at.5-1 mg/kg daily, starting at and increasing to the target dosage in 1 week). If atrial fibrillation is present, digoxin (and diltiazem, if needed) are added, to control the ventricular response (<120 bpm, ideally) within hours. After approximately 2 weeks carvedilol or atenolol is added (for a large-breed dog, mg QD x 2 weeks, then bid x 2 weeks, then 6.25/3.125 mg x 2 weeks, etc) until a full dose of mg daily, divided BID, is achieved or the patient shows signs of intolerance. If intolerance develops (usually lassitude, inappetance, and hypotension), the dosage is dropped to the last tolerated dosage for 2-4 weeks and then an attempt is made to increase as previously described. If the patient cannot tolerate increases in carvedilol, the last tolerated dosage is accepted as maximum. Human studies indicate that, though lessened, sub-optimal dosages still provide benefit. Pimobendan can be used in instances of beta-blocker intolerance through inotropic and vasodilatory support. Lastly, if signs of low output heart failure are present (syncope, exercise intolerance), we may begin pimobendan prior to the onset of CHF (pulmonary edema). Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy typically affects cats of middle age (6.5 years on average). Most are affected with a murmur or gallop, but a significant number (22% of 260 cats) with heart failure, described by Rush, et al. had neither. This suggests that clinical indicators, prior to onset of signs, are often absent, minimizing the chance of intervention. Drugs that enhance ventricular relaxation and slow the heart include the beta adrenergic (atenolol), and calcium channel (diltiazem) blockers are indicated in treatment of the diastolic dysfunction of HCM. Beta blockers improve diastolic performance only indirectly, enhancing ventricular filling by reducing heart rate and improving myocardial perfusion. Traditionally, beta-blockers have been administered orally to reduce and prevent elevations in LVEDP, to lower systolic pressure gradients and myocardial oxygen requirements, to prevent stress-induced tachycardia and reduce resting heart rate, and for their antiarrhythmic effects. When arrhythmias are present, this drug may be initiated earlier in the disease course. This is the author s treatment of choice for asymptomatic HCM, for cats with documented outflow obstruction (HOCM), and when tachycardia is noted. Calcium channel blocking agents have been effective in human HCM by reducing heart rate, myocardial oxygen consumption, and diastolic dysfunction. In addition to directly enhancing myocardial relaxation, these drugs dilate peripheral and coronary arteries. Bright has demonstrated the utility of diltiazem (3-7.5 mg po tid) in the treatment of symptomatic feline HCM, including those cases refractory to the beta-blocker, propranolol. Unfortunately, current packaging for human use makes accurate feline dosing of diltiazem difficult. Long-acting diltiazem may be substituted and includes Cardizem CD (45 PO qd; requires disassembling capsules) or Dilacor (30 mg PO bid; requires disassembling capsules). Combining a calcium channel blocker and a beta blocker has theoretical advantages and is often done, using a long-acting form of each drug, one in the morning and one in the evening. There is no role for amlodipine in the normotensive cat with HCM as it has no theoretical or proven benefit and it may precipitate hypotension. This author does not use diltiazem in HCM prior to the onset of heart failure. A report by Rush, et al. demonstrated a reduction in wall thickness with the administration of enalapril to cats with HCM. This suggests a potential role for ACE-inhibitors in the treatment of HCM. These drugs are generally safe and do play a role in some symptomatic cats. While it is logical that the renin-angiotensin-aldosterone system is not pathologically activated in asymptomatic patients, and hence ACE-inhibitors might not be useful, Rush s data argue otherwise. In a double-blind, placebo-controlled study, MacDonald, et al. evaluated the role of the ACE-inhibitor, Clarke E. Atkins DVM, DACVIM 3 Canine & Feline Cardiology

5 ramipril (12 months therapy), in asymptomatic HCM in Maine Coon Cats and found no benefits in terms of diastolic function, myocardial mass, or suppression of aldosterone or BNP levels. This author does not use ACE-Inhibitors in asymptomatic HCM unless there is evidence of myocardial damage (infarctions) for which this drug group has shown to be efficacious in man. Other therapies, including, aspirin or low molecular weight heparin, home confinement, and moderate salt restriction should be instituted as needed. Taurine supplementation is not indicated in the treatment of HCM. In asymptomatic cats with HCM, the author advises home confinement, moderate salt restriction, Beta- and/or calcium channel blockade and aspirin (with left atrial enlargement) indefinitely. If left atrial enlargement is severe (>2.4 cm), if clots or spontaneous left atrial echo ( smoke ) are noted, or with a history of systemic thromboemboli, low molecular weight heparin (dalteparin, Fragmin) is administered at 100 units/kg SQ qd. Additional Reading Dog 1. Improve Study Group. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally occurring acquired heart failure: Results of invasive multicenter prospective veterinary evaluation of enalapril study. J Vet Intern Med 1995; 9: Cove Study Group. Controlled clinical evaluation of enalapril in dogs with heart failure: Results of the cooperative veterinary enalapril study group. J Vet Intern Med 1995; 9: LIVE Study Group. Effects of enalapril on survival in dogs naturally acquired heart disease: Results of long-term investigation of veterinary enalapril (LIVE) study group. J Amer Vet Med Assoc 1998; 213: Hamlin, RL, Benitz, AM, Ericsson, GF, et al.: Effects of enalapril on exercise tolerance and longevity in dogs with heart failure produced by iatrogenic mitral regurgitation. J Vet Intern Med 1996; 10: Bench Study Group: The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: Results of a multicenter, prospective, randomized, double-blinded, placebo-controlled, long-term clinical trial. J Vet Cardiol 1999; 1: VETPROOF Study Group. Renal safety of chronic enalapril therapy in dogs with compensated mitral regurgitation (abst). J Vet Intern Med 1999; 13: Pitt, B, Zannad, F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Eng J Med 1999; 341: Atkins, CE: Enalapril Monotherapy in Asymptomatic Mitral Regurgitation: Results of the VETPROOF (Veterinary Enalapril Trial to Prove Reduction in Onset of Failure). Proceedings American College of Veterinary Internal Medicine, 75-76, Atkins, CE, Brown, WA, Coats, JR, et al. Effects of long-term administration of enalapril on clinical indicators of renal function in dogs with compensated mitral regurgitation. J. Amer. Vet Med Assoc. 2002; 221: Kvart, C, Haggstrom J, Pedersen, D, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med 2002, 16: Nemoto S, Hamawaki M, De Freitas G, Carabello BA. Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol 2002; 40(1): Additional Reading - Cat 12. Ferasin, L. Sturgess, C.P., Cannon, M.J., et al. Feline idiopathic cardiomyopathy: a retrospective study of 106 cats ( ). J Fel Med and Surg 2003; 5: Clarke E. Atkins DVM, DACVIM 4 Canine & Feline Cardiology

6 The ACVIM Consensus Statement: Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease - What this Means for the General Practitioner Clarke E. Atkins, DVM, Diplomate, ACVIM (Internal Medicine & Cardiology) Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine Introduction The most important cardiovascular disease in veterinary medicine is canine chronic mitral valvular disease (canine chronic valvular heart disease CCVHD, endocardiosis, myxomatous valve degeneration, mitral regurgitation [MR]), affecting 85% of dogs aged 13 years or older and constituting 75% of canine heart disease. 1 Controversy and a general lack of agreement exists as to the appropriate medical management of CCVHD, both prior to and after the onset of heart failure. The American College of Veterinary Internal Medicine s Board of Regents selected a group of European and U.S. ACVIM-boarded cardiologists (Bruce Keene, Panel Chair; and alphabetically, Clarke Atkins, John Bonagura, Steve Ettinger, Phil Fox, Virginia Luis-Fuentes, Sonya Gordon, Jens Haggstrom, Robert Hamlin, and Rebecca Stepien) to arrive at a consensus as to the diagnosis and treatment of CCVHD and to produce a consensus document. 1 Appropriately, the 10 panel members represented diverse points of view on cardiac therapeutics. As with all such consensus statements, the results do not necessarily represent cutting edge recommendations, but the result of a group of individuals compromise or collective wisdom. In making these recommendations, based on all available evidence, panelists determined that the potential benefits of a particular treatment option clearly outweigh the risk of adverse events and that the financial impact on the client is justified. Evidence was derived from sources ranging from placebo-controlled, double-blind clinical trials and other experimental data to anecdote, clinical experience, and expert opinion, with greater weight put on the former. To achieve consensus, all 10 panelists had to agree on the recommendation. In addition to putting forth consensus recommendations on diagnostic and therapeutic options, the panel revealed instances when the majority of panelists agreed upon a recommendation, even if consensus was not reached. The group chose to use a new grading system for cardiac disease severity and progression, which is described below. In this manuscript the ACVIM Consensus Panel s recommendations are put forth, including both those for which consensus was reached and those for which only a majority recommended a therapy. In addition to the panels recommendations, I will render my own personal opinion, when I feel that it is appropriate to do so. Space constraints preclude discussion of the panel s recommendations on diagnostic steps for each category of CCVHD and treatment recommendations for refractory heart failure (Stage D). Hence, I will cover only management recommendations for dogs at risk for CCVHD, those with very early disease, those with cardiac enlargement, those hospitalized for heart failure, and those treated for heart failure at home. Mitral Valve Disease Severity Classification There are a number of classification schemes for cardiac disease in dogs, including the Modified New York Heart Association and the International Small Animal Cardiac Health Council (ISACHC) systems, both of which are widely used in veterinary medicine. The panel chose to adapt a novel classification scheme modeled after that put forth by the American Heart Association and the American College of Cardiology. This scheme avoids the NYHA classification pitfall of using progressive loss of exercise tolerance to grade disease severity. In addition, it adds an early category (A), during which dogs are without evidence of disease, but which are at risk for developing disease (e.g. Cavalier King Charles Spaniels). The ACVIM classification system is shown in Figure 1. Class A CCVHD patients are at risk, B1 have murmurs but no cardiomegaly, B2 have cardiomegaly, C a have acute heart failure, requiring hospitalization, C c have chronic heart failure and are treated at home, D a patients have refractory heart failure, requiring hospitalization, while D c have refractory heart failure but can be managed at home. The panel attempted to achieve consensus on the management of dogs in all categories of severity. As mentioned, only the therapeutic recommendations for ACVIM Class A through C are discussed herein. However, Figure 2 demonstrates the Panel s Consensus AND Majority recommendations and Figure 3, the Consensus recommendations, for all stages A through D. Clarke E. Atkins DVM, DACVIM 5 Canine & Feline Cardiology

7 Stage A CCVHD CONSENSUS: The panel recommends no drug therapy during this stage. Breeding stock in which a murmur of mitral regurgitation is discovered during the normal breeding years (6-8 years) should be removed from the breeding program. Stage B1 CCVHD CONSENSUS: No drug or dietary therapy is recommended for either small or large dogs with MR. Author s Comment: This author suggests that owners might benefit in long-term by starting mild salt restriction at B1 and B2, while appetite is presumably still good; this avoids the necessity of abrupt changes later and allows the dog s palate to be trained to a lower salt preference. The panel did not address the possibility of hypertension in B1 patients, but would likely agree that if hypertension is diagnosed, its control is imperative, probably by the administration of both an ACE-Inhibitor and amlodipine. This logic would apply to all stages of CCVHD. Stage B2 CCVHD CONSENSUS: None (The panel was not unanimous on any recommendation at this state.) MAJORITY: ACE-Inhibitors were recommended by the majority of panelists for dogs with CCVHD and cardiac remodeling (enlargement). A majority of panelists recommended AGAINST the use of Beta-blockers at this disease stage. A majority of panelists suggested dietary alteration, including mild salt restriction, high palatability and adequate protein and carbohydrate content. Author s Comment: Although controversial 2, this author does utilize ACE-Inhibitors in Stage B2 CCVHD, as the majority of evidence supports their use. 3,4 In an unpublished survey of 100 ACVIM-boarded cardiologists, nearly 60% used ACE-Inhibitors in small breeds and nearly 70% in large breeds, at this stage of CCVHD. 5 For more dedicated clients, I sometimes prescribe up-titration of a Beta-blocker (e.g., carvedilol or atenolol) and would consider the use of spironolactone based on recent evidence from our laboratory indicating that aldosterone escape occurs with benazepril in normal dogs undergoing furosemide-induced RAAS activation. This indicates that, for complete renin-angiotensin-aldosterone (RAAS) suppression, drugs which blunt this system at different points in the cascade are possibly indicated. 6 Specific data from clinical trials, for the moment, are lacking for both Beta- and aldosterone-receptor blockade in Stage B2 CCVHD. Stage C hospitalized/acute (C a ) CCVHD CONSENSUS: A consensus was reached by the panel on the use of furosemide (PO, IM, IV, CRI 7,8 ) and pimobendan for hospitalized heart failure patients. As clinical conditions dictate, the panel also agreed that oxygen, using cage or nasal tube; mechanical fluid removal (thoracic or abdominal fluid which contributes to dyspnea); specific nursing measures to relieve dyspnea/discomfort (appropriate humidity and temperature and body positioning); sedation (e.g., buprenorphine and/or acepromazine; morphine); and nitroprusside (mixed vasodilator) and/or dobutamine (inotropic effect, afterload reduction, mitral orifice size reduction) by CRI. MAJORITY: Although consensus was not reached, a majority of panelists recommended ACE-inhibitors as offloading (vasodilators) in the acute Stage C patient. This approach is supported by human studies evaluating IV enalaprilat (the active metabolite of enalapril) in acute heart failure 9,10 and the results of the IMPROVE Trial which demonstrated a fall in pulmonary artery wedge pressure (equivalent to left atrial pressure, the driving pressure producing pulmonary edema) with oral enalapril therapy. 11 Author s Comment: Only a minority of panelists advocate the use of nitroglycerin in these patients. My view is that this additional off-loading therapy is beneficial and is used in place of the somewhat cumbersome nitroprusside. My standard approach to the hospitalized Stage C patient includes administration furosemide (IV or IM bolus or CRI), enalapril, and pimobendan, with oxygen (in most), dobutamine, digoxin (if in atrial fibrillation) and nitroglycerine added as patient needs dictate. Clarke E. Atkins DVM, DACVIM 6 Canine & Feline Cardiology

8 Stage C outpatient/chronic (C c ) CCVHD CONSENSUS: Consensus was reached by the panel on the use of oral furosemide, an ACE-Inhibitor 11-16, and pimobendan 17 ( triple therapy ) for Stage C patients after release from the hospital. The panel also unanimously recommends that Beta-blockers not be instituted in Stage C dogs exhibiting signs of heart failure. MAJORITY: The majority of panelists recommended the use of the aldosterone receptor blocker, spironolactone, for chronic Stage C patients. Likewise, the majority of panelists advocated the use of twice daily enalapril if this is the ACE-Inhibitor being used or an equivalent dosage of another agent. In the face of atrial fibrillation, the majority of panelists advocate the use of digoxin to support cardiac function and to slow the ventricular response to atrial fibrillation. Author s Comment: It is noteworthy that the Consensus Report was prepared prior to the publication of a placebo-controlled, double blind study demonstrating the positive impact achieved with the addition of spironolactone to standard therapy in dogs in heart failure. 18 While it cannot be said with certainty, the panel may well have reached consensus on the use of spironolactone in Stage C dogs had this information been available during the panel s deliberations. As mentioned above, the argument for adding spironolactone is strengthened by the study from the author s laboratory demonstrating early aldosterone escape with ACEinhibition in a model of heart failure therapy, indicating that an ACE-Inhibitor alone may not adequately suppress the circulating RAAS. 6 CCVHD, if of sufficient severity, is in actuality a surgical disease. To date, unfortunately, efforts at valve repair or replacement have not been met with adequate success. Recently published case series of surgical mitral valve repair have provided disappointing results with high peri-operative mortality with valve repair 19 and postoperative thrombus formation with valve replacement 20, although some individual successes have been achieved. These results are certainly due, in part, to the fact that surgical correction is delayed until heart failure has ensued. Nevertheless, because of the cost, small numbers of participating centers and limited success, surgical correction of CCVHD is not currently practical, leaving this as a medically-managed disease in veterinary patients for the time being. Consensus statements by their very nature represent a compromise of positions, regardless of the subject under discussion. The ACVIM Consensus Statement on Canine Chronic Valvular Heart Disease is no different. The very act of compromising creates a safer, less daring approach to cardiac therapeutics that most can agree upon. It takes out of the mix, the more aggressive, less well-proven approaches that might be part of the next consensus statement, but reduces the risk of partaking in such practices. It should be noted that this paper reviews only a portion of the consensus statement and I recommend that the whole document be read for the recommendations on diagnosis in CCVHD, for subtle nuances in treatment approaches, drug dosages, and recommendations for diagnosis and management of refractory heart failure. Abbreviations ACE Angiotensin Converting Enzyme ACVIM American College of Veterinary Internal Medicine CCVD Canine Chronic Valvular Disease CRI Continuous Rate Infusion IM Intramuscular ISACHC International Small Animal Cardiac Health Council IV - Intravenous MR Mitral Regurgitation NYHA New York Heart Association RAAS Renin-Angiotensin-Aldosterone System Clarke E. Atkins DVM, DACVIM 7 Canine & Feline Cardiology

9 References 1. Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23: Kvart C, Haggstrom J, Pedersen HD, et al. Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. J Vet Intern Med 2002;16: Atkins CE, Keene BW, Brown WA, et al. Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. J Am Vet Med Assoc 2007;231: Pouchelon JL, Jamet N, Gouni V, et al. Effect of benazepril on survival and cardiac events in dogs with asymptomatic mitral valve disease: a retrospective study of 141 cases. J Vet Intern Med 2008;22: Bonagura J. Current Clinical Practices Survey. ACVIM Heart Failure Symposium 2010;Oral presentation. 6. Lantis AC, Atkins, CE, DeFrancesco TC, et al. Aldosterone Escape in Furosemide-Activated Circulating Renin- Angiotensin-Aldosterone System (RAAS) in Normal Dogs (abst). J Vet Intern Med 2010;24:xx-yy. 7. Adin DB, Taylor AW, Hill RC, et al. Intermittent bolus injection versus continuous infusion of furosemide in normal adult greyhound dogs. J Vet Intern Med 2003;17: Johansson AM, Gardner SY, Levine JF, et al. Furosemide continuous rate infusion in the horse: evaluation of enhanced efficacy and reduced side effects. J Vet Intern Med 2003;17: Tohmo H, Karanko M, Korpilahti K. Haemodynamic effects of enalaprilat and preload in acute severe heart failure complicating myocardial infarction. Eur Heart J 1994;15: Sabbah HN, Levine TB, Gheorghiade M, et al. Hemodynamic response of a canine model of chronic heart failure to intravenous dobutamine, nitroprusside, enalaprilat, and digoxin. Cardiovasc Drugs Ther 1993;7: The IMPROVE Study Group. Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: Results of the Invasive Multicenter PROspective Veterinary evaluation of Enalapril study. J Vet Intern Med 1995;9: Ettinger SJ, Benitz AM, Ericsson GF, et al. Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. J Am Vet Med Assoc 1998;213: The BENCH Study Group. The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multi center, prospective, randomized, double-blinded, placebo-controlled, longterm clinical trial. J Vet Cardiol 1999;1: Besche B, Chetboul V, Lachaud Lefay MP, et al. Clinical evaluation of imidapril in congestive heart failure in dogs: results of the EFFIC study. J Small Anim Pract 2007;48: Amberger C, Chetboul V, Bomassi E, et al. Comparison of the effects of imidapril and enalapril in a prospective, multicentric randomized trial in dogs with naturally acquired heart failure. J Vet Cardiol 2004;6: The COVE Study Group. Controlled clinical evaluation of enalapril in dogs with heart failure: results of the cooperative veterinary enalapril study group. J Vet Intern Med 1995: Haggstrom J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. J Vet Intern Med 2008;22: Bernay F, Bland JM, Haggstrom J, et al. Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease. J Vet Intern Med;24: Orton EC, Hackett TB, Mama K, Boon JA. Technique and outcome of mitral valve replacement in dogs. J Am Vet Med Assoc May 1;226(9): , Griffiths LG, Orton EC, Boon JA. Evaluation of techniques and outcomes of mitral valve repair in dogs. J Am Vet Med Assoc Jun 15;224(12): Clarke E. Atkins DVM, DACVIM 8 Canine & Feline Cardiology

10 Figure 1. The American College of Veterinary Internal Medicine (ACVIM) Classification of cardiac disease. Figure 2. The ACVIM Consensus Panel on Chronic Canine Valvular Heart Disease (CCVHD) Consensus and Majority Recommendations for medical management of various stages of CCVHD are presented. Lasix, furosemide; Pimo, pimobendan; O 2, oxygen; NP/Dob, nitroprusside and/or dobutamine; -centesis, abdominocentesis and/or thoracocentesis; ACE-I, ACE-Inhibitor; Vent, ventilator therapy; Spirono, spironolactone. Clarke E. Atkins DVM, DACVIM 9 Canine & Feline Cardiology

11 Figure 3. The ACVIM Consensus Panel on Chronic Canine Valvular Heart Disease (CCVHD) Consensus Recommendations for medical management of various stages of CCVHD are presented. Lasix, furosemide; Pimo, pimobendan; O 2, oxygen; NP/Dob, nitroprusside and/or dobutamine; -centesis, abdominocentesis and/or thoracocentesis; ACE-I, ACE-Inhibitor; Vent, ventilator therapy; Spirono, spironolactone. Clarke E. Atkins DVM, DACVIM 10 Canine & Feline Cardiology

12 DIFFERENTIATION OF CARDIAC AND RESPIRATORY DISEASE IN THE DOG Clarke E. Atkins, DVM, Diplomate, ACVIM (Internal Medicine & Cardiology) Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine The coughing dog commonly presents both a diagnostic and therapeutic dilemma to the practicing veterinarian, the former often begetting the latter. This is particularly true in middle-aged to aged, small breed dogs which are often afflicted with chronic respiratory disease and mitral insufficiency, each of which may result in coughing. The problem then becomes one of distinguishing the degree to which respiratory and/or cardiovascular disease are contributing to the cough. This is important because the therapies are quite different and, in some instances, appropriate therapy for one worsens the other. Causes of coughing are many, but in the population of dogs under discussion, cough most commonly results from upper airway disease, tracheobronchial collapse, chronic bronchitis of varying etiologies, pulmonary fibrosis, bronchiectsis, pulmonary neoplasia, pneumonia, and mitral regurgitation (the latter, usually but not always with heart failure). In mitral regurgitation, the cause of cough is not entirely clear, but left atrial impingement on the left main bronchus and/or recurrent laryngeal nerve, edema of the respiratory mucosa, interstitial fluid pressure on airways, and excessive bronchial mucous production have all been suggested as being contributory. The diagnosis of chronic, unresponsive cough is challenging, particularly when concurrent cardiac disease is identified. Often, referral of such cases is warranted, providing such diagnostic opportunities as fluoroscopy, electrocardiography, echocardiography, oximetry, bronchoscopy, bronchoalveolar lavage, culture and sensitivity, cytological evaluation, lung biopsy or fine needle aspiration, serology (e.g. fungal, toxoplasma, heartworm, etc), specialized fecal examinations (sedimentation and Baerman examination for respiratory parasites), and arterial and venous blood gas analysis. In many instances however, referral centers are inconvenient, owners decline referral, or referral is unnecessary. Virtually all small animal practices can, through careful historical, physical, and special procedural examination, provide an excellent diagnostic workup for dogs with cough and mitral regurgitation. Special procedures typically available to private practitioners include inspiratory and expiratory thoracic and cervical radiographs to evaluate for airway collapse or infiltrate, cardiac size, evidence of heart failure, and the pulmonary parenchyma; electrocardiography to determine heart rate and the presence of left and/or right atrial and/or ventricular enlargement; transtracheal wash as a substitute for bronchoscopy, with culture and cytological evaluation; and trial diuresis. Historical and physical findings which may indicate a respiratory cause for chronic cough include obesity, harsh cough, mucopurulent nasal discharge, harsh, "honking" and/or productive cough, and respiratory wheezes. Contrarily, loss of condition, soft, non-productive cough, often worse at night, accompanying dyspnea (may occur with severe respiratory disease as well), and tachycardia with weak pulses are more indicative of a cardiac cause for the cough. The complete blood count may be useful in indicating eosinophilia and possibly basophilia which are most compatible with allergic or parasitic disorders, such as parasitic or eosinophilic pneumonias or heartworm disease. With bacterial pneumonia, there may be indicators of sepsis, such as neutrophilia, toxic changes in neutrophils, and monocytosis. It is emphasized that hemotalogical changes are inconsistent, at best. In heartworm-endemic areas, appropriate testing (antigen Elisa for dogs on monthly preventative; antigen Elisa and/or Knott test if on no or daily preventative). Overall, the most useful tool is the thoracic radiograph. It is beyond the scope of this manuscript to review thoracic radiography. Specific changes useful in differentiating cardiac from respiratory causes of cough include distinction of left vs right heart enlargement, indicative respectively of cardiac and respiratory causes. The status of the lung, airways, and pulmonary vasculature is, likewise, often elucidating. Bronchial thickening, pulmonary infiltrate (other than pulmonary edema), pulmonary arterial enlargement (apical pulmonary artery larger than accompanying vein Clarke E. Atkins DVM, DACVIM 11 Canine & Feline Cardiology

13 or proximal one-third of the fourth rib where they intersect) suggest respiratory disease with the latter finding most consistent with pulmonary hypertension (typically heartworm disease). Contrarily, enlargement of the pulmonary vein (apical pulmonary vein greater than accompanying artery or greater than the proximal one-third of the fourth rib where they intersect) suggests pulmonary venous congestion (left heart failure). Evaluation of the airways for dynamic function is best performed with fluoroscopy but can be approximated by maximizing the information gleaned from conventional radiography. This can be accomplished by supplementing routine full inspiratory lateral and ventrodorsal radiographs with a lateral exposure at full expiration, and ideally, a full inspiratory exposure focused over the cervical trachea. The former will demonstrate intrathoracic and the latter, extrathoracic airway collapse. It should be emphasized that a negative dynamic study, such as this, does not definitively rule out airway collapse. Electrocardiographic findings compatible with respiratory disease (and heartworm disease which in reality is respiratory - or pulmonary arterial - disease) include slow rate, sinus arrhythmia, P-pulmonale (P waves >0.4mv, indicating right atrial enlargement), and occasionally a right ventricular enlargement pattern (S waves in leads 1, 2 and 3, right axis deviation, and deep S waves in V 3 ). Alternatively, dogs with mitral valvular insufficiency typically have normal mean electrical axis, tachycardia if in heart failure, P mitrale (widened and sometimes notched P waves), and possibly, left ventricular enlargement pattern (tall R waves and/or prolonged QRS complexes). Specific information about the nature of respiratory disease can be obtained routinely with transtracheal aspiration (wash). This is accomplished under mild sedation (or none in debilitated animals) so that the cough reflex is not blunted. Standard surgical preparation is performed over the larynx. The cricothyroid ligament is palpated by feeling the indentation; this is accentuated by flexing and extending the neck. Lidocaine is infiltrated subcutaneously over this site. The dog is positioned in sternal recumbency or in a sitting position. It is important to keep the dog symmetrically positioned to allow accurate assessment of anatomic landmarks. The neck is extended and a small stab incision made over the cricothyroid membrane. A 12 to 18 inch 14 to 16 gauge intravenous catheter is used to puncture the membrane, with the trachea digitally stabilized. The catheter is directed down into the airway and the catheter advanced. Coughing indicates successful entry into the airway. Once the catheter has been fully advanced, the needle is backed from the trachea and the needle guard applied. The metal stylet is removed and nonbacterostatic saline (approximately.4 ml/kg) is rapidly infused and reaspirated. Only a small fraction of the infusate is retrieved. This washing procedure may be repeated once or twice. The evidence of mucous or pus in the retrieved material suggests a successful wash. The material is placed in appropriate transport media and submitted for bacterial (and possibly fungal) culture and for cytological evaluation. Pressure should be applied to the entry site for a full 5 minutes after the catheter is removed. I prefer not to perform this procedure on dogs less than approximately kg; in smaller dogs, the procedure is performed through a sterile endotracheal tube, using a red rubber feeding tube and brief general anesthesia. Complications to this procedure are uncommon but hospitalization or close observation at home are advised. Sedation for the first 12 hours is useful in excitable dogs or those with intractible, violent coughing. Bronchoscopy provides the advantage of allowing direct visualization of the airways and selective sampling of specific sites. Disadvantages include cost, the need for special expertise and equipment, and the necessity of anesthesia. Superior cytological samples can be obtained using bronchoalveolar lavage, a technique which also requires general anesthesia and is best performed using bronchoscopy. This technique, which may compromise animals with severe respiratory disease, samples specific lung lobes by filling the alveoli in the region with sterile saline and aspirating the contents. Large numbers of cells are recovered and, because samples are diluted, clumping of cells with mucous is minimized. Bronchoalveolar lavage is generally reserved for cases in which less invasive methods are unsuccessful. Like the techniques mentioned above, bronchoalveolar lavage is most advantageously employed in cases with other than pure interstitial disease, as the samples represent primarily the airways and alveoli. The use of biomarkers in the differentiation of cardiac and respiratory disease has become a reality. NT-proBNP appears to be the most promising is currently under heavy scrutiny for its ability to differentiate not only failing from non-failing hearts but for differentiating diseased from non-diseased hearts as well. Clarke E. Atkins DVM, DACVIM 12 Canine & Feline Cardiology

14 Lastly, a therapeutic trial of an off-loading drug, such as furosemide, can be useful in ruling in or out cardiac disease as the cause for coughing. Such therapy will clear edema and shrink the left atrium, relieving the cause of cardiac cough. If the cough is purely respiratory in origin, this maneuver is unlikely to be of benefit. Several concepts are important if this approach is used. First, the dosage of furosemide must be adequate and the duration of therapy long enough (.5-1 mg/kg tid for 2-4 days) to allow firm conclusion as to its efficacy in controlling the cough. Second, this approach should not involve any other drugs, so that the exact cause of a favorable response is evident. Lastly, the owner needs to be educated to the fact that this is a diagnostic test, that his or her evaluation of the response is important, and that if successful, the dosage will be lowered and other drugs, such as angiotensin converting enzyme inhibitors, will be added to the regimen. It should be emphasized that, in some cases, respiratory and cardiac diseases may coexist and work in concert to produce the cough. In addition, neither respiratory nor chronic mitral valvular diseases are static, so conclusions drawn regarding the cause of a cough correctly drawn today may no longer be valid over time. Clarke E. Atkins DVM, DACVIM 13 Canine & Feline Cardiology

15 Differentiating Cough Due to Cardiac and Respiratory Disease Respiratory Disease Cardiac Disease Body Weight Normal or obese Thin or weight loss Cough Often with exercise, Worse at night, +/- mucopurulent sputum, +/- pink sputum (rare), harsh, debilitating soft cough Dyspnea +/- dyspnea +/- dyspnea/orthopnea Murmur With or without Always murmur with MR Lung sounds None, wheezes, crackles; None, crackles, wheezes; wheezes most common crackles most common Heart rate/rhythm Usually normal to slow, Usually rapid, sinus sinus arrhythmia rhythm/tachycardia ECG NSR or NSA +/- p-pulmonale, NSR or sinus tachycardia, right ventricular enlargement p-mitrale, left ventricular enlargement Radiographs No pulmonary edema +/- Pulmonary edema, left heart right heart enlargement (RA, RV), enlargement (LA, LV), no +/- airway collapse and parenchymal airway collapse or airway and/or bronchial infiltrate infiltrate Echocardiogram Variable right heart enlargement, Left heart enlargement, MR, variable high velocity TR or PI (PHT) enlarged pulmonary veins Airway cytology Inflammatory or neoplastic Normal Hemogram Variable inflammation, Normal or stress leukogram +/- polycythemia Diuretic Unresponsive Responsive NT-proBNP Elevated Normal Note that findings vary and not all abnormalities are seen in a given case and that overlap of diseases and signs may occur. NSR = normal sinus rhythm, NSA = normal sinus arrhythmia, MR = mitral regurgitiation, RA = right atrium, RV = right ventricle, LA = left atrium, LV = left ventricle, TR = tricuspid regurgitation, PI = pulmonary insufficiency, PHT = pulmonary hypertension. Clarke E. Atkins DVM, DACVIM 14 Canine & Feline Cardiology

16 WHEN TO USE AND NOT TO USE RAAS ANTAGONISTS Clarke E. Atkins, DVM, Diplomate, ACVIM (Internal Medicine & Cardiology) Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine Our understanding of the pathogenesis and management of heart failure has markedly changed over the last 20 years. During this time we have learned that the heart may fail due to diastolic dysfunction, as well as systolic dysfunction; that hemodynamic alterations and their management are less important than the body s own maladaptive neurohormonal response to a fall in cardiac output; that drugs which improve hemodynamics may actually result in long-term harm; and that the greatest clinical benefits result from therapies which blunt the body s neurohormonal response in heart failure. In addition, there have been a plethora of new procedures, drugs, and even drug classes introduced for the management of cardiac disease. Some of the most important clinical ramifications of heart failure, such as dyspnea (due to pulmonary edema or pleural effusion) and ascites, are directly attributable to sodium and fluid retention resulting from activation of the renin-angiotensin-aldosterone system (RAAS). Management of the signs of congestive heart failure (CHF) has relied upon the use of natriuretic diuretics (furosemide), restriction of dietary sodium, and more recently angiotensin converting-enzyme inhibitors (ACE-I) which, by blocking aldosterone production, combat sodium retention and congestion. In addition, as vasodilators, ACE-I unload the heart, improving cardiac output and exercise, normalize electrolyte abberations, and blunt the pathological cardiovascular remodeling produced by angiotensin II and aldosterone. While off-loading therapy with the aforementioned drug groups can be life-saving, their use can be associated with adverse side-effects. Most notable of these are hypotension, azotemia, renal failure, and arrhythmias. Certain complications are more apt to occur when combinations of drugs are used. Because of the potential for such side effects, these drugs are best employed in specific sequence and combinations. The following discussion relates to their use in the management of chronic heart failure. ANGIOTENSIN CONVERTING-ENZYME INHIBITORS In landmark veterinary studies of enalapril in NYHA phase III and IV heart disease (moderate to severe heart failure), due to mitral regurgitation (MR) and dilated cardiomyopathy (DCM), enalapril improved survival by >100% as well as reducing pulmonary edema and, improving quality of life scores. 1-3 Exercise capacity is also improved in dogs with experimental mitral insufficiency. 4 Benazepril has likewise been shown to improve survival. 5 ACE-I have proven to provide additional benefits in human patients by blocking pathological remodeling, presumably slowing progression of heart disease and by normalizing serum electrolyte concentrations. Today, ACE-I represent the cornerstone in the chronic management of CHF. They are indicated in virtually all cases of systolic heart failure in which they are tolerated. There was early concern regarding the renal safety of these compounds 6-8 and all ACE-I, which have enjoyed extensive clinical use, have been associated with renal dysfunction, usually temporary. 9 There has been speculation that, at very high doses (180x the clinical dosage), ACE-I have direct nephrotoxic effects but it is generally felt that the major impact of ACE-I on the kidney, with clinically relevant dosages, is through production of hypotension, with reduced renal perfusion pressure and resulting in worsening of azotemia. 10 To date, veterinary clinicians have had experience with enalapril, captopril, benazepril, and lisinopril. Of these, only enalapril has been extensively studied and is licensed for use in management of heart failure in the United States, though benazepril has been marketed in Japan, Europe and Canada. The active metabolite of benazepril is reportedly excreted both in the bile and in the urine so that lower serum concentrations are evident in experimental renal disease. 11 The clinical relevance of this is unclear. Over 10 years of veterinary clinical experience with ACE-I (mainly captopril and enalapril) have taught us that their impact on kidney function is minimal even in the face of severe heart failure. When azotemia is observed, ACE-I are almost always being used in conjunction with diuretics and sodium restriction and hypotension results. Typically, cessation of diuretic therapy or reduction in the dosage results in the reversal of azotemia. 9 Clarke E. Atkins DVM, DACVIM 15 Canine & Feline Cardiology