Read a French paper on the same topic: Thérapies des Cardiopathies Félines Fondées sur les Preuves
Hypertrophic cardiomyopathy (HCM) is the most common feline heart disease and remains a major cause of morbidity and mortality associated with risk of sudden death, congestive heart failure (CHF) and aortic thromboembolism.1-4 Most recent studies have focused on the genetic aspect of feline HCM namely the identification of a causative mutation in the cardiac Myosin Binding Protein C (MyBPC3) sarcomeric gene in Maine Coon cats5 and in Ragdoll cats,6 and the relationship between the genotype and clinical phenotypes.7 However, treatment of feline HCM still remains confusing, and as in human HCM, many questions are still unresolved. Because of its high prevaence and potential deleterious consequences, the purpose of this lecture is to focus on this single heart disease, and after a brief review of its main characteristics, to provide an objective and systematic survey of the literature regarding its treatment according to based-evidence principles.
Evidence-Based Medicine--Strength of Evidence Levels
The classical definition of evidence-based medicine (EBM) is ''the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients".8 Evidence-based veterinary medicine (EBVM) according to Cockcroft and Holmes also uses current based evidence in making clinical decisions, stating that the best clinical decision for a patient incorporates equal proportions of evidence, clinical expertise, and patient needs or client preferences.9,10 Ranking the evidence after critical appraisal of the literature is pivotal in using such approach. A hierarchic ''pyramid of evidence'' may be used to rank the evidence from strongest to weakest.11-13 Items toward the top of the pyramid are considered to represent stronger sources of evidence [systematic reviews of randomized controlled trials (RCT), meta-analysis, RCT], and those toward the base of the pyramid represent weaker sources of evidence (case reports, expert opinions, consensus reports etc.). Different systems have been developed to stratify evidence in human medicine. However, as very few clinical trials have been reported in cats with HCM, a simplified classification seems more suitable in this species, such as that slightly modified from the ACVIM Forum consensus statement published by Lees et al in the JVIM in 2005, initially adapted from the work of Mc Gowan et al by Polzin and including 3 levels of evidence.14-16 Level 1 (best evidence) is based on data obtained from at least 1 properly randomized controlled clinical trial. Level 2 is based on data obtained from at least 1 well-designed clinical trial without randomization, cohort or case-controlled analytic studies, studies using acceptable laboratory models or simulations in the target species, or dramatic results in uncontrolled experiments. Level 3 is based on descriptive studies (case reports, case series), studies in other species, pathophysiologic justification, opinions of respected authorities on the basis of clinical experience, or reports from expert committees.
Medical Therapy in Cats with HCM: An Attempted Evidence-Based Approach
The classification proposed by the American Heart Association and recently used in a Consensus Statement of the ACVIM for the diagnosis and treatment of dogs with chronic valvular disease may be applied to feline HCM to clarify the different therapeutic situations.17,18 This classification includes 4 stages from A to D. Stage A corresponds to cats at risk of developing heart disease (HCM), but that currently have no identifiable structural disorder of the heart. Stage B includes cats with structural heart disease (e.g., hypertrophic myocardial walls on conventional echocardiography), but that have never developed clinical signs. Stage C refers to cats with past or current mild to moderate clinical signs of HCM (symptoms of CHF, syncope, fainting, exercise intolerance...) associated with structural HCM. Stage D applies to cats with severe clinical signs due to end-stage HCM.
Stage A
Cats at risk of HCM include those of breeds known to be predisposed to the disease (Persian, Maine Coon, Ragdoll, Sphynx, British Shorthair etc.), all the more if they have a known familial history of HCM. In the Maine Coon breed, the presence of the MYBPC3 mutation is considered as a risk factor of HCM, although homozygous wild-type cats may also be affected by the disease.7 Cats at high risk of HCM also include those from other breeds with a familial history of the disease. At this stage no treatment is indicated, as the disease is not present. However, screening for HCM using echocardiography with a longitudinal follow-up is recommended (although the ideal frequency of echocardiographic examinations is unknown).
Stage B
Similarly to humans, cats with asymptomatic HCM may live years without any clinical sign, and therefore treatment of patients at this stage remains controversial.19,20 No prospective study is currently available in humans.20 However, according to the ACC/ESC Clinical Expert Consensus Document on HCM, some particular cases (corresponding to risk situations) can lead to medical treatment of asymptomatic human patients.20 If we refer to this report (level 3 evidence), it might be prudent to consider several categories of asymptomatic cats that could require medical treatment: those with left atrial dilation (which is a predictor of survival time and a risk factor of arterial thromboembolism19), arrhythmias, marked dynamic left ventricular outflow tract obstruction (DLVOTO), familial history of sudden death or CHF at young age. However, as in humans, no studies have been performed on the efficacy of drugs (e.g., ACE inhibitors, calcium channel blockers, beta-blockers) in delaying the onset of CHF and prolonging survival time in this category of population. Considering pharmacological justification and expert reports in humans (level 3 evidence), beta-blockers could be the first treatment of choice in the case of marked DLVOTO (e.g., atenolol 6.25 to 12.5 mg per cat q12 to 24h).2,20 In one recent RCT involving 21 cats with sub-clinical HCM (level 1 evidence), the administration of an ACE inhibitor (benazepril, 0.5 mg/kg PO q24h), as compared to diltiazem controlled delivery (10 mg/kg PO q24h), was shown to improve some echo-Doppler variables.21 Conflicting results were however obtained in a RCT (level 1 evidence) showing that Maine Coon cats with asymptomatic HCM did not show an improvement of LV mass or diastolic function when treated with ramipril (0.5 mg/kg).22
Stage C
The first goal of therapy in cats with mild to moderate CHF is to eliminate pulmonary edema, pleural effusion or both using diuretics. Furosemide (1-4 mg/kg q12-24h PO) is highly recommended by experts although paradoxically RCT have never been undertaken to confirm its efficacy in cats with CHF (level 3 evidence). The dosage should be reduced as soon as the congestive signs have improved.2,3,23 Once initiated, it is usual to maintain furosemide treatment every day or sometimes every two days for the rest of the animal's life (level 3 evidence).2,3,23 In very rare cases (stressful events) furosemide can be discontinued (level 3 evidence).23
Beta-blockers, calcium channel blockers, and ACE inhibitors are the most commonly used drugs associated with diuretics in humans and in cats with HCM and CHF. However, in both species, the level of evidence regarding these drugs is mainly derived from non-randomized or retrospective investigations performed in relatively small patient groups or from expert opinions.20 Beta-blockers are preferred as the first-line therapy in humans with HCM, particularly in the case of DLVOTO.20 The beneficial effects of beta-blockers on symptoms appear to be largely attributable to their negative chronotropic and inotropic action.24 A double-blinded RCT, the Multicenter Feline Chronic Heart Failure Study (theoretically level 1 evidence, but presented as a research abstract and unpublished at that time), performed on 118 cats with CHF (including 57 cats with HCM) showed that atenolol was associated with a shorter survival time than other drugs (atenolol, diltiazem, or enalapril),25 and cats receiving atenolol and furosemide survived for a shorter time than cats treated with furosemide alone. One study (theoretically level 2 evidence, but presented as a research abstract and unpublished at that time) showed that intravenous esmolol was able to reduce heart rate and pressure gradient more efficiently than diltiazem in cats with HCM and DLVOTO associated with systolic anterior motion (SAM).26
Calcium channel blockers have benefits of directly improving diastolic dysfunction as well as decreasing heart rate and pressure gradient in the case of DLVOTO. The calcium channel blocker of choice in humans with HCM is verapamil.20 However, side-effects may occur due to a potent vasodilatory action, and diltiazem is usually preferred in the cat. Diltiazem has been shown to improve active diastolic function in humans with HCM,27 and to have a beneficial effect in cats with HCM.28 A prospective randomized study performed on 17 cats with HCM either treated with propranolol, diltiazem, or verapamil (level 1 evidence for cardiovascular effects, survival not studied) showed that the 12 cats treated with diltiazem became asymptomatic with no adverse effect.28 However, in the Multicenter Feline Chronic Heart Failure Study, a beneficial effect on survival time was not demonstrated, as the survival rate for cats receiving diltiazem was slightly lower than for those on furosemide and placebo alone.25
Angiotensin II has been shown to induce myocyte hypertrophy and fibroblast hyperplasia,29,30 and animal studies have demonstrated that LVH is reduced by administration of angiotensin receptor blockers in genetic systemic arterial hypertension and in animal models of HCM (level 3 evidence for cats).31,32 One multicenter RCT (level 2 evidence) suggested that benazepril was well tolerated in cats with HCM and that it had some beneficial effects on clinical signs and myocardial hypertrophy.33 In the Multicenter Feline Chronic Heart Failure Study, cats in the enalapril group had the highest survival rate, but the differences between treatment groups were not statistically significant.25 A recent study (level 2 evidence, but unpublished) also demonstrated that SAM was not worsened by benazepril administration in cats34 and one retrospective study in 19 cats with CHF (level 3 evidence) suggested that enalapril was well tolerated and might contribute to clinical and echocardiographic improvement.35
Stage D
In the case of medical-refractory pleural effusion, periodic pleurocentesis is necessary.2,3,22 In some severe cases, furosemide dosage can be increased to 6-8 mg/kg q24h (level 3 evidence) if the cats continue to eat and drink, although at this dosage they are usually mildly dehydrated and azotemic.2,22 Another diuretic (thiazide) can be added with caution to furosemide (hydrochlorothiazide, 1-2 mg/kg q12-24h, level 3 evidence).2,3,22 Spironolactone is not licensed for use in the cat but can be administered in refractory cases (1 mg/kg q24h, level 3 evidence) to inhibit aldosterone action. In a RCT performed on Maine Coon cats (level 1 evidence), one third of animals treated with spironolactone at high dosage (2 mg/kg q12h) developed severe ulcerative facial dermatitis approximately 2.5 months after beginning treatment.36 However, the effect of a lower dosage on survival is still unknown and the effect on diastolic function is still unclear (the tissue Doppler imaging protocol used in this study will be discussed). Pimobendan is an inodilator licensed for the treatment of canine CHF but not licensed in cats. It may be prescribed in refractory CHF with systolic dysfunction, although no published studies have confirmed its efficacy (level 3 evidence).37,38
In conclusion, whatever the stage of feline HCM, RCT (level 1 evidence or at least level 2) performed on large populations of cats with HCM are needed to better define the therapeutic strategy and the associated benefit-to-risk ratio.
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