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Therapeutic TherapeuticOptions Options FOCUS FOCUS ONON HEART HEART FAILURE FAILURE HeartHeart failure failure (HF) is(HF) a common is a common condition, condition, affecting affecting 1–2% 1–2% of theof the adultadult population population in developed in developed 1 1 countries. countries. Among Among thosethose aged aged 70 70 yearsyears or older, or older, the prevalence the prevalence of of 1 1 HF is HF ≥10%. is ≥10%. Despite Despite advances advances in in detection detection and therapy, and therapy, HF remains HF remains a significant a significant causecause of morbidity of morbidity 2,3 2,3 and mortality. and mortality. In Canada, In Canada, HF is HF reported is reported to beto the bemost the most common common causecause of hospitalization of hospitalization in patients in patients over 65 over years 65 years of age, of age, as well as as well theascause the cause of 9%ofof9% allof all 4 4 deaths deaths nationwide. nationwide. Obviously, Obviously, therethere is an urgent is an urgent need need for for aggressive aggressive measures measures to reduce to reduce the burden the burden of illness of illness associated associated 4 4 with this withclinical this clinical syndrome. syndrome. In theInpresence the presence of LV of systolic LV systolic dysfunction dysfunction (the most (the most common common causecause of HF), ofthe HF),body the body activates activates several several neurohumoral neurohumoral pathways pathways to increase to increase circulating circulating bloodblood volume volume in an in attempt an attempt to maintain to maintain 6 adequate adequate cardiac cardiac output. output. Two6key Two key neurohumoral neurohumoral systems systems activated activated are the arerenin–angiotensin– the renin–angiotensin– aldosterone aldosterone system system and the and the 1 1 sympathetic sympathetic nervous nervous system. system. Initially, Initially, activation activation of these of these pathways pathways is compensatory is compensatory and and beneficial, beneficial, but itbut eventually it eventually leadsleads to detrimental to detrimental effects, effects, including including pathologic pathologic LV remodelling LV remodelling with dilation, with dilation, hypertrophy, hypertrophy, and and 1,6 1,6 impaired impaired contractility. contractility. 7 classification classification system system (see7 Table (see Table 1). 1). Additionally, Additionally, patients patients may be may be classified classified basedbased on whether on whether LV LV ejection ejection fraction fraction (EF) is(EF) reduced is reduced (HF with (HF reduced with reduced EF [HF-REF]) EF [HF-REF]) or preserved or preserved (HF with (HF preserved with preserved EF [HF-PEF]) EF [HF-PEF]) (see Table (see Table 2). 2). The hallmark The hallmark manifestations manifestations of HFof are HFdyspnea are dyspnea (shortness (shortness of breath), of breath), fatigue, fatigue, and edema and edema 1,2,5,7 1,2,5,7 (fluid(fluid retention). retention). Other Other typical typical symptoms symptoms include include orthopnea, orthopnea, paroxysmal paroxysmal nocturnal nocturnal dyspnea, dyspnea, and and 1 reduced reduced exercise exercise tolerance. tolerance. Less1 Less typically, typically, patients patients may complain may complain of nocturnal of nocturnal cough, cough, wheezing, wheezing, weight weight gain, anorexia, gain, anorexia, palpitations, palpitations, and confusion and confusion (the latter (the latter is most is most 1 1 in theinelderly). the elderly). ETIOLOGY ETIOLOGY AND PATHOPHYSIOLOGY AND PATHOPHYSIOLOGY CLASSIFICATION CLASSIFICATION AND SYMPTOMS AND SYMPTOMS likelylikely It is notable It is notable that symptom that symptom severity severity can vary can vary substantially substantially during during the course the course of of ThereThere are many are many known known etiologies etiologies HeartHeart failure failure is often is often classified classified the disease the disease and may and not maycorrelate not correlate of HF,ofand HF,several and several risk factors risk factors according according to thetoNew the York New Heart York Heart 1,2 1,2 with changes with changes in underlying in underlying have have been been identified. identified. Association Association (NYHA) (NYHA) functional functional Coronary Coronary arteryartery disease disease is cited is cited to beto be 1,2 1,2 TableTable 1 – New 1 – York New Heart York Heart Association Association functional functional classification classification responsible responsible for roughly for roughly two- two1 thirdsthirds of systolic of systolic HF cases HF cases (see1 (see NYHANYHA class*class* Description Description TableTable 2, below, 2, below, for descriptions for descriptions of systolic of systolic and diastolic and diastolic HF). HF). No limitation No limitation of physical of physical activity; activity; ordinary ordinary physical physical Hypertension Hypertension is also is aalso major a major I I activity activity does does not cause not cause HF symptoms HF symptoms 2 2 risk factor risk factor in HF in development. HF development. SomeSome otherother risk factors risk factors include include SlightSlight limitation limitation of physical of physical activity; activity; comfortable comfortable at rest, at rest, II II valvular valvular heartheart disease, disease, diabetes diabetes but ordinary but ordinary physical physical activity activity results results in HF in symptoms HF symptoms mellitus, mellitus, hyperlipidemia, hyperlipidemia, Marked Marked limitation limitation of physical of physical activity; activity; comfortable comfortable at rest, at rest, excessive excessive alcohol alcohol intake, intake, use use III III but less butthan less ordinary than ordinary activity activity causes causes HF symptoms HF symptoms of certain of certain chemotherapy chemotherapy drugsdrugs (e.g., doxorubicin (e.g., doxorubicin or trastuzumab), or trastuzumab), Unable Unable to carry to carry on any onphysical any physical activity activity without without 1,2 1,2 IV IV physical physical inactivity, inactivity, and smoking. and smoking. HF symptoms HF symptoms or symptoms or symptoms of HFof atHF rest at rest Most Most patients patients with HF with have HF have symptoms symptoms due to due lefttoventricular left ventricular 5 5 (LV) myocardial (LV) myocardial dysfunction. dysfunction. HF = heart HF =failure; heart failure; NYHA =NYHA New York = New Heart YorkAssociation Heart Association 1 1 * Patients * Patients in NYHAinclasses NYHA II, classes III, andII,IVIII,are and sometimes IV are sometimes said to have said mild, to have moderate, mild, moderate, and severe andsymptoms, severe symptoms, respectively. respectively. THERAPEUTIC THERAPEUTIC OPTIONS OPTIONS APRIL/MAY/JUNE APRIL/MAY/JUNE 2014 2014 I I cardiac function.2 Importantly, any deterioration in symptoms indicates a heightened risk of hospitalization and death, and warrants prompt medical attention.1 MANAGEMENT The main goals of treatment in patients with HF are to improve/ relieve symptoms and signs, reduce morbidity (including hospital admissions), and improve survival.1 Recommendations for managing patients with HF-REF and HF-PEF are summarized below. In addition to the specific therapies discussed, comorbidities should be appropriately treated, particularly those that are major risk factors for HF and those that directly impact HF symptoms and/ or progression (e.g., hypertension, atrial fibrillation, anemia).1,2,5 A thorough discussion of such holistic management is beyond the scope of this review; however, recommendations are provided in guidelines available online1,2,5 (see References, below, for URLs). Pharmacotherapy for HF-REF There is general consensus among recent guidelines1,5,7 that the foundation of treatment for most patients with HF-REF should be a multidrug regimen consisting of an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker [ARB]) and a beta-blocker. A mineralocorticoid receptor antagonist (MRA) is considered standard additional therapy for individuals who continue to meet NYHA class II–IV criteria despite optimized treatment with an ACE inhibitor (or ARB) and a beta-blocker.1,5,7 Each of the aforementioned drug classes has been shown to improve survival in trials involving patients with HF-REF.1,5,7 These core therapies are generally used in conjunction with diuretics to relieve congestive symptoms/fluid retention.1,5,7 Adjunctive or alternative therapies such as digoxin, isosorbide dinitrate plus hydralazine, and omega-3 polyunsaturated fatty acids may also be beneficial in certain scenarios.1,5,7 Evidence-based dosing strategies for disease-modifying therapies are summarized in Table 3; recommendations and practical tips regarding these agents are provided in Box 1. Recommendations and II Table 2 – Classification based on left ventricular ejection fraction1,5 Classification* LVEF Heart failure with reduced ejection fraction (HF-REF) ≤40% Heart failure with preserved ejection fraction (HF-PEF) ≥50 % Comments • Also referred to as “systolic HF”† • Best understood type of HF in terms of pathophysiology and treatment; RCTs proving therapies to be efficacious in HF have primarily enrolled patients with HF-REF • Also referred to as “diastolic HF”‡ • To date, efficacious therapies for patients with HF-PEF have not been identified HF = heart failure; LVEF = left ventricular ejection fraction; RCTs = randomized controlled trials * Classifications in addition to those listed have been described: (1) HF-PEF, borderline: LVEF 41–49% (overall patient characteristics, treatment patterns, and outcomes appear similar to those of patients with HF-PEF); and (2) HF-PEF, improved: LVEF >40% (a subset of patients who previously had HF-REF; further research is necessary to better characterize these patients).5 † In systolic HF, cardiac contractility is reduced.6 ‡ In diastolic HF, cardiac relaxation is impaired and ventricular filling is abnormal.6 Table 3 – Doses of disease-modifying medications for HF-REF1,5,7,8 Dosage Drug Initial* Target† Angiotensin-converting enzyme inhibitors Captopril 6.25 mg tid 50 mg tid Enalapril 1.25–2.5 mg bid 10 mg bid Lisinopril 2.5–5 mg od 20–35 mg od Perindopril 2 mg od 4–8 mg od Ramipril 1.25–2.5 mg od 5 mg bid Trandolapril 0.5–1 mg od 4 mg od Bisoprolol 1.25 mg od 10 mg od Carvedilol 3.125 mg bid 25 mg bid‡ Metoprolol CR/XL§ 12.5–25 mg od 200 mg od Beta-blockers Angiotensin receptor blockers Candesartan 4 mg od Valsartan 40 mg bid 32 mg od 160 mg bid Mineralocorticoid receptor antagonists ¶ Eplerenone 25 mg od 50 mg od Spironolactone 12.5 mg od 25–50 mg od Hydralazine 37.5 mg tid 75 mg tid Isosorbide dinitrate 20 mg tid 40 mg tid Vasodilators bid = twice daily; HF-REF = heart failure with reduced ejection fraction; od = once daily; tid = three times daily * In instances where initial recommended doses varied among guidelines consulted, lower doses have been listed. † If target doses cannot be reached, use maximum tolerated doses. ‡ 50 mg bid if weight >85 kg. § The metoprolol CR/XL (succinate) formulations are not commercially available in Canada. ¶ Also referred to as aldosterone antagonists. THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014 Box 1 – Recommendations* and practical tips† for disease-modifying medications for HF-REF 1,5,7,9 Angiotensin-converting enzyme inhibitors Recommended use: • All symptomatic (and previously symptomatic) patients with EF ≤40% (in addition to a beta-blocker) Tips/comments: • When initiating therapy, double the dose at intervals of no less than 2 weeks in the community; quicker up-titration may occur in hospital or in other settings where patients are closely monitored • An increase in serum creatinine is expected upon initiating therapy; there is no immediate need to lower the dose if the increase stabilizes at ≤30% • Symptom improvement occurs within a few weeks to a few months after starting treatment • Abrupt withdrawal can lead to clinical deterioration and should be avoided • The combination of an ACE inhibitor and ARB increases the risk of hypotension, hyperkalemia, and renal dysfunction, and should be used with caution Beta-blockers Recommended use: • All symptomatic (and previously symptomatic) patients with EF ≤40% (in addition to an ACE inhibitor) Tips/comments: • When initiating therapy, double the dose at intervals of no less than 2 weeks (slower up-titration may be necessary) • Therapy should generally be initiated in stable patients (e.g., not during or within 4 weeks of a HF exacerbation); attempts should be made to relieve congestion/fluid retention prior to starting therapy • Major dose reduction or abrupt withdrawal can lead to clinical deterioration and should be avoided • Symptom improvement may occur slowly after starting treatment, sometimes taking 3–6 months or longer Angiotensin receptor blockers Recommended uses:‡ • As an alternative to an ACE inhibitor in patients who: (1) cannot tolerate ACE inhibitor therapy,§ or (2) are already taking an ARB for another indication • In combination with an ACE inhibitor and beta-blocker for persistently symptomatic patients when a MRA is not tolerated (see tips/ comments for ACE inhibitors, above, for statement regarding combined use of an ACE inhibitor and ARB) Tips/comments: • Tips/comments for ACE inhibitors (see above) apply to ARBs Mineralocorticoid receptor antagonists¶ Recommended uses:** • All patients with persistent symptoms (NYHA Class II-IV††) and an EF ≤35% despite treatment with an ACE inhibitor (or ARB) and beta-blocker • Following an acute MI in patients with: (1) symptoms of HF and an EF ≤40%, or (2) an EF ≤40% and a history of diabetes mellitus Tips/comments: • Consider dose up-titration 4–8 weeks after initiation of therapy • Symptom improvement occurs within a few weeks to a few months after starting treatment • Hyperkalemia is the main concern with MRA therapy, and risk is increased when therapy is combined with an ACE inhibitor or ARB; vigilant monitoring of serum potassium and renal function is essential‡‡ • Interruption of therapy may be necessary during periods of worsening renal function and/or dehydration Vasodilators Recommended use: • The combination of isosorbide dinitrate and hydralazine may be considered: (1) for black patients with persistent symptoms despite standard therapy with an ACE inhibitor (or ARB) and beta-blocker (and MRA as appropriate), and (2) as an alternative to an ACE inhibitor or ARB in any patient unable to use/tolerate these therapies ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; EF = ejection fraction; HF = heart failure; HF-REF = heart failure with reduced ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association * Recommendations provided were summarized/synthesized from guidelines consulted; refer to complete online documents1,5,7 for details of recommendations made in individual guidelines, including grade/level of evidence (see References, below, for URLs). † Many useful tips and comments in addition to those listed (including ones related to contraindications, precautions, drug interactions, monitoring, and management of adverse effects) are made in the full guidelines; refer to complete online documents1,5,7,9 for details (see References, below, for URLs). Web tables 11, 12, 13, and 15 from the European guidelines9 are particularly helpful. ‡ In addition to the listed uses, Canadian guidelines7 propose ARBs be considered “as adjunctive therapy to ACE inhibitors when β-blockers are either contraindicated or not tolerated after careful attempts at initiation.” § Intolerable ACE inhibitor-induced cough is the primary indication for ARB therapy; caution is advised in patients who developed angioedema with an ACE inhibitor.5 ¶ Also referred to as aldosterone antagonists. ** Recommendations from Canadian guidelines7 are more restrictive (based on EF) than those from US5 or European1 guidelines; Canadian guidelines7 also make differential recommendations for eplerenone and spironolactone, whereas US5 and European1 guidelines do not. †† According to US guidelines,5 patients with NYHA class II HF should have a history of prior cardiovascular hospitalization, or elevated plasma natriuretic peptide levels, to be considered for MRA therapy. ‡‡ Refer to online guidelines1,5,7 for detailed recommendations (see References, below, for URLs). tips for use of adjunctive therapies are summarized in Box 2. In instances where a drug with proven mortality or morbidity benefits (i.e., those listed in Table 3) seems to be poorly tolerated (e.g., low blood pressure, low heart rate, renal dysfunction), concomitant drugs that have less proven benefit should be re-evaluated to determine if their dose can be reduced (or the drug discontinued) to allow better tolerance of the proven drug.7 Medications that are not specifically used to treat HF-REF per se, but THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014 which may be used in patients with other indications for therapy include platelet inhibitors, anticoagulants, and statins.1,5,7 Drugs that should generally be avoided based on risk of HF exacerbation include thiazolidinediones (“glitazones”), traditional nonsteroidal anti-inflammatory drugs, III Box 2 – Recommendations* and practical tips† for adjunctive therapies for HF-REF1,5,7,9 Diuretics Recommended use: • Patients with signs and symptoms of fluid retention/congestion (e.g., dyspnea, edema) Tips/comments: • Loop diuretics (e.g., furosemide) are preferred for most patients; once acute congestion resolves, use the lowest dose‡ that maintains stable signs and symptoms (continuous treatment may not be necessary for all patients) • When volume overload persists despite optimal medical therapy (including increased loop diuretic doses), cautious addition of a second diuretic (e.g., a thiazide or low-dose metolazone) may be considered, with close monitoring of daily weight, renal function, and serum potassium • Symptoms improve quickly, usually within days of starting treatment in the range of 0.6–1.1 nmol/L [0.5– 0.9 ng/mL] have been suggested based on limited evidence) Digoxin Recommended use: • Digoxin may be considered for: (1) patients in sinus rhythm who continue to have moderate to severe symptoms despite optimized therapy, and (2) patients with chronic atrial fibrillation and poor ventricular rate control despite optimal beta-blocker therapy (or when a beta-blocker cannot be used) Tips/comments: • Therapy is typically initiated and maintained at a dose of 0.125–0.25 mg daily, although lower doses may be appropriate for some patients (target plasma drug concentrations Omega-3 polyunsaturated fatty acids Recommended use: • An n-3 PUFA preparation may be considered as adjunctive therapy in patients with persistent symptoms to reduce the risk of death and CV hospitalizations Tips/comments: • In the main study supporting the recommended use, patients received a dose of 1 g n-3 PUFA§ daily • The small treatment effect in the main study was only detected after covariate adjustment in the statistical analysis CV = cardiovascular; HF-REF = heart failure with reduced ejection fraction; n-3 PUFA = omega-3 polyunsaturated fatty acid * Recommendations provided were summarized/synthesized from guidelines consulted; refer to complete online documents1,5,7 for details of recommendations made in individual guidelines, including grade/level of evidence (see References, below, for URLs). † Many useful tips and comments in addition to those listed (including ones related to contraindications, precautions, drug interactions, monitoring, and management of adverse effects) are made in the full guidelines; refer to complete online documents1,5,7,9 for details (see References, below, for URLs). ‡ Detailed diuretic dosing recommendations are provided in Table 14 of the online US guidelines5 (see References, below, for URL). § Including 850–882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters in the average ratio of EPA/DHA 1:1.2. cyclooxygenase-2 inhibitors, nondihydropyridine calcium channel blockers (amlodipine and felodipine may be used if otherwise clinically indicated), and nonamiodarone antiarrhythmics.1,5,7 The routine combined use of ACE inhibitor + ARB + MRA should also be avoided due to risk of renal dysfunction and hyperkalemia.1,5,7 Pharmacotherapy for HF-PEF No treatment has been shown to definitively reduce morbidity and mortality in patients with HF-PEF.1 As a result, the main treatment approach is to control potentially etiologic risk factors such as hypertension and myocardial ischemia.1,7 Control of ventricular rate in patients with atrial fibrillation is also considered important.1 Where appropriate for the aforementioned indications, ACE inhibitors, ARBs, and betablockers are reasonable choices.5,7 Diuretics are used to relieve dyspnea and edema.1,5,7 In contrast to HF-REF, nondihydropyridine calcium channel blockers may be used if indicated.1,7 www.chfn.ca/clinic-resource-manual/ rationale-for-hf-clinics Nonpharmacological Interventions Various lifestyle interventions and device-related or surgical procedures may be indicated for patients with HF. A full review of these interventions is beyond the scope of this review; however, recommendations are provided in guidelines available online1,2,5,7 (see References, below, for URLs). 5. Yancy CW, et al. Circulation. 2013 Oct 15;128(16):e240-319. Available from: http://circ.ahajournals.org/ content/128/16/e240.full.pdf+html 6. Hobbs R, Boyle A. Heart failure. Available from: http://www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/ cardiology/heart-failure/ 7. McKelvie RS, et al. Can J Cardiol. 2013 Feb;29(2):168-81. Available from: http:// download.journals.elsevierhealth. com/pdfs/journals/0828-282X/ References PIIS0828282X12013797.pdf 8. McKelvie RS, et al. Can J Cardiol. 2013 1. Feb;29(2). [supplemental material] McMurray JJ, et al. Eur Heart J. 2012 Jul;33(14):1787-847. Available from: Available from: http://download.journals. http://eurheartj.oxfordjournals.org/ elsevierhealth.com/mmcs/journals/0828282X/PIIS0828282X12013797.mmc1.pdf content/33/14/1787.full.pdf 9. McMurray JJ, et al. Eur Heart J. 2012 2. Heart Failure Society of America. J Card Fail. 2010 Jun;16(6):475-539. Available from: Jul;33(14). [supplemental material] http://download.journals.elsevierhealth. Available from: http://www.escardio. com/pdfs/journals/1071-9164/ org/guidelines-surveys/esc-guidelines/ PIIS1071916410001740.pdf GuidelinesDocuments/GuidelinesHeart-Failure-Web-Tables.pdf 3. Shearer F, et al. Clin Pharmacol Ther. 2013 Oct;94(4):459-67. 4. Canadian Heart Failure Network. Rational for HF clinics. Available from: http:// Disclaimer: The Drug Information and Resource Centre (DIRC) of the Ontario Pharmacists Association provides this material to health professionals for informational purposes only. It is provided without warranty of any kind by DIRC and DIRC assumes no responsibility for any errors, omissions or inaccuracies therein. It is the responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data. IV THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014