7.1.1.1 Pharmacologic therapy<\/h4>\n\n\n\n
In addition to initiating, titrating, and monitoring pharmacologic therapy, there are circumstances in which some therapies may be withdrawn (Table 12). There are additionally some common effects of GDMT requiring active surveillance and management. A suggested approach to hyperkalemia is presented in Table 13.<\/p>\n\n\n\n Recommendation<\/p> 26. We recommend that most patients with HFrEF be treated with triple therapy including an ACEi (or an ARB in those who are ACEi-intolerant), a \u03b2-blocker and an MRA unless specific contraindications exist (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> Preference is given to the use of pharmacotherapy in most patients with HFrEF across the spectrum of symptoms. There are limited clinical trial data to inform decision-making surrounding the use of MRAs as part of GDMT in those without symptoms of HF or high-risk features.<\/p>\n 27. We recommend preferentially using the specific drugs at target doses that have been proven to be beneficial in clinical trials as optimal medical therapy. If these doses cannot be achieved, the maximally tolerated dose is acceptable (Table 11) (Strong Recommendation; High-Quality Evidence).<\/p>\n<\/div>\n\n\n Practical Tip (general)<\/p> If a drug with proven mortality or morbidity benefits does not appear to be tolerated by the patient (eg, low BP, low heart rate, or renal dysfunction), other concomitant drugs, including diuretics, with less proven benefit should be carefully re-evaluated to determine whether their dose can be reduced or the drug discontinued.<\/p>\n<\/div>\n\n\n Practical Tip (general)<\/p> HFrEF GDMT should be continued at the usual dose during acute intercurrent illness (eg, pneumonia, exacerbation of chronic obstructive pulmonary disease, other systemic infection, etc), unless they are not tolerated (eg, if significant reactive airway disease is present). GDMT should be restarted before discharge if temporarily withheld.<\/p>\n<\/div>\n\n\n Practical Tip (general)<\/p> In a life-threatening complication, GDMT may be discontinued abruptly, but generally, if there is concern about their use, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, it should be uptitrated to the previous tolerated dose as soon as safely possible.<\/p>\n<\/div>\n\n\n Practical Tip (general)<\/p> If symptomatic hypotension persists with GDMT, consider separating the administration of the dose from the timing of other medications that could also lower BP.<\/p>\n<\/div>\n\n\n Practical Tip (ACEi\/ARB)<\/p> ACEi intolerance describes a patient who is unable to tolerate ACEi therapy secondary to a bothersome cough (most commonly, 10%-20%) or those who experience angioedema with ACEi therapy (uncommon; < 1%). ARB therapy is a reasonable alternative in both of these cases, however, caution should be used in patients who develop angioedema while receiving ACEi therapy because there have been case reports of patients who subsequently develop angioedema with ARB therapy. There is no significant difference in rates of hypotension, hyperkalemia, or renal dysfunction between these agents to warrant a substitution between agents.<\/p>\n<\/div>\n\n\n Practical Tip (ACEi\/ARB)<\/p> An increase in serum creatinine or eGFR of up to 30% is not unexpected when an ACEi or ARB is introduced; if the increase stabilizes at \u2264 30%, there is no immediate need to decrease the drug dose but closer long-term monitoring might be required.<\/p>\n<\/div>\n\n\n Practical Tip (ACEi\/ARB)<\/p> BP might lower when an ACEi or ARB is introduced, especially if introduced at a high dose or in combination with diuretic therapy. Check BP with the patient supine and erect to detect whether hypotension is present, requiring slower uptitration.<\/p>\n<\/div>\n\n\n\n Practical Tip (ACEi\/ARB)<\/p> Cough occurs in 10%-20% of patients receiving ACEis and does not require discontinuation of the agent unless it is bothersome to the patient.<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> Objective improvement in cardiac function might not be apparent for 6-12 months after b-blocker initiation.<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> Patients in NYHA class I or II can be safely initiated and titrated with a b-blocker by nonspecialist physicians.<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> Patients in NYHA class III or IV should have their b-blocker therapy initiated by a specialist experienced in HF management and titrated in the setting of close follow-up, such as can be provided in a specialized clinic, if available.<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> The starting dose of b-blockers should be low and increased slowly (eg, double the dose every 2-4 weeks). Transient fluid retention might occur with initiation or uptitration of b-blockers and might require assessment of diuretic dosage (eg, might consider deferring dosage reduction).<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> If concomitant reactive airways disease is present, consider using more selective b-1 blockade (eg, bisoprolol).<\/p>\n<\/div>\n\n\n Practical Tip (\u03b2-blockers)<\/p> If atrioventricular (AV) block is present, consider decreasing other AV-blocking drugs, such as digoxin or amiodarone (when appropriate). The type and severity of AV block and the patient\u2019s history of arrhythmias will help guide the most appropriate treatment modifications.<\/p>\n<\/div>\n\n\n Practical Tip (MRA)<\/p> MRAs can increase serum potassium, especially during an acute dehydrating illness in which renal dysfunction can worsen, and close monitoring of serum creatinine and potassium is required. High-risk groups include those with diabetes, pre-existing renal dysfunction, and older age.<\/p>\n<\/div>\n\n\n\n There are extensive data on the use of ACEi and \u03b2-blocker treatment for patients with HFrEF to reduce morbidity and mortality and improve quality of life.[112]<\/a>,[113]<\/a><\/sup> A notable deletion from these guidelines is the recommendation to consider combination ACEi and ARB therapy, previously recommended. The combination of an ACEi with an ARB is no longer recommended. Although some evidence exists to support a reduction in clinically relevant outcomes with the combination, there is also substantial evidence that was published after the previous recommendation, outlining harm in terms of adverse effects (eg, hypotension, hyperkalemia, and renal dysfunction).[108]<\/a>,[114]<\/a>,[115]<\/a><\/sup> More contemporary treatments with MRAs and ARNIs have a stronger evidence base across the spectrum of outcomes (eg, morbidity and mortality) and therefore further limit the role of combination ACEi and ARB therapy.<\/p>\n\n\n\n Recommendation<\/p> 28. We recommend an ACEi, or ARB in those with ACEi intolerance, in patients with acute MI with HF or an EF < 40% post-MI to be used as soon as safely possible post-MI and be continued indefinitely (Strong Recommendation; High-Quality Evidence)<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n\n \u03b2-Blockers are part of the first-line therapy in the treatment of HFrEF, because they have been proven to improve survival and decrease hospitalizations in this population of patients, in a number of large clinical trials.[101],[103],[116]-[121]<\/sup><\/p>\n\n\n Recommendation<\/p> 29. We recommend NYHA class IV patients be stabilized before initiation of a \u03b2-blocker (Strong Recommendation; High-Quality Evidence).<\/p>\n 30. We recommend that \u03b2-blockers be initiated as soon as possible after diagnosis of HF, including during the index hospitalization, provided that the patient is hemodynamically stable. Clinicians should not wait until hospital discharge to start a \u03b2-blocker in stabilized patients (Strong Recommendation; High-Quality Evidence).<\/p>\n 31. We recommend that \u03b2-blockers be initiated in all patients with an LVEF < 40% with previous MI (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n\n A single RCT supports the use of eplerenone (target 50 mg daily) compared with placebo post-MI.[122]<\/a><\/sup> The E<\/strong>plerenone P<\/strong>ost-Acute Myocardial Infarction H<\/strong>eart Failure E<\/strong>fficacy and Su<\/strong>rvival S<\/strong>tudy (EPHESUS) trial enrolled 6642 patients who had an MI 3-14 days previously with an LVEF < 40% and symptoms of HF or an LVEF < 30% and diabetes without symptoms of HF. The primary outcome included all-cause mortality and cardiovascular mortality or hospitalization for cardiovascular events. After a median follow-up of 16 months, there was a 15% relative decrease in mortality and 13% relative decrease in cardiovascular mortality or hospitalization for cardiovascular events in the eplerenone group. There was more hyperkalemia in the eplerenone group.<\/p>\n\n\n\n Recommendation<\/p> 32. We recommend an MRA for patients with acute MI with EF < 40% and HF or with acute MI and an EF < 30% alone in the presence of diabetes (Strong Recommendation; High-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n\n In those who remain symptomatic despite triple therapy, consideration should be made to change an ACEi\/ARB to an ARNI. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including NPs, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodelling.[123]<\/a>,[124]<\/a><\/sup> In the P<\/strong>rospective Comparison of AR<\/strong>Ni With A<\/strong>CEi to D<\/strong>etermine I<\/strong>mpact on G<\/strong>lobal M<\/strong>ortality and Morbidity in H<\/strong>eart F<\/strong>ailure (PARADIGM-HF) trial, the ARNI sacubitril\/valsartan was compared with enalapril in patients with HFrEF.[125]<\/a><\/sup> A total of 8442 patients were randomized to sacubitril\/valsartan 200 mg twice daily or enalapril 10 mg twice daily after a 6-8 week runin phase. Patients were included if they were NYHA class II-IV (70% class II), LVEF \u2264 40% (amended to \u2264 35%), had a BNP \u2265 150 pg\/mL (or NT-proBNP \u2265 600 pg\/mL), or hospitalization for HF in the past year and BNP \u2265 100 pg\/mL (or NT-proBNP \u2265 400 pg\/mL). The primary outcome was a composite of death from cardiovascular causes or hospitalization for HF. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months. The primary outcome occurred in 914 patients (21.8%) in the sacubitril\/valsartan group and 1117 patients (26.5%) in the enalapril group, a 20% relative reduction. There was also a decrease in all-cause mortality, cardiovascular mortality, HF hospitalization, and symptoms of HF. The sacubitril\/valsartan group had a higher proportion of patients with hypotension but a smaller risk of renal impairment, hyperkalemia, and cough than the enalapril group. The type of patients and magnitude of effect were similar to other landmark trials in HFrEF including ACEis, \u03b2-blockers, and MRAs. This trial also closely reflects contemporary practice with high utilization of ACEis, \u03b2-blockers, and MRAs (100%, 92%, and 55%, respectively) at baseline and had an active gold standard comparator.<\/p>\n\n\n\n Recommendation<\/p> 33. We recommend that an ARNI be used in place of an ACEi or ARB, in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT to decrease cardiovascular death, HF hospitalizations, and symptoms (Strong Recommendation; High-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> This recommendation places high value on medications proven in large trials to reduce mortality, HF re-hospitalization, and symptoms. It also considers the health economic implications of new medications.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> Drug tolerability, side effects, and laboratory monitoring with use of ARNIs is similar to that of ACEi or ARB noted previously.<\/p>\n The PARADIGM-HF trial excluded patients with a serum potassium > 5.2 mmol\/L, an eGFR < 30 mL\/min, and symptomatic hypotension with a systolic BP of < 100 mm Hg.<\/p>\n When switching between an ARNI and an ACEi, a washout period of at least 36 hours is required to decrease the risk of angioedema. No washout period is required for conversion between ARNIs and ARBs.<\/p>\n ARNIs should not be used in anyone with a history of angioedema.<\/p>\n Currently, there is only 1 ARNI, sacubitrilvalsartan, available on the Canadian market. Initial dosing and rate of titration is dependent on pre-existing treatment and comorbidities and should be individualized (Table 14). When selecting a dose or titration schedule consideration should be given to the likelihood of tolerability and ultimately successful titration to doses shown to improve important HF outcomes.<\/p>\n<\/div>\n\n\n\n Resting heart rate independently predicts CVD events, including HF hospitalization.[126]<\/a>,[127]<\/a><\/sup> Systematic reviews have shown that a major contributor to the benefits of b-blocker therapy might be their rate-lowering effect.[128]<\/a>–[130]<\/a><\/sup> Despite their benefits, \u03b2-blockers are generally underused and underdosed.[129]<\/a>–[131]<\/a><\/sup> Ivabradine is approved for the treatment of HF by Health Canada. The latter drug selectively inhibits the depolarizing If current in the sinus node. It thus requires sinus rhythm to provide its pharmacological effect. In contrast to \u03b2-blockers, ivabradine does so without lowering BP or myocardial contractility.[132]<\/a>,[133]<\/a><\/sup> Recommendation<\/p> 34. We recommend that ivabradine be considered in patients with HFrEF, who remain symptomatic despite treatment with appropriate doses of GDMT, with a resting heart rate > 70 beats per minute (bpm), in sinus rhythm, and a previous HF hospitalization within 12 months, for the prevention of cardiovascular death and HF hospitalization (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> High value is placed on the improvement of cardiovascular death and HF hospitalizations as adjunctive therapy to standard HF medication treatments in a selected HF population. The health economic implications are unknown. Differing criteria for heart rate eligibility have been approved by various regulatory authorities ranging from 70 to 77 bpm with the trial entry criteria of 70 bpm.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> Every effort should be made to achieve target or maximally tolerated doses of b-blockers before initiation of ivabradine.<\/p>\n Ivabradine has no effect on BP or myocardial contractility.<\/p>\n<\/div>\n\n\n\n Three RCTs inform the use of H-ISDN in HFrEF. The V<\/strong>asodilator in He<\/strong>art F<\/strong>ailure T<\/strong>rial (V-HeFT) trial, the first RCT, compared the effect of H-ISDN, prazosin and placebo in HFrEF on mortality (n = 642).[136]<\/a><\/sup> After a mean follow-up of 2.3 years, there was no difference in mortality for the entire follow-up period (primary outcome), but showed a 66% relative improvement in survival in the H-ISDN group at 2 years. This trial predated the era of ACEis and \u03b2-blockers. The second trial to evaluate H-ISDN (300 mg and 160 mg) compared with enalapril (20 mg daily) in HFrEF on the outcome of mortality (n = 804).[137]<\/a><\/sup> There was a reduction in mortality in the enalapril arm after a mean of 2.5 years (32.8% vs 38.2%; P = 0.016) and no difference in hospitalizations. Neither of these trials provide an insight into the role of H-ISDN in the face of contemporary therapy. The third trial was the A<\/strong>frican-American He<\/strong>art F<\/strong>ailure T<\/strong>rial (A-HeFT) trial, in which H-ISDN was investigated in additional to optimal therapy (ACEi\/ARB, \u03b2-blocker, MRA) in self-identified black patients with NYHA class III\/IV HFrEF.[138]<\/a><\/sup> Black patients were specifically evaluated in this trial because it had been noted that this population has a less active renin-angiotensin system and seemed to respond better to H-ISDN. In this trial H-ISDN (225 mg or 120 mg) was evaluated vs placebo (in addition to standard therapy) on the outcome of all-cause mortality, first hospitalization for HF, and quality of life. A total of 1050 black patients were enrolled and followed for a mean of 10 months. The study was terminated early secondary to higher mortality in the placebo group. The primary outcome was a weighted score, but individual components of the outcome showed a difference favouring H-ISDN for all-cause mortality, first hospitalization for HF, and change in quality of life score. It is unclear if these results can be extrapolated to other groups.<\/p>\n\n\n\n Recommendation<\/p> 35. We recommend the combination of hydralazine and isosorbide dinitrate (H-ISDN) be considered in addition to standard GDMT at appropriate doses for black patients with HFrEF and advanced symptoms (Strong Recommendation; Moderate-Quality Evidence).<\/p>\n 36. We recommend that H-ISDN be considered in patients with HFrEF who are unable to tolerate an ACEi, ARB, or ARNI because of hyperkalemia or renal dysfunction (Strong Recommendation; Low-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> There is limited high-quality clinical trial evidence in the modern era from which to base an H-ISDN recommendation without considering the tolerability and adverse effects. Adverse effects related to H-ISDN are frequent, limit uptitration, and result in discontinuation in a significant proportion of patients. Every effort should be made to use ACEi\/ARB\/ARNI therapy including a low dose and\/or rechallenge therapy before changing to H-ISDN.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> Renal dysfunction warranting a trial of H-ISDN includes those who have a significant change in creatinine from baseline with ACEi\/ARB\/ARNI therapy that persists despite modification of dose, rechallenge, and\/or removal of other potentially nephrotoxic agents. It may also be considered in those with a serum creatinine (Scr) > 220 mmol\/L who experience significant worsening in renal function with the use of ACEi\/ARB\/ARNI therapy, or in a trial of these agents (eg, potential worsened renal function requiring renal replacement therapy) is thought to outweigh benefits.<\/p>\n Hyperkalemia warranting a trial of H-ISDN includes those with persistent hyperkalemia (K > 5.5 mmol\/L) despite dietary intervention, dosage reduction of ACEi\/ARB\/ARNI, and removal of other agents known to increase potassium levels.<\/p>\n Nitrates alone might be useful to relieve orthopnea, paroxysmal nocturnal dyspnea, exercise-induced dyspnea, or angina in patients when used as tablet, spray, or transdermal patch, but continuous (ie, around the clock) use should generally be avoided because most patients will develop tolerance.<\/p>\n<\/div>\n\n\n\n The effect of digoxin on mortality and morbidity in patient with heart failure (D<\/strong>igitalis I<\/strong>nvestigation G<\/strong>roup [DIGtrial])[139]<\/a><\/sup> enrolled 6800 patients with HF and a LVEF \u2264 45% and were randomized to digoxin (median dose 0.25 mg\/d) or placebo. The primary outcome was mortality over a mean follow-up of 37 months. Fifty-four percent were NYHA class II and 94% of patients were receiving an ACEi. There was no difference in all-cause mortality. There was a decrease in HFrelated deaths but an increase in \u201cother cardiac deaths,\u201d which has led to speculation that it might be due to arrhythmic death and led to an overall neutral effect on mortality. There were fewer patients hospitalized for HF in the digoxin group. Suspected digoxin toxicity was higher in the digoxin group (11.9% vs 7.9%). A systematic review included 13 studies (n = 7896, 88% of participants from the DIG-trial) showed similar results.[140]<\/a><\/sup> None of these studies provide much insight into the relative benefit or harm of digoxin in light of contemporary therapy with \u03b2-blockers and MRAs, however, many landmark trials of these agents had a substantial background therapy of digoxin with no apparent change in the overall results if a patient was or was not receiving digoxin.<\/p>\n\n\n\n Recommendation<\/p> 37. We suggest digoxin be considered in patients with HFrEF in sinus rhythm who continue to have moderate to severe symptoms, despite appropriate doses of GDMT to relieve symptoms and reduce hospitalizations (Weak Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> These recommendations place a high value on the understanding that the use of cardiac glycosides in HFrEF remains controversial in light of contemporary therapy, and digoxin had no effect on mortality, cardiovascular hospitalizations, exercise, or the primary end point in DIG-trial. Digoxin can cause atrial and ventricular arrhythmias particularly in the presence of hypokalemia or in the presence of worsening of renal function (with increased digoxin levels).<\/p>\n<\/div>\n\n\n Practical Tip<\/p> In patients receiving digoxin, serum potassium and creatinine should be measured with increases in digoxin or diuretic dose, the addition or discontinuation of an interacting drug, or during a dehydrating illness, to reduce the risk of digoxin toxicity. Patients with reduced or fluctuating renal function, elderly patients, those with low body weight, and women are at increased risk of digoxin toxicity and might require more frequent monitoring including digoxin levels.<\/p>\n Routine digoxin levels are not required other than to assess for digoxin toxicity. Digoxin levels should not be used to guide chronic therapy. Titration to digoxin levels has not been tested in clinical trials.<\/p>\n<\/div>\n\n\n\n The G<\/strong>ruppo I<\/strong>taliano per <\/strong>lo S<\/strong>tudio della S<\/strong>opravvivenza nell\u2019I<\/strong>nsufficienza cardiaca-H<\/strong>eart F<\/strong>ailure (GISSI-HF) study was an RCT designed to assess the effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in HF.[141]<\/a><\/sup> More than 4600 patients with NYHA class II to IV HF, irrespective of etiology or EF, were randomly assigned to a fish-based n-3 PUFA (daily 850 mg to 882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1.2) or placebo. The primary end points were time to death, and time to death or admission to hospital for cardiovascular reasons. After a median 3.9-year follow-up, there was a decrease in both primary outcomes favouring n-3 PUFA (9% relative reduction in all-cause death and an 8% relative reduction in death or admission to hospital). The therapy was well tolerated with primarily gastrointestinal side effects, and fewer than 10% of patients required study drug withdrawal. Current sources of n-3 PUFA in Canada are food supplements, therefore, are not subject to the regulatory review (including predefined tolerances for drug content) that is required for any drug approval. As such, it is difficult to be certain of the amount of n-3 PUFA present in any given commercial preparation. Indeed, evidence suggests a large degree of variability between different available forms of n-3 PUFA.[142]<\/a><\/sup> Patients and caregivers who wish to use n-3 PUFA are therefore referred to a local medical practitioner, pharmacy, or other reputable source of information to determine their best source of n-3 PUFA. Reports of excessive bleeding have been associated with doses < 3 g\/d, but this remains controversial.[143]<\/a>,[144]<\/a><\/sup><\/p>\n\n\n\n Recommendation<\/p> 38. We suggest n-3 PUFA therapy at a dose of 1 g\/d be considered for reduction in morbidity and cardiovascular mortality in patients with HFrEF (Weak Recommendation; Moderate-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Values and Preferences<\/p> Although there is an effect of fish oils on important HF outcomes, this recommendation also considers the modest effect size and issues surrounding the lack of standardization of commercial preparations in Canada.<\/p>\n<\/div>\n\n\n Practical Tip<\/p> With most data, the dose of n-3 PUFA is 1 g\/d. It is unknown whether higher or lower doses would confer clinical benefit and they are therefore not suggested. Doses greater than 3 g\/d are associated with excessive bleeding.<\/p>\n n-3 PUFA therapy might affect measures of anticoagulation. Close monitoring of the international normalized ratio (INR) in patients receiving warfarin after institution of n-3 PUFA is suggested.<\/p>\n There is evidence of significant variability in the content of n-3 PUFA. Patients considering n-3 PUFA should consult with their pharmacist to select a reliable supplement brand that most closely matches formulations shown to be effective in clinical trials.<\/p>\n<\/div>\n\n\n\n Many patients with HF have coexistent ischemic heart disease; however, these patients were systematically excluded from many of the early landmark statin trials. Two RCTs give insight into the benefit of statins specifically in patient with HF. Recommendation<\/p> We recommend against statins used solely for the indication of HF in the absence of other indications for their use. Statin treatment should be in accordance with primary and secondary prevention guidelines for CVD (Strong Recommendation; High-Quality Evidence).<\/p>\n <\/div>\n <\/div>\n<\/div>\n\n\n Practical Tip<\/p> Routine statin therapy is unlikely to provide clinical benefit for patients with HF due to nonischemic causes and in the absence of a very high risk of vascular events (such as recent MI, diabetes, and known vascular disease).<\/p>\n In those already receiving statin therapy, it is reasonable to consider statin withdrawal in patients with advanced HF, in polypharmacy where risks outweighs benefits, or when palliative care is an overriding concern.<\/p>\n<\/div>\n\n\n\n There are no RCTs that evaluate the role of ASA in comparison with placebo in patients with HF. A meta-analysis showed a reduction in serious vascular events, stroke, and coronary events with ASA therapy in secondary prevention trials.[148]<\/a><\/sup>![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-10-1024x777.png\")
<\/figure>\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-11-1.png\")
<\/figure>\n\n\n7.1.1.2 ACEi\/ARB<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-12-1-1024x434.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-13-1024x741.png\")
<\/figure>\n\n\n7.1.1.3 \u03b2-Adrenergic receptor blocker (\u03b2-blocker)<\/h4>\n\n\n\n
7.1.1.4 MRAs<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-14-1024x338.png\")
<\/figure>\n\n\n7.1.1.5 ARNI<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-5-1-1024x720.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-15-1024x864.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-18-1-1024x542.png\")
<\/figure>\n\n\n7.1.1.6 Ivabradine<\/h4>\n\n\n\n
The first trial to assess ivabradine in CAD was the Morb<\/strong>idity-Mortality E<\/strong>va<\/strong>lu<\/strong>at<\/strong>ion of the If<\/sub><\/strong> Inhibitor Ivabradine in Patients With Coronary Disease and Left-Ventricul<\/strong>ar Dysfunction (BEAUTIFUL) trial.[134]<\/a><\/sup> In this trial the effect of ivabradine 7.5 mg twice daily was evaluated in patients with CAD and LVEF < 40% in sinus rhythm with a heart rate > 60 bpm in > 10,000 patients. Although ivabradine did not reduce the primary composite end point of cardiovascular death, hospitalization for MI, or new-onset or worsening HF, it did reduce the incidence of the secondary end point of fatal and nonfatal MI in patients with a baseline heart rate \u2265 70 bpm.
The S<\/strong>ystolic H<\/strong>eart Failure Treatment With the If<\/sub><\/strong> Inhibitor Ivabradine T<\/strong>rial (SHIFT) trial was the key trial to address the use of ivabradine in symptomatic HF.[135]<\/a><\/sup> Inclusion criteria were NYHA class II-IV, sinus rhythm, resting heart rate \u2265 70 bpm, LVEF \u2264 35%, and HF admission within 12 months. Patients were randomized to a target dose of ivabradine 7.5 mg twice daily vs placebo. The primary end point was a composite of cardiovascular death or HF admission. Ninety percent of patients were receiving a \u03b2-blocker, and 56% were receiving 50% of target doses. Heart rate was 8 bpm lower in the ivabradine group at the end of the study. There was an 18% decrease in the primary outcome, which was largely driven by hospital admission for worsening HF (RRR, 26%). Treatment effect was consistent across prespecified subgroups, although the difference between treatment groups did not reach statistical significance in the subgroup with a baseline heart rate lower than the median of 77 bpm. Additionally, in those receiving > 50% of the target dose of a \u03b2-blocker, the overall trial results were similar. Ivabradine did not reduce all-cause or cardiovascular mortality. There were more withdrawals (21% vs 19%) and bradycardia in the ivabradine group (10% vs 2%). Only 1% of patients withdrew from the study as a consequence of bradycardia. Visual symptoms specific to ivabradine occurred rarely (3% vs 1% with placebo; P < 0.0001 and led to withdrawal in 1% of cases).<\/p>\n\n\n7.1.1.7 Hydralazine and isosorbide dinitrate<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-6-1024x564.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-7-1024x828.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-19-1-1024x634.png\")
<\/figure>\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-20-1024x658.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-21-868x1024.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-22-1024x334.png\")
<\/figure>\n\n\n\n7.1.1.8 Digoxin<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-23-1.png\")
<\/figure>\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-24.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-25-1024x284.png\")
<\/figure>\n\n\n\n7.1.1.9 Omega-3 polyunsaturated fatty acid<\/h4>\n\n\n\n
![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-8-1024x564.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-26-1024x835.png\")
<\/figure>\n\n\n7.1.1.10 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins)<\/h4>\n\n\n\n
The Co<\/strong>ntrolled Ro<\/strong>suvastatin Multina<\/strong>tional Trial in Heart Failure (CORONA) study was an RCT of 5011 patients with HF that compared rosuvastatin 10 mg\/d with placebo.[145]<\/a><\/sup> There was no difference in the primary end point of cardiovascular mortality, nonfatal MI, or nonfatal stroke. There was an 8% relative reduction in the secondary outcome of cardiovascular hospitalizations, but not HF hospitalizations. Rosuvastatin was well tolerated, with fewer withdrawals from therapy than with placebo. Despite achieving the expected low-density lipoprotein cholesterollowering of rosuvastatin, there was little benefit in this cohort of patients with CAD.[146]<\/a><\/sup>
The second trial was the GISSI-HF study; 4574 patients with chronic HF, NYHA class II-IV, irrespective of cause and LVEF, were randomly assigned to rosuvastatin 10 mg\/d or placebo, and followed for a median of 3.9 years.[147]<\/a><\/sup> There was no difference in the primary end points of time to death, and time to death or admission to hospital for cardiovascular reasons. There was no difference in any other outcomes or subgroups.<\/p>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-9-1-1024x518.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Table-27-1024x254.png\")
<\/figure>\n\n\n7.1.1.11 Anticoagulation and antiplatelet therapy<\/h4>\n\n\n\n
The 2 largest RCTs both compared warfarin with ASA (with or without clopidogrel) rather than placebo. The W<\/strong>arfarin and A<\/strong>ntiplatelet T<\/strong>herapy in C<\/strong>hronic H<\/strong>eart Failure (WATCH) trial compared warfarin (INR, 2.5-3), ASA (162 mg) and clopidogrel (75 mg) in patients with HFrEF in sinus rhythm. A total of 1587 patients were followed for a mean of 1.9 years.[149]<\/a><\/sup> The study was stopped early secondary to poor recruitment. There was no difference in the primary end point of all-cause mortality, nonfatal MI, or nonfatal stroke in any of the groups. However, there was a reduction in stroke in the warfarin arm compared with the antiplatelet arms, but there was also a higher risk of bleeding in the warfarin group compared with the clopidogrel group. The W<\/strong>arfarin versus A<\/strong>spirin in R<\/strong>educed C<\/strong>ardiac E<\/strong>jection F<\/strong>raction (WARCEF) trial, the largest trial to date, had similar results with a single comparison arm of ASA 325 mg daily vs warfarin (INR, 2-3.5). A total of 2305 patients were enrolled with a mean follow-up of 42 months.[150]<\/a><\/sup> There was no difference in the primary outcome of ischemic stroke, intracerebral hemorrhage, or all-cause mortality, but there was a decrease in ischemic stroke and an increase in major hemorrhage for patients who received warfarin. In a meta analysis of the 4 main RCTs, there was no difference in all-cause mortality, HFrelated hospitalization, or nonfatal MI.[151]<\/a><\/sup> There was a decrease in all cause stroke and ischemic stroke and an increase in major bleeding for patients who received warfarin.[152]<\/a><\/sup> The ongoing A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of Rivaroxaban With Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects With Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated Heart Failure (COMMANDERHF) trial is testing the additional use of rivaroxaban vs placebo in patients with sinus rhythm, HFrEF, and a recent hospital admission (NCT01877915).<\/p>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-10-1024x627.png\")
<\/figure>\n\n\n\n![\"\"](\"https:\/\/ccs.ca\/wp-content\/uploads\/2022\/12\/Figure-11-1-1024x425.png\")
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