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Canadian Journal of Cardiology

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis

      Abstract

      In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

      Résumé

      Dans cette mise à jour, nous nous intéressons à des thématiques précises ayant une pertinence clinique d’importance pour les fournisseurs de soins de santé qui traitent des patients atteints d'insuffisance cardiaque (IC), sur la base d'essais cliniques publiés après 2017. Notre objectif était d'examiner les données probantes et de fournir des recommandations et des conseils pratiques concernant la prise en charge des candidats aux différents traitements d'IC suivants : (1) la réparation de la valve mitrale par cathéter dans le cadre d'une IC avec une fraction d'éjection réduite; (2) un nouveau traitement pour l'amylose de la transthyrétine ou l'amyloïdose cardiaque à la transthyrétine; (3) l'inhibition du récepteur de l'angiotensine et de la névrilysine chez les patients atteints d'IC avec une fraction d'éjection préservée (ICFEP); et (4) les inhibiteurs du cotransporteur sodium-glucose pour la prévention et le traitement de l'IC chez les patients avec et sans diabète de type 2. Nous mettons l’emphase sur le rôle d’une thérapie médicale optimale encadrée par les lignes directrices et sur le rôle des équipes multidisciplinaires lorsqu'une réparation de la valve mitrale par cathéter est envisagée, ceci afin de garantir l’excellence dans l’évaluation et les soins portés à ces patients. En présence de signes cliniques manifestes, les fournisseurs de soins de santé devraient envisager l’éventualité d'une amylose cardiaque et procéder à un examen approprié. Le tafamidis est le premier agent dont une étude prospective a démontré qu'il remanie les effets d'une amylose cardiaque à transthyrétine chez les patients. L'utilisation du sacubitril/valsartan pourrait être bénéfique pour les sous-groupes de patients atteints d’ICFEP; toutefois, des données complémentaires sont nécessaires pour clarifier l'effet de ce traitement chez les patients atteints d’ICFEP. Les inhibiteurs du cotransporteur sodium-glucose réduisent le risque d'incidence de l'IC, les hospitalisations liées à l'IC et les décès d'origine cardiovasculaire chez les patients atteints de diabète de type 2 et de maladie cardiovasculaire. Un vaste essai clinique a récemment montré que la dapagliflozine procure des bénéfices importants sur le plan des répercussions chez les patients correctement traités atteints d'IC avec une fraction d'éjection réduite (fraction d'éjection du ventricule gauche ≤ 40 %), avec ou sans diabète de type 2.
      The Canadian Cardiovascular Society (CCS) heart failure (HF) guidelines program provides guidance to clinicians, policy makers, and health systems as to the evidence supporting existing and emerging management of patients with HF. The 2019 update on clinical trial data is a brief set of guidelines incorporating new evidence from randomized controlled trials published after the 2017 update on topics of importance for health care providers in HF management. It updates the last version of the CCS HF guidelines on those specific topics.
      The constitution and roles of the primary and secondary panels, systematic review strategy, and methods for formulating the recommendations are described at www.ccs.ca. The recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) standards.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ,
      • Andrews J.
      • Guyatt G.
      • Oxman A.D.
      • et al.
      GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.
      Primary panelists were responsible for writing and reviewing the document, with writing participation of 3 secondary panelists and 6 external content experts.
      The objective of this update was to highlight new clinical trial evidence on 4 topics of high importance in terms of changes and evolution in the care of patients with HF: (1) transcatheter mitral valve repair; (2) potential treatments for transthyretin amyloidosis (ATTR) or transthyretin cardiac amyloidosis (CA); (3) the role of angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) prevention of HF outcomes with sodium glucose cotransport (SGLT2) inhibitors. We collaborated with content experts on each topic who provided critical external input and perspective.

      1. Percutaneous Mitral Valve Repair for Patients With HF and Reduced Ejection Fraction and Severe Functional Mitral Regurgitation

      Functional mitral regurgitation (FMR) secondary to left ventricular (LV) dysfunction and dilatation is an important contributor to the high mortality
      • Cioffi G.
      • Tarantini L.
      • De Feo S.
      • et al.
      Functional mitral regurgitation predicts 1-year mortality in elderly patients with systolic chronic heart failure.
      observed in patients with HF and reduced ejection fraction (HFrEF). Observational studies and 1 previous randomized trial
      • Glower D.D.
      • Kar S.
      • Trento A.
      • et al.
      Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study.
      showed the potential benefits of surgical correction or percutaneous mitral valve repair (PMVR) for improving symptoms and promoting reverse remodelling. However, this has not been routinely recommended to date.
      • Glower D.D.
      • Kar S.
      • Trento A.
      • et al.
      Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study.
      • Schillinger W.
      • Hunlich M.
      • Baldus S.
      • et al.
      Acute outcomes after MitraClip therapy in highly aged patients: results from the German TRAnscatheter Mitral valve Interventions (TRAMI) Registry.
      • Maisano F.
      • Franzen O.
      • Baldus S.
      • et al.
      Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe.
      • Nickenig G.
      • Estevez-Loureiro R.
      • Franzen O.
      • et al.
      Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011-2012 Pilot European Sentinel Registry.
      Such data have raised awareness regarding the importance of FMR on progression of HF and the potential for treatment of FMR to improve outcomes. Although a number of technologies are in clinical development, edge-to-edge leaflet repair with the MitraClip system (Abbott Structural Heart) is currently the only Health Canada-approved device for PMVR.
      In a previous retrospective observational study mitral interventions (either transcatheter or surgical) were compared with conservative management.
      • Kortlandt F.
      • Velu J.
      • Schurer R.
      • et al.
      Impact of mitral valve treatment choice on mortality, according to aetiology.
      Conservative management in patients with FMR was associated with a higher mortality compared with PMVR (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.34-2.39), with no significant mortality difference identified between the PMVR and surgical arms (HR, 0.86; 95% CI, 0.54-1.38). Of note, the death rate was numerically higher for patients treated with PMVR vs surgery (33% vs 23%), in keeping with the higher mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) II observed in this group of patients (8.9 vs 4.7; P < 0.001). Because of the nonrandomized observational study design, these findings are not conclusive with respect to the role of PMVR in patients with HF and severe FMR.
      In 2018, 2 randomized controlled trials were published that compared the efficacy of PMVR using the MitraClip device (Abbott Structural Heart) in addition to guideline-directed medical therapy (GDMT) with GDMT alone in patients with FMR for whom mitral valve surgery was not deemed appropriate.
      • Nickenig G.
      • Estevez-Loureiro R.
      • Franzen O.
      • et al.
      Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011-2012 Pilot European Sentinel Registry.
      ,
      • Kortlandt F.
      • Velu J.
      • Schurer R.
      • et al.
      Impact of mitral valve treatment choice on mortality, according to aetiology.
      These trials differed with respect to patient characteristics and outcome definitions. The Percutaneous Repair with the MitraClip device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) 9 trial enrolled 304 patients with at least moderate-severe FMR (mean effective regurgitant orifice area of 31 mm2) and severe LV dilatation (indexed left ventricular end-diastolic volume of 135 ± 37 mL/m2). PMVR did not provide a benefit in survival over GDMT alone (24.3% vs 22.4%; HR, 1.11; 95% CI, 0.69-1.77) or in the rate of unplanned hospitalization for HF (HHF; 48.7% vs 47.4%; HR, 1.13; 95% CI, 0.81-1.56) during the 1-year follow-up period.
      In contrast, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT)
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      trial enrolled 614 patients after optimization of GDMT (only one-third of the screened patients were eventually randomized; Table 1) with longer (2-year) follow-up. Trial participants had higher brain natriuretic peptide (BNP) concentrations (mean, 1043 vs 800 ng/L), smaller indexed LV end-diastolic volume (101 ± 34 mL/m2), and more severe FMR (mean effective regurgitant orifice area, effective regurgitant orifice area of 40.5 mm2 compared with the MITRA-FR population).
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      ,
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Patients who received PMVR had lower all-cause mortality at 2 years compared with GDMT alone (29.1% vs 46.1%; HR, 0.62; 95% CI, 0.46-0.82; P < 0.001). PMVR also reduced the risk of HF hospitalizations (35.8% vs 67.9% per patient-year; HR, 0.53; 95% CI, 0.4-0.7; P < 0.001) and resulted in significant improvements in Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life scores and 6-minute walk distances.
      Table 1Comparison of trial patients and outcomes in the MITRA-FR and COAPT studies
      VariableMITRA-FRCOAPT
      Trial and patient characteristics
       ComparisonMitraClip vs GDMTMitraClip vs GDMT
       Heart team evaluation and GDMTHeart team evaluation, GDMT not described over timeHeart team evaluation, GDMT described over time
       Study period2013-20172012-2017
       Follow-up period, year(s)1 (2)
      At this time, the 2-year follow-up data have been presented but are not published.
      2
       Patients enrolled/patients considered for trial, n (%)307/452 (67.9)665/1576 (42.2)
       Mean LVEDVI (SD), mL/m2135 (35)101 (34)
       Mean baseline EROA (SD), mm231 (10)41 (15)
       Mean LVEF (SD), n %33 (7)31 (9)
      Outcomes
       Procedural complications
      MitraClip group only.
      21/144 (14.6)25/293 (8.5)
       MR grade ≥ 2 at discharge30/123 (24.4%)46/260 (17.7)
       MR grade ≥ 2 at 1 year48/97 (49.5)65/210 (31.0)
       All-cause mortality/HF hospitalization at 1 year, n (%)
      MitraClip arm83/151 (54.6)102/302 (33.9)
      GDMT arm78/152 (51.3)145/312 (46.5)
      P0.53< 0.001
      MitraClip is from Abbott Structural Heart.
      COAPT, Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation; EROA, effective regurgitant orifice area; GDMT, guideline-directed medical therapy; HF, heart failure; LVEDVI, left ventricular end diastolic volume index; LVEF, left ventricular ejection fraction; MITRA-FR, Percutaneous Repair with the MitraClip device for Severe Functional/Secondary Mitral Regurgitation; MR, mitral regurgitation.
      Modified from Tang, et al.
      • Tang H.L.
      • Sudbodh V.
      Two randomized clinical trials on the treatment of secondary mitral regurgitation—contradictory or complementary?.
      with permission from the American Medical Association.
      At this time, the 2-year follow-up data have been presented but are not published.
      MitraClip group only.
      Taken together, these 2 trials suggest that PMVR has the potential to reduce mortality and HF hospitalization for selected patients with symptomatic moderate to severe or severe (3+ to 4+) FMR despite optimal GDMT. For patients with moderate FMR or severely dilated left ventricles, the benefits, if any, remain unproven.
      • Obadia J.F.
      • Messika-Zeitoun D.
      • Leurent G.
      • et al.
      Percutaneous repair or medical treatment for secondary mitral regurgitation.
      Some have suggested that the lack of demonstrable benefit with PMVR in the MITRA-FR trial might have been attributable to the extent of LV dilatation and negative remodelling in the context of less severe FMR and the absence of forced medical GDMT optimization. Conversely, in the COAPT trial,
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      intervention occurred earlier in the course of the disease process, with optimized GDMT having already been in place (Table 1).
      A third randomized controlled trial of GDMT vs PMVR therapy, a European study, A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF 2, NCT02444338) is currently enrolling patients with results expected by the end of 2021. Finally, a trial designed to evaluate the potential benefits of early transcatheter intervention in HFrEF patients with less severely dilated left ventricles and moderate FMR, the Evaluation of Outcomes of Transcatheter Mitral Valve Repair for the Treatment of Low Ejection Fraction and Moderate Functional Mitral Valve Regurgitation in Heart Failure (EVOLVE-HF; NCT03705312) trial, is currently under way. These trials might further refine our understanding of optimal patient selection and timing for intervention.
      Neither the COAPT nor the MITRA-FR trials included a surgical arm. Whether surgery or PMVR results in similar clinical benefit in patients with FMR is being addressed in the Multicenter, Randomized, Controlled Study to Assess Mitral Valve Reconstruction for Advanced Insufficiency of Functional or Ischemic Origin (MATTERHORN) randomized trial (NCT02371512) including 210 participants, with the study completed in December 2019.
      • 1.
        We recommend that maximally tolerated GDMT, including cardiac resynchronization therapy and revascularization where appropriate, be implemented before consideration of PMVR for patients with HFrEF and severe FMR (Strong Recommendation, High-Quality Evidence).
      • 2.
        We suggest that patients with symptomatic HF (HFrEF) despite maximal GDMT and severe mitral regurgitation be evaluated for PMVR (Weak Recommendation, Moderate-Quality Evidence).
      • 3.
        We recommend that a multidisciplinary dedicated heart team (including interventionalists, cardiac surgeons, imaging specialists, and HF specialists) perform the evaluation and care of potential candidates for PMVR (Strong Recommendation, Low-Quality Evidence).
      Values and preferences. These recommendations emphasize optimization of all other established therapies for HFrEF and FMR before consideration of PMVR. They also highlight the role of optimizing GDMT (because this has been clearly associated with improved outcomes)
      • Metze C.
      • Matzik A.S.
      • Scherner M.
      • et al.
      Impact of frailty on outcomes in patients undergoing percutaneous mitral valve repair.
      vs reduction in FMR severity per se. The use of multidisciplinary teams reflects the approach taken in the clinical trials to ensure excellent evaluation, care, and follow-up associated with PMVR.
      Practical tip. Caution should be used when treating FMR in patients with HFrEF because the encouraging results from the COAPT trial
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      must be considered in the context of new medical treatments that were not frequently incorporated into clinical practice when the trial was performed (sacubitril-valsartan, ivabradine),
      • Piriou N.
      • Al Habash O.
      • Donal E.
      • et al.
      The MITRA-HR study: design and rationale of a randomised study of MITRACLIP(R) transcatheter mitral valve repair in patients with severe primary mitral regurgitation eligible for high-risk surgery.
      as well as treatments currently under study in patients with HFrEF.
      Practical tip. The identification of candidates with HFrEF and FMR most likely to benefit from the PMVR procedure might be informed by the characteristics of patients enrolled in the COAPT and MITRA-FR studies (Table 1). Patients with severe LV dilatation (typically LV end diastolic dimension > 70 mm) and less than severe mitral regurgitation might be poor candidates for MitraClip (Abbott Structural Heart).
      Practical tip. Patients with FMR should first receive maximally tolerated GDMT, including pharmacological and nonpharmacological HF therapies (eg, cardiac resynchronization therapy where applicable) for a reasonable minimum period of time (eg, 3 months), before PMVR is considered.
      Practical tip. Patients considered for PMVR should be referred to centres with:
      • Experience in the evaluation of patients with advanced HF;
      • High volumes of patients with valve disease managed medically and surgically;
      • High likelihood of achieving the volume of PMVR (eg, 2-4 per month) required for developing and maintaining competence in well selected patients.
        • Ezekowitz J.A.
        • O’Meara E.
        • McDonald M.A.
        • et al.
        2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
        ,
        • Merlini G.
        • Bellotti V.
        Molecular mechanisms of amyloidosis.

      2. Treatment of CA: Focus on Transthyretin CA

      A comprehensive CCS/Canadian Heart Failure Society (CHFS) joint position statement on the evaluation and management of CA is forthcoming and will include GRADE standard recommendations on the diagnostic workup and therapeutic approaches for management of this disease. For the purposes of this update, practical tips are provided in the context of recent clinical trial evidence for the management of a subtype of amyloidosis known as ATTR.
      Amyloidosis is a group of heterogeneous disorders in which a specific precursor protein pathologically misfolds, aggregates, and forms amyloid fibrils that deposit extracellularly within various organs including the heart, resulting in organ failure.
      • Merlini G.
      • Bellotti V.
      Molecular mechanisms of amyloidosis.
      CA is a form of infiltrative cardiomyopathy that develops when amyloid deposits infiltrate myocardial tissue. This infiltrative process results in progressive ventricular stiffness, wall thickening, and diastolic filling abnormalities, which typically manifest as HFpEF and restrictive physiology.
      • Falk R.H.
      Diagnosis and management of the cardiac amyloidoses.
      When the disease is severe and advanced, systolic dysfunction might also be seen.
      • Siddiqi O.K.
      • Ruberg F.L.
      Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment.
      The most common subtypes of CA are ATTR and the immunoglobulin light chain amyloidosis (known as AL amyloidosis). ATTR is further categorized into a hereditary form, due to one of numerous disease-causing genetic mutations and the “wild type” ATTR, in which a mutation is not present.
      • Rapezzi C.
      • Merlini G.
      • Quarta C.C.
      • et al.
      Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types.
      ,
      • Benson M.D.
      • Buxbaum J.N.
      • Eisenberg D.S.
      • et al.
      Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.
      Rarely, other types of amyloid proteins can affect the heart, including amyloid A, apolipoprotein A1, heavy chain, and atrial natriuretic peptide. Because recent clinical trial evidence applies only to the pharmacologic treatment of ATTR-CA, it is of the utmost importance to accurately identify the amyloid subtype to initiate specific treatment and avoid inappropriate application of therapy.
      • Pereira N.L.
      • Grogan M.
      • Dec G.W.
      Spectrum of restrictive and infiltrative cardiomyopathies: part 1 of a 2-part series.

      Recognizing the possibility of CA

      It must be emphasized that the clinical phenotypes of all forms of CA are similar, which makes distinction between subtypes difficult using clinical assessment alone. When CA is suspected, AL amyloidosis should be ruled out using serum free light chains (kappa and lambda), and serum and urine protein electrophoresis with immunofixation. The presence of light chains alone is not specific for AL-CA because > 20% of patients with ATTR have an unrelated monoclonal gammopathy of unknown significance.
      • Pinney J.H.
      • Whelan C.J.
      • Petrie A.
      • et al.
      Senile systemic amyloidosis: clinical features at presentation and outcome.
      In this scenario, tissue biopsy (bone marrow or endomyocardial) with immunohistochemistry or mass spectrometry is necessary to determine the subtype of CA. Further, when AL amyloidosis has been ruled out, technetium-labelled scintigraphy such as pyrophosphate scan can be used to help confirm a diagnosis of ATTR-CA.
      • Gertz M.A.
      • Brown M.L.
      • Hauser M.F.
      • Kyle R.A.
      Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis.
      • Hutt D.F.
      • Quigley A.M.
      • Page J.
      • et al.
      Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis.
      • Bokhari S.
      • Castano A.
      • Pozniakoff T.
      • et al.
      (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses.
      This imaging modality is > 99% sensitive and 86% specific for ATTR CA, with false positive tests occurring almost exclusively in the setting of AL-CA. In one study, the presence of a positive scan in the absence of a monoclonal gammopathy had 100% specificity and positive predictive value for ATTR-CA.
      • Gillmore J.D.
      • Maurer M.S.
      • Falk R.H.
      • et al.
      Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
      Practical tip. In the setting of undifferentiated CA, the presence of light chains does not confirm the diagnosis of AL-CA because monoclonal gammopathy of unknown significance and ATTR-CA can coexist. In such settings, tissue biopsy is frequently necessary to exclude AL-CA.
      Practical tip. Technetium-labelled scintigraphy should be performed, where available, to diagnose ATTR-CA when plasma cell dyscrasias have been ruled out.
      Until recently, treatment of ATTR-CA was mostly supportive in nature with a median survival of 3.5 years
      • Grogan M.
      • Scott C.G.
      • Kyle R.A.
      • et al.
      Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system.
      after diagnosis. Different therapeutic modalities have been investigated in recent years using transthyretin stabilizers (eg, diflunisal and tafamidis), suppressors of ATTR synthesis (gene silencers), and amyloid fibrils degraders (doxycycline with tauroursodeoxycholic acid or ursodeoxycholic acid and epigallocatechin 3-gallate found in green tea extracts).
      • Maurer M.S.
      • Grogan D.R.
      • Judge D.P.
      • et al.
      Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.
      • Ikram A.
      • Donnelly J.P.
      • Sperry B.W.
      • et al.
      Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center’s experience.
      • Rosenblum H.
      • Castano A.
      • Alvarez J.
      • et al.
      TTR (transthyretin) stabilizers are associated with improved survival in patients with TTR cardiac amyloidosis.
      • Cappelli F.
      • Martone R.
      • Taborchi G.
      • et al.
      Epigallocatechin-3-gallate tolerability and impact on survival in a cohort of patients with transthyretin-related cardiac amyloidosis. A single-center retrospective study.
      • Solomon S.D.
      • Adams D.
      • Kristen A.
      • et al.
      Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis.
      • Benson M.D.
      • Waddington-Cruz M.
      • Berk J.L.
      • et al.
      Inotersen treatment for patients with hereditary transthyretin amyloidosis.
      Historically,
      • Cappelli F.
      • Martone R.
      • Taborchi G.
      • et al.
      Epigallocatechin-3-gallate tolerability and impact on survival in a cohort of patients with transthyretin-related cardiac amyloidosis. A single-center retrospective study.
      most studies that have investigated these drugs have been small and observational in nature and used surrogate end points. The recently published Transthyretin Amyloidosis Cardiomyopathy Trial (ATTR-ACT) randomized 441 patients with wild type or mutant (hereditary) ATTR-CA to either tafamidis, a transthyretin tetramer stabilizer, or placebo, and were followed for 30 months.
      • Maurer M.S.
      • Schwartz J.H.
      • Gundapaneni B.
      • et al.
      Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.
      At the end of the study, patients who received tafamidis had significantly lower all-cause mortality (HR, 0.70; 95% CI, 0.51-0.96) and reduced cardiovascular hospitalizations (HR, 0.68; 95% CI, 0.56 to 0.81). Tafamidis also significantly reduced the rate of decline in functional capacity and quality of life (P < 0.001 for both outcomes).
      • Maurer M.S.
      • Schwartz J.H.
      • Gundapaneni B.
      • et al.
      Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.
      As of the time of writing, tafamidis is not approved by Health Canada for the treatment of ATTR-CA (it was recently approved by the US Food and Drug Administration). However, it is the first agent that has been shown in a prospective study to alter patient outcomes by improving survival and reducing cardiovascular hospitalizations. The CCS/CHFS joint position statement will address formal recommendations on the use of tafamidis and other therapeutic options for ATTR-CA on the basis of the totality of published evidence. Pending the availability of ATTR-CA-specific treatments in Canada, and the forthcoming comprehensive amyloid recommendations, it is reasonable to consider the following practical tips.
      Practical tip. Patient selection for tafamidis should reflect the inclusion criteria for the major randomized controlled clinical trial that showed clinical benefits of tafamidis over placebo with respect to mortality and cardiovascular hospitalization, including established ATTR-CA and objective evidence of HF (with elevated natriuretic peptides where available).
      Practical tip. Patients with New York Heart Association (NYHA) class IV symptoms or severe functional disability, measured using a 6-minute walk test < 100 m, were excluded from ATTR-ACT and should not routinely be considered for treatment with tafamidis.
      Practical tip. Subgroup analysis from the ATTR-ACT trial suggested that the reduction in cardiovascular hospitalizations seen with tafamidis might be limited to patients with less severe symptoms (NYHA class I or II).
      Practical tip. Because of the complexity in diagnosing CA and the potential for offering advanced or experimental treatment options, consideration should be given to referring patients with CA to experienced centres.
      Practical tip. Other agents are currently under investigation, which might modify current treatment recommendations.

      3. New Evidence for Angiotensin Receptor Neprilysin Inhibitors in Patients With HFpEF

      HFpEF is rising in prevalence and is associated with significant morbidity and mortality.
      • Dunlay S.M.
      • Roger V.L.
      • Redfield M.M.
      Epidemiology of heart failure with preserved ejection fraction.
      ,
      • Redfield M.M.
      Heart failure with preserved ejection fraction.
      Although evidence-based and mortality-reducing therapies exist for HFrEF, no therapies have shown a mortality benefit in those with an ejection fraction (EF) > 40%. In PARAMOUNT (Prospective Comparison of ARNI with ARB on Management of Heart Failure With Preserved Ejection Fraction) (NCT02371512), a phase II trial with patients with HFpEF, sacubitril/valsartan reduced N-terminal pro–B-type natriuretic peptide levels and left atrial enlargement and also improved NYHA class compared with valsartan.
      • Solomon S.D.
      • Zile M.
      • Pieske B.
      • et al.
      The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.
      Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) was a randomized double blind active comparator trial that tested the hypothesis that sacubitril/valsartan compared with valsartan would reduce the composite primary end point of total (first and recurrent) HF hospitalizations and cardiovascular death.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
      After a run-in phase, patients were randomized to sacubitril/valsartan 97/103 mg twice daily vs valsartan 160 mg twice daily. Secondary end points included improvement in NYHA functional class at 8 months, changes in KCCQ clinical summary score at 8 months, time to first occurrence of worsening renal function, and time to all-cause mortality.
      Eligible patients were 50 years of age or older with symptomatic HF (NYHA II-IV) and an EF ≥ 45%. Inclusion criteria also specified treatment with diuretics for at least 30 days before enrollment as well as structural heart disease identified as left atrial enlargement or LV hypertrophy using echocardiography. Natriuretic peptide thresholds were stratified for the presence or absence of atrial fibrillation.
      • Solomon S.D.
      • Rizkala A.R.
      • Gong J.
      • et al.
      Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial.
      In an attempt to capture the total burden of disease, the primary analysis incorporated total HF hospitalizations and cardiovascular death. In total 4822 patients were randomized, and treatment discontinuation for any reason other than death occurred in 25% of the sacubitril/valsartan arm vs 27% in the valsartan arm. The mean age in this trial was 73 years and 52% were female. Most patients had NYHA class II symptoms. Before randomization, 87% of patients in both arms were treated with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). All baseline characteristics were balanced with the exception of mineralocorticoid receptor antagonists use, which was more common in the valsartan arm (27.1% vs 24.6%). In the PARAGON-HF trial, 1009 events were observed, equivalent to 14.6 per 100 patient-years in the valsartan arm in contrast to 894 events with a rate of 12.8 per 100 patient-years in the sacubitril/valsartan arm. This equated to a 13% relative risk reduction in the sacubitril/valsartan arm that did not meet clinical significance (95% CI, 0.75-1.01; P = 0.06). The reduction in the primary end point was driven predominantly by a reduction in HF hospitalizations, which were reduced by 15% and also narrowly missed statistical significance (P = 0.06). The KCCQ score was improved greater than 5 points more often in the sacubitril/valsartan group (odds ratio, 1.30; 95% CI, 1.04-1.61; P = 0.02). Worsening renal function defined by a composite renal end point was significantly less frequent in the sacubitril/valsartan arm. A similar safety profile was seen in PARAGON-HF as was seen in previous studies of sacubitril/valsartan in patients with HFrEF.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      In a multivariable model of prespecified subgroups that incorporated all interaction terms, only sex and LV EF (LVEF) appeared to modify the treatment effect. Women achieved a significant 27% overall reduction in the primary end point, and patients at or below the trial median LVEF of 57% achieved a 22% reduction in primary end point. The P values for both were significant in multivariable interaction testing.
      In summary, in a comparison of sacubitril/valsartan with valsartan in HFpEF patients, PARAGON-HF showed a modest but nonsignificant 13% reduction in the primary outcome, which was driven by a reduction in first and recurrent HF hospitalizations. In secondary end point analysis, improvement in quality of life and renal function suggested potential benefits with sacubitril/valsartan compared with valsartan. The data further suggest heterogeneity in the treatment response with greater benefit in women and in individuals with a lower LVEF.
      Although these results are intriguing, they should be considered hypothesis-generating; important patient subgroups with HFpEF might benefit from sacubitril/valsartan treatment, but further data are needed to clarify the effect of this therapy in patients with HFpEF. Key outstanding issues to be addressed include:
      • More granular understanding of the biological and pathophysiological differences in HFpEF according to sex.
      • Further analysis of the interaction between sex and LVEF.
      • LVEF thresholds at which clinically important benefits of angiotensin receptor-neprilysin inhibition are seen.
      • Possible heterogeneity of treatment effect according to etiology and/or phenotype.
      The statistically negative results of the PARAGON-HF primary end point analysis preclude any recommendation for the general use of sacubitril/valsartan in patients with HFpEF. The PARAGON-HF trial has provided a number of interesting insights; further analysis and investigation might inform future specific recommendations on the management of HFpEF.

      4. New Evidence for SGLT2 Inhibitors and HF

      SGLT2 inhibitors lead to a reduction in plasma glucose by inhibiting renal tubular glucose reabsorption, with resultant glucosuria. These glycemia-related changes are also associated with natriuresis, an osmotic diuresis, modest weight loss, an increase in hematocrit, and a reduction in blood pressure. All of these effects represent potentially favourable changes that might lead to a reduction in incident HF in patients with type 2 diabetes, as initially shown in the landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - Removing Excess Glucose (EMPA-REG OUTCOME) trial.
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial.
      In 2017, the CCS HF guidelines
      • Ezekowitz J.A.
      • O’Meara E.
      • McDonald M.A.
      • et al.
      2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
      recommended the use of SGLT2 inhibitors for prevention of HF events in patients with type 2 diabetes and known history of cardiovascular disease. In view of the rapidly evolving research on this topic, we have updated our recommendations.
      The SGLT2 inhibitor empagliflozin was the first glucose-lowering drug to show an improvement in cardiovascular outcomes in a large randomized controlled clinical trial.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      The EMPA-REG OUTCOME trial randomized 7020 patients with type 2 diabetes and established cardiovascular disease (with estimated glomerular filtration rate [eGFR] > 30 mL/min/1.73 m2) to receive either empagliflozin 10 mg or 25 mg or placebo. The study showed a statistically significant reduction in the composite outcome of cardiovascular death or HHF (HR, 0.83; 95% CI, 0.73-0.95; P = 0.005) in the empagliflozin group vs placebo. A prespecified outcome, adjudicated HHF, was also significantly reduced with empagliflozin, with an HR of 0.73 (95% CI, 0.61-0.88).
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      The benefit of empagliflozin was observed in patients with and without an investigator-reported history of HF, and unrelated to baseline level of renal function (eGFR) or conventional risk factors, such as A1c, blood pressure, or lipids.
      • Fitchett D.
      • Zinman B.
      • Wanner C.
      • et al.
      Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial.
      The Canagliflozin Cardiovascular Assessment Study–Renal (CANVAS-R) Program was the second major study of an SGLT2 inhibitor to show cardiovascular benefit in patients with type 2 diabetes.
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • et al.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      In total, 10,142 patients with type 2 diabetes (eGFR > 30 mL/min/1.72 m2) with established cardiovascular disease or aged > 50 years with ≥ 2 risk factors for cardiovascular disease were randomized to receive canagliflozin (either 100 or 300 mg/d), or placebo.
      • Neal B.
      • Perkovic V.
      • Matthews D.R.
      • et al.
      Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial.
      The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program also showed a 33% reduction in HF hospitalization with canagliflozin therapy (HR, 0.67; 95% CI, 0.52-0.87). A subsequent analysis
      • Radholm K.
      • Figtree G.
      • Perkovic V.
      • et al.
      Canagliflozin and heart failure in type 2 diabetes mellitus.
      showed that this benefit occurred in patients with and without a preexisting atherosclerotic cardiovascular disease.
      In the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-Thrombolysis in Myocardial Infarction (TIMI) 58 study,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 trial.
      dapagliflozin vs placebo was evaluated in 17,160 patients, 10,186 of whom did not have documented existing atherosclerotic cardiovascular disease.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      Furthermore, unlike the previous studies, patients with a creatinine clearance of 60 mL or more per minute were enrolled. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or HHF. The rates of MACE were not statistically different (HR, 0.93; 95% CI, 0.84-1.03; P = 0.17), however, the composite of cardiovascular death or HHF was reduced (HR, 0.83; 95% CI, 0.73-0.95; P = 0.005). The latter finding was driven primarily by a reduction in HHF (HR, 0.73; 95% CI, 0.61-0.88) and similar relative benefits were observed in patients with or without preexisting atherosclerotic cardiovascular disease or HF.
      In a secondary analysis of the DECLARE study, 671 patients were noted to have an LVEF < 45% (documented in patients with available echocardiograms) whereas 1316 had a history of HF without a reduced EF (808 with a documented EF ≥ 45% and 508 without a documented EF).
      • Kato E.T.
      • Silverman M.G.
      • Mosenzon O.
      • et al.
      Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
      In this analysis, subjects with LVEF < 45% treated with dapagliflozin derived a larger decrement of cardiovascular death or HF hospitalization (HR, 0.62; 95% CI, 0.45-0.86) compared with those without known lower LVEF (HR, 0.88; 95% CI, 0.76-1.02; P interaction = 0.046), the difference driven by a reduction in cardiovascular mortality (HR, 0.55; 95% CI, 0.34-0.90). In addition, only those with lower EF treated with dapagliflozin experienced a reduction in all-cause mortality (HR, 0.59; 95% CI, 0.40-0.88; P = 0.01). Because these analyses were not prespecified, the findings are hypothesis-generating and require confirmation in prospective studies of well characterized patients with established HF.
      Preexisting renal disease is a known risk factor for cardiovascular death and HF hospitalization. Recently the results of Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE),
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      the first renal-dedicated SGLT2 inhibitor trial has been reported. In this trial, 4401 patients with type 2 diabetes and chronic albuminuric renal disease (eGFR 30-90 mL/min/1.73 m2) were randomized to receive placebo or canagliflozin 100 mg/d. Importantly, all patients were required to be receiving background stable doses of ACE inhibitor or ARB for at least a 4-week period. The trial was stopped early for efficacy at a median follow-up of 2.6 years and showed a 30% lower rate in the primary outcome of renal progression or cardiovascular death (HR, 0.70; 95% CI, 0.59-0.82; P = 0.00001). In addition, lower rates of HHF (HR, 0.61; 95% CI, 0.47-0.80; P < 0.001) were observed. There was no significant between group difference in the risk of cardiovascular death (HR, 0.78; 95% CI, 0.61-1.00; P = 0.05) or in the risk of death from any cause (HR, 0.83; 95% CI, 0.68-1.02). These findings confirm the renal benefits observed in subanalyses from the earlier prevention trials and extend the HF benefits of SGLT2 inhibitors to patients with albuminuric chronic kidney disease.
      The TIMI Study Group recently published a systematic review and meta-analysis of 3 large trials of SGLT2 inhibitors: EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI 58.
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • et al.
      SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      The meta-analysis included 34,322 patients, of whom, 60.2% had established cardiovascular disease. Overall, patients treated with SGLT2 inhibitors experienced a lower rate of nonfatal myocardial infarction, stroke, or cardiovascular death (HR, 0.89; 95% CI, 0.83-0.96; P = 0.0014), however, this benefit was limited to patients with established cardiovascular disease. The composite rate of cardiovascular death or HHF was reduced by 23% (HR, 0.77; 95% CI, 0.71-0.84; P < 0.001) and the rate of HHF alone was reduced by 31% (HR, 0.69; 95% CI, 0.61-0.7, P < 0.001) in patients who received SGLT2 inhibitors.
      • Zelniker T.A.
      • Wiviott S.D.
      • Raz I.
      • et al.
      SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
      The benefits of SGLT2 inhibitors on preventing hospitalizations for HF were observed to a greater degree in those with mild to moderate renal dysfunction and with a history of HF, although only 10%-15% of patients with diabetes included in this meta-analysis had a history of HF.
      Taken together, the available data clearly show the efficacy of SGLT2 inhibition to reduce incident HF in a broad group of patients with type 2 diabetes.

      Established HF due to reduced LVEF

      The landmark study to evaluate the effect of Dapagliflozin on Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with CHF (DAPA-HF) has recently been pubslished.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      In this large, international, multicentre, double-blind, parallel, randomized, placebo-controlled trial 4744 patients were enrolled with stable class II-IV HFrEF and receiving optimal medical therapy and serum N-terminal pro- B-type natriuretic peptide > 600 pg/mL (> 400 if hospitalized within the past year, > 900 if atrial fibrillation or flutter present) and eGFR > 30 mL/min/1.73 m2 to either placebo or dapagliflozin 10 mg daily. Baseline characteristics and medical therapy of study participants in this study were well balanced between the two groups and were similar to those of other recently reported large randomized trials of HFrEF. Importantly, patients with (45%) and without (44%) diabetes were included in this event-driven study. Over a median 18-month follow-up, treatment with dapagliflozin reduced the primary end point, the composite of time to first worsening of HF (hospitalization or urgent visit requiring intravenous therapy for HF) or death due to cardiovascular causes (386 vs 502; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). This was driven by hospitalization (237 vs 326; HR, 0.70; 95% CI, 0.59-0.83) and cardiovascular death (227 vs 283; HR, 0.82; 95% CI, 0.69-0.98). There were also fewer total deaths observed in the dapagliflozin group (276 vs 329; HR, 0.83; 95% CI, 0.71-0.97). In subgroup analysis, only increasing NYHA class was associated with attenuated efficacy of dapagliflozin, although this finding might have been because of chance because no such interaction of outcomes was observed in the prespecified groups with increased baseline natriuretic peptides, those with lower EF, or those with previous hospitalization.
      Notably, the DAPA-HF study participants were well treated, with > 90% ACE/ARB and β-blocker use and > 70% mineralocorticoid use at baseline. No treatment interaction with baseline medical therapy was seen, including with angiotensin receptor-neprilysin inhibitors (ARNI), whereas the primary end point showed statistical consistency with the overall trial (HR, 0.75; 95% CI, 0.50-1.10), which reinforces the efficacy of SGLT2 inhibitors in the setting of contemporary optimal medical therapy. Treatment with ARNI was used in approximately 11% of patients at baseline considering the timing of recruitment for this trial in relation to the publication of the Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.
      The DAPA HF study included most participants (approximately 58%) who did not have concomitant diabetes. Subgroup analysis revealed a nearly identical reduction in the primary end point among nondiabetic patients (HR of 0.73 [95% CI, 0.60-0.88] in those without diabetes vs an HR of 0.75 [95% CI, 0.60-0.90] in those with diabetes). As such, SGLT2 inhibition with dapagliflozin has been shown for the first time to reduce morbidity and mortality in nondiabetic patients with HFrEF. Analyses of adverse events of interest in all patients, including volume depletion, adverse renal events, hypoglycemia, amputation, and ketoacidosis showed no increase in the dapagliflozin arm, reinforcing the favourable safety profile of this treatment in patients with HFrEF. Table 2 summarizes the results of large published clinical trials regarding the impact of SGLT2 inhibitors on heart failure and other cardiovascular outcomes.
      Table 2Clinical trial results regarding the impact of SGLT2 inhibitors on HF and other cardiovascular outcomes
      Relevant clinical trialNumber of patientsHospitalization for HF Only, HR (95% CI)Hospitalization for HF and cardiovascular death, HR (95% CI)Major adverse cardiac events, HR (95% CI)Cardiovascular death, HR (95% CI)
      Type 2 diabetes and multiple risk factors (no known cardiovascular disease)
       EMPA-REG OUTCOME, CANVAS-R, DECLARE-TIMI 5813,6720.64 (0.48-0.85)0.84 (0.69-1.01)1.00 (0.87-1.16)1.02 (0.80-1.30)
      Type 2 diabetes and known cardiovascular disease
       EMPA-REG OUTCOME, CANVAS-R, DECLARE-TIMI 5820,6500.71 (0.62-0.82)0.76 (0.69-0.84)0.86 (0.80-0.93)0.80 (0.71-0.91)
      Type 2 diabetes and albuminuric chronic kidney disease
       CREDENCE44010.69 (0.57-0.83)0.61 (0.47-0.80)0.80 (0.67-0.95)0.78 (0.61-1.00; P = 0.0502)
      Stable heart failure and reduced left ventricular ejection fraction irrespective of diabetes
       DAPA-HF47440.70 (0.59-0.83)0.75 (0.65-0.85)N/A0.82 (0.69-0.98)
      CANVAS-R, CANagliflozin cardioVascular Assessment Study–Renal; CI, confidence interval; CREEDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-HF, Dapagliflozin on Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with CHF; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events -Thrombolysis in Myocardial Infarction 58; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients - Removing Excess Glucose; HF, heart failure; HR, heart rate; N/A, not available.

      Future directions

      Although potential theories have been advanced to explain the benefits observed with SGLT2 inhibitors in preventing HF events, including reduction of preload via osmotic diuresis, lowering of afterload, alteration of myocardial energy substrate toward a more efficient glucose oxidation, modulation of renal sympathetic afferent tone, or direct reduction in myocardial mass, precise mechanisms associated with the clinical effect remain unknown. Further work in this area, including mechanistic studies in patients with established and treated HF, are needed and will be forthcoming. In addition, effective dosage of SGLT2 inhibitors is not yet known.
      • Verma S.
      • McMurray J.J.V.
      SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.
      • Zelniker T.A.
      • Braunwald E.
      Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC State-of-the-Art Review.
      • Verma S.
      • Rawat S.
      • Ho K.L.
      • et al.
      Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors.
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      There are several other outstanding issues regarding the effect of SGLT2 inhibitors and prevention of HF events. First, additional data are required to clarify the relative effect of SGLT2 inhibitors according to LVEF and according to disease severity. Ongoing HF outcome studies should address existing evidence gaps across a range of EF values and clinical status. Accordingly, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced), the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR PRESERVED), the Dapagliflozin Evaluation to Improve the Lives of Preserved Ejection Fraction Heart Failure (DELIVER) trials, and the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial will further clarify the role of these agents in a broad spectrum of HF patients. For now, uncertainty remains regarding potential benefits of SGLT2 inhibitors for the following patient subgroups:
      • Preserved or midrange LVEF;
      • Acute HF;
      • Isolated right HF or pulmonary hypertension;
      • Advanced HF;
      • Patients taking target doses of concomitant HF therapies including mineralocorticoid receptor antagonists, sacubitril-valsartan, ivabradine;
      • Stage 4 and 5 kidney disease.
      • 5.
        Updated. We recommend SGLT2 inhibitors, such as empagliflozin, canagliflozin or dapagliflozin, be used for treatment of patients with type 2 diabetes and atherosclerotic cardiovascular disease to reduce the risk of HF hospitalization and death (Strong Recommendation, High-Quality Evidence).
      • 6.
        New. We recommend SGLT2 inhibitors, such as dapagliflozin be used in patients with type 2 diabetes aged > 50 years with additional risk factors for atherosclerotic cardiovascular disease to reduce the risk of HHF (Strong Recommendation, High-Quality Evidence).
      • 7.
        New. We recommend SGLT2 inhibitors, such as canagliflozin, be used in patients aged > 30 years with type 2 diabetes, and macroalbumineric renal disease, to reduce the risk of HF hospitalization and progression of renal disease (Strong Recommendation, High-Quality Evidence).
      • 8.
        New. We recommend SGLT2 inhibitors, such as dapagliflozin be used in patients with mild to moderate HF due to reduced LVEF (≤ 40%) and concomitant type 2 diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (Strong Recommendation, High-Quality Evidence).
      • 9.
        New. We recommend SGLT2 inhibitors, such as dapagliflozin be used in patients with mild to moderate HF due to reduced LVEF (≤ 40%) and without concomitant diabetes, to improve symptoms and quality of life and to reduce the risk of hospitalization and cardiovascular mortality (Conditional Recommendation, High-Quality Evidence).
      Values and preferences. These recommendations place weight on the results of multiple large, randomized, placebo-controlled trials, which have tested 3 different SGLT2 inhibitors. These trials have conclusively shown that SGLT2 inhibitors reduce the risk of the incidence of HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease. A strong recommendation for these agents in patients with type 2 diabetes with multiple risk factors for but without evidence of established cardiovascular disease is made despite the lack of reduction in cardiovascular death.
      We considered the large relative benefit observed, the strong clinical priority for reduction of HF hospitalization, and the lack of any similar benefits associated with other antidiabetic agent in preventing incident HF.
      The strong recommendation for SGLT2 inhibitors for patients with type 2 diabetes and HFrEF reflects the large clinical benefit observed in this population and the current availability of these agents for patients with type 2 diabetes. A second, conditional recommendation for patients with HFrEF without concomitant diabetes is made because regulatory approval for this patient population in Canada is not currently available, and further data from the DAPA-HF trial regarding glucose status in those without diabetes might be clinically impactful.
      These medications are well tolerated and associated with an acceptable side effect profile within the clinical trials studied, with a low risk of genital mycotic infections, diabetic ketoacidosis or hypoglycemia, provided other antidiabetic medications are adjusted appropriately. The efficacy of this medication class is unproven at eGFR levels < 30 mL/min/1.73 m2. Table 3 summarizes practical issues surrounding initiation of SGLT2 inhibitors.
      Table 3Practical issues surrounding initiation of SGLT2 inhibitors
      IssueConcomitant diabetesNo concomitant diabetes
      Glycemic control
      • Collaboration with diabetes team if available
      • Concomitant insulin or sulfonurea therapy: no adjustment necessary with poorly controlled glucose, consider 25% reduction of each medication
      • Reinforce glucose monitoring
      • SGLT2 inhibitors contraindicated in type 1 diabetes
      No concerns for hypoglycemia
      Volume control
      • Euvolemia: optional to reduce loop diuretic by 25-50%
      • Volume overloaded: no need to reduce concomitant loop diuretic
      • Hypovolemia: do not start until volume depletion corrected
      Same as with diabetes
      Renal functionSafe with eGFR 30 mL/min/1.73 m2. Early 20% decrease in eGFR acceptable. With larger change in eGFR, evaluate clinically, consider reduction of loop diureticSame as with diabetes
      Peripheral vascular diseaseCaution with history of amputation or active peripheral arterial ulcerCaution with history of amputation or active peripheral arterial ulcer
      Perineal hygieneCareful local hygiene—single dose of fluconazole typically effective in event of fungal infection
      Urinary tract infectionSGLT2 inhibitors might lead to increased urinary frequency but not directly associated with infection.

      However, urinary tract infection might occur independently of SGLT2 inhibitor use, and requires index of suspicion
      Same as with diabetes
      Diabetic ketoacidosisAs per CDA guidelines, this medication is on the “Sick Day” list. High index of suspicion for DKA required during clinical deterioration. Direct serum anion gap measurement suggested.

      In addition to volume-depleting conditions, hold for concomitant infection, trauma, surgery, or other major physiologic stressor
      Hold during volume depleting intercurrent illness until oral intake adequate

      DKA not specifically recognized as a risk in nondiabetic patients
      CDA, Centers for Disease Control and Prevention; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; SGLT2, sodium glucose cotransport.
      Practical tip. It is worth emphasizing that SGLT2 inhibitors are currently contraindicated for patients with type 1 diabetes.
      Practical tip. The most common adverse effect of this class of medications are genital mycotic infections (GMIs). Women (10%-15% risk), those with previous GMIs, and uncircumcised men are at highest risk. Typically, GMIs can be managed with antifungal drugs and do not require discontinuation of therapy.
      Practical tip. SGLT2 inhibitors might result in temporary reduction of eGFR up to 15%, which generally resolves within 1-3 months. SGLT2 inhibitors have also been associated with acute kidney injury and increased monitoring is warranted in those at risk.
      Practical tip. SGLT2 inhibitors do not cause hypoglycemia in the absence of concomitant insulin and/or secretagogue therapy. Background therapies might need to be adjusted to prevent hypoglycemia.
      Practical tip. SGLT2 inhibitors should be held in the setting of concomitant dehydrating illness as part of “Sick Day” management. Patients should be educated on “Sick Day” management.
      • Lipscombe L.
      • Booth G.
      • Butalia S.
      • et al.
      Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada.
      Practical tip. These agents have been associated with diabetic ketoacidosis (incidence 0.1%). Patients might present with normal or only modestly elevated blood glucose level (< 14 mmol/L). On rare occasions, SGLT2 inhibitors might be associated with normal anion gap acidosis, which is best detected with measurement of serum ketones. Nonspecific symptoms associated with diabetic ketoacidosis include: shortness of breath, nausea, vomiting, abdominal pain, confusion, anorexia, excessive thirst, and lethargy.
      Practical tip. Caution should be exercised when combining SGLT2 inhibitors, ARNI, and diuretics because of their concomitant effects to promote diuresis.

      Conclusions

      The definition of optimal care for patients with HF continues to evolve. Identifying the exact diagnoses and the best treatments for patients with HF can be challenging and health care providers must strive to maintain knowledge on new therapies that can improve the lives of these patients. These guidelines are aimed to provide a timely evidence-based brief update on topics currently at the centre of the changing face of HF management. Practitioners will continue to make the best clinical judgements and decisions with their patients.

      Acknowledgements

      The authors acknowledge the contribution of Christianna Brooks from CCS for her continued support throughout the guideline update writing process and thank the CCS Guideline Committee reviewers for providing insightful comments. The authors also acknowledge the volunteer contributions of panel members, organizations, and individuals involved in the creation and dissemination of best practices since the inception of the guidelines process.

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