Heart failure: how to optimize guideline-directed medical therapy

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure (HF) and cardiomyopathies contains the State of the Art Review ‘Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies’ by Stefan Frantz from the University of Würzburg in Germany, and colleagues.1 The authors point out that most patients survive acute myocardial infarction (MI).2–8 Yet this encouraging development has certain drawbacks: HF prevalence is increasing, and patients affected tend to have more comorbidities, worsening economic strain on healthcare systems and impeding effective medical management. The heart's pathological changes in structure and/or function, termed myocardial remodelling, significantly impact on patient outcomes. Risk factors such as diabetes, chronic obstructive pulmonary disease, female sex, etc. distinctly shape disease progression on the ‘road to HF’. Despite the availability of HF drugs that interact with general pathways involved in myocardial remodelling, targeted drugs remain absent, and patient risk stratification is poor. Hence, in this review, Frantz et al. highlight the pathophysiological basis, current diagnostic methods, and available treatments for cardiac remodelling following MI. The authors further aim to provide a roadmap for developing improved risk stratification and novel medical and interventional therapies. Breast cancer treatment trajectory and protective effects of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers. ACEI, angiotensin-converting enzyme inhibitor; ARBs, angiotensin receptor blockers; BB, beta-blocker; MD, mean difference.10 Cardiotoxicity of drugs used in cancer is a topic of growing relevance.9–13 Randomized controlled trials (RCTs) have evaluated the effects of beta-blockers (BBs), angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEIs) on trastuzumab- and anthracycline-associated cardiotoxicity. In a Meta-Analysis article entitled ‘A systematic review and meta-analysis of beta-blockers and renin–angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer’, Christian Lewinter from the Karolinska University Hospital in Stockholm, Sweden, and colleagues report a meta-analysis of these RCTs in patients with breast cancer.14 The primary analysis was on the effect of BBs or ACEIs/ARBs on left ventricular ejection fraction (LVEF) in patients treated with trastuzumab and/or anthracyclines. A secondary analysis was done investigating the effect of BBs or ACEI/ARBs on LVEF in trastuzumab or anthracycline treatments. Only RCTs were included using the search term ‘ARBs, ACEIs, BBs, anthracyclines, trastuzumab, and breast cancer’ in PubMed, Embase, and CENTRAL up to 31 March 2021. A meta-analysis was conducted to estimate the mean difference (MD) in LVEF between intervention and placebo groups at follow-up. A total of nine RCTs (n = 1362) were included in the analysis. BBs or ACEIs/ARBs were shown to attenuate the decline in LVEF during trastuzumab and/or anthracycline treatments (MD 2.4 and 1.5, respectively; this difference was significant for BB but not for ACEIs/ARBs). LVEF was significantly higher in patients assigned to a BB or ACEI/ARB on trastuzumab (MD 2.3) but not on anthracyclines (MD 1.9) (Figure 1). The authors conclude that both BB and ACEI/ARB therapies are associated with the preservation of LVEF during trastuzumab- and anthracycline-containing regimens as compared with placebo, suggesting both to be beneficial. The contribution is accompanied by an Editorial by Geeta Gulati from Akershus University Hospital in Lørenskog, Norway.15 Gulati concludes that the results of this very important meta-analysis rather justify the concept of risk-based initiation of cardioprotective strategies as opposed to a universal implementation of cardioprotective treatment with BBs and/or angiotensin antagonists in breast cancer patients with low risk of developing cardiotoxicity, i.e. low cardiovascular risk factors and no previous cardiotoxic cancer treatment. Another approach is to use alternative drug interventions such as sacubitril/valsartan, a mineralocorticoid receptor antagonist, a sodium–glucose co-transporter protein 2 inhibitor, or exercise programmes, but studies to justify their use are still lacking. The goal is not to burden these patients with additional medication and fear of side effects but rather to target those in need of cardioprotective therapy with effective and safe cardiac drugs. Potential reductions in events from accelerated up-titration and optimized ordering of treatment sequence compared with the conventional schedule.17 Previously, guidelines recommended initiating therapy in patients with HF and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment.16 In a Clinical Research article entitled ‘Accelerated and personalized therapy for heart failure with reduced ejection fraction’, Li Shen from the University of Glasgow in Glasgow, UK, and colleagues indicate that it remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes.17 The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials) and (ii) accelerated up-titration and using treatments in orders different from what is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of HF hospitalization or cardiovascular death and 7 fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and 6 fewer deaths at 12 months. The optimal alternative sequences included sodium–glucose co-transporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies (Figure 2). Shen and colleagues conclude that modelling of an accelerated up-titration schedule and optimized ordering of treatment suggests that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials. The contribution is accompanied by an Editorial by Adriaan Voors and Jasper Tromp from the University Medical Center Groningen in the Netherlands.18 Voors and Tromp conclude that the study of Shen et al. provides convincing evidence for using alternative treatment strategies to reduce the time to initiate and up-titrate HF pharmacotherapy. Importantly, their results emphasize the need for quick but responsible initiation and up-titration of the ‘foundational 4’ therapies in patients with HFrEF and new implementation strategies to facilitate this. Cardiac resynchronization therapy (CRT) is an established treatment for HF.19–21 There is contradictory evidence as to whether defibrillator capability improves prognosis in patients receiving CRT. In a Clinical Research article entitled ‘Survival of patients undergoing cardiac resynchronization therapy with or without defibrillator: the RESET-CRT project’, Moritz Hadwiger from the University of Lübeck in Germany, and colleagues compared the survival of patients undergoing de novo implantation of a CRT with defibrillator (CRT-D) option and CRT with pacemaker (CRT-P) without any indication for defibrillator implantation for secondary prevention of sudden cardiac death enrolled in a large health claims database from 2014 to 2019.22 The analysis comprised 847 CRT-P and 2722 CRT-D patients. Overall, 714 deaths were recorded during a median follow-up of 2.35 years. A higher cumulative incidence of all-cause death was observed with CRT-P in the initial unadjusted Kaplan–Meier time-to-event analysis [hazard ratio (HR) 1.63]. After adjustment for age, HR and entropy balancing the HRs were no longer significant (1.13 and 0.99, respectively). The results were robust in sensitivity analyses. The authors conclude that in a large health claims database of CRT implantations performed in a contemporary setting, CRT-P treatment was not associated with inferior survival compared with CRT-D. Age differences accounted for the greatest part of the survival difference that was observed in the initial unadjusted analysis. This manuscript is accompanied by an Editorial by Cecilia Linde from the Karolinska Institutet in Stockholm, Sweden.23 Linde concludes that CRT-D is technically more complex and related to greater risk for peri-operative complications and for inappropriate shocks. Many patients may prefer CRT-P given detailed information on its risks and benefits. The results of this observational study are a promising prelude to the ongoing randomized RESET-CRT study and raise hopes that it will give a more definitive answer and guidance in the choice between CRT-P and CRT-D. In the meantime, clinical judgement is the best we have and that is not so bad. After all, that is what being a cardiologist is all about. During the coronavirus disease 2019 (COVID-19) pandemic, important changes in heart HF event rates have been widely reported.24,25 In a Clinical Research article entitled ‘The GUIDE-HF trial of pulmonary artery pressure monitoring in heart failure: impact of the COVID-19 pandemic’, Michael R. Zile from the Medical University of South Carolina in the USA, and colleagues point out that few data address potential causes of these changes; several possibilities were examined in the GUIDE-HF study.26 From 15 March 2018 to 20 December 2019, patients were randomized to haemodynamic-guided management (treatment) vs. control for 12 months, with a primary endpoint of all-cause mortality plus HF events. Pre-COVID-19, the primary endpoint rate was 0.553 vs. 0.682 events/patient-year in the treatment vs. control group (HR 0.81, P = 0.049). Treatment difference was no longer evident during COVID-19 (HR 1.11, P = 0.526), with a 21% decrease in the control group (0.536 events/patient-year) and no change in the treatment group (0.597 events/patient-year). Data reflecting provider-, disease-, and patient-dependent factors that might change the primary endpoint rate during COVID-19 were examined. Subject contact frequency was similar in the treatment vs. control group before and during COVID-19. During COVID-19, the monthly rate of medication changes fell 19.2% in the treatment vs. 10.7% in the control group to levels not different between groups (P = 0.362). COVID-19 was infrequent and not different between groups. Pulmonary artery pressure area under the curve decreased −98 mmHg-days in the treatment group vs. −100 mmHg-days in the controls (P = 0.867). Patient compliance with the study protocol was maintained during COVID-19 in both groups. Zile et al. conclude that during COVID-19, the primary event rate decreased in the controls and remained stable in the treatment group, resulting in an effacement of group differences that were present pre-COVID-19. These outcomes did not result from changes in provider- or disease-dependent factors; pulmonary artery pressure decreased despite fewer medication changes, suggesting that patient-dependent factors played an important role in these outcomes. The contribution is accompanied by an Editorial by Martin R. Cowie from the Royal Brompton Hospital, and John G.F. Cleland from the University of Glasgow in the UK.27 Cowie and Cleland note that this study suggests that during COVID-19, patients genuinely seem to have improved, with a change in behaviour leading to improved haemodynamics, which translated into a reduced risk of worsening HF. We need to find better ways of replicating this effect than another lockdown! Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I.28,29 In a Clinical Research article entitled ‘Characteristics and natural history of early-stage cardiac transthyretin amyloidosis’, Steven Law from the University College London in the UK, and colleagues point out that the natural history of early-stage ATTR-CM remains poorly characterized.30 This is a retrospective multicentre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal probrain natriuretic peptide (NT-proBNP) and troponin T blood levels, and TTR genotype. Patients were then categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ia patients was significantly higher than in the 12% Stage Ib patients (HR for death 5.06, P = 0.025) despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable with that of UK general population controls (P = 0.297). The authors conclude that patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival. The manuscript is accompanied by an Editorial by Claudio Rapezzi and Matteo Serenelli from the University of Ferrara, and Alberto Aimo from the Scuola Superiore Sant’Anna in Pisa, Italy.31 The authors note that tafamidis is the only approved treatment for cardiac amyloidosis patients without polyneuropathy. The criteria for prescription usually reflect the inclusion criteria of the ATTR-ACT trial, which substantially corresponds to the definition of Stage Ib ATTR-CM. Subjects with Stage Ia disease were thus not enrolled in the ATTR-ACT trial and are not eligible for tafamidis therapy because of the lack of demonstrated prognostic benefit from this drug. On the other hand, tafamidis seemed more effective in less symptomatic patients, and treatment initiation in early-stage ATTR-CM might be equally as effective, at least when assessing the impact on HF hospitalization and quality of life. It is not unreasonable to propose clinical trials on patients with early-stage disease (either ATTRwt or ATTRv with a cardiac phenotype) with the goal of reducing the burden of HF hospitalizations and improving the quality of life. A major hindrance to such trials is the high cost of drugs, making them not cost-effective even in patients with more advanced disease, where they can reduce mortality rates. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘A laboratory viewpoint of the consensus paper from the European Society of Cardiology regarding the utilization of the American College of Medical Genetics and Genomics pathogenic criteria for cardiomyopathy’, Zongzhe Li from the Huazhong University of Science and Technology in China and colleagues comment on the recent publication ‘Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics’ by Eloisa Arbustini from the Fondazione IRCCS Policlinico San Matteo in Pavia, Italy.32,33 Arbustini et al. respond in a separate comment.34 Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The editors hope that readers of this issue of the European Heart Journal will find it of interest.