Cardiologia Croatica. 2020;15(7-8)

Tina Kuhar, Alenka Kmecl, Mateja Grošelj, Breda Barbič-Žagar

Endothelial dysfunction is the earliest vascular abnormality and it is involved in all stages of the cardiovascular continuum. Antihypertensive compounds should ideally have additional endothelial protective properties beyond their ability to reduce blood pressure. Among angiotensin-converting enzyme inhibitors, perindopril appears to have the greatest endothelial protective effects. Amlodipine is well known for its atheroprotective effect. Clinical evidence has shown that perindopril and amlodipine could individually interrupt and slow the progression of cardiovascular disease with long-term beneficial effects of treatment on mortality. The effect is enhanced and broadened if both agents are used together. Early prescription of perindopril and amlodipine appears to be important, as most of the treatment benefits of both agents occur in the early or middle stages of the cardiovascular continuum. Clinical evidence also supports the beneficial effect on the vascular endothelium offered by the triple combination of perindopril and amlodipine with indapamide.

Christian Heiss, Alex Pitcher, Jill J.F. Belch, Marco De Carlo, Holger Reinecke, Iris Baumgartner, Lucia Mazzolai, Victor Aboyans

Reproduced from: Heiss C, Pitcher A, Belch JJF, De Carlo M, Reinecke H, Baumgartner I, et al. The year in cardiology: aorta and peripheral circulation. Eur Heart J. 2020 Jan 21;41(4):501-508b. https://doi.org/10.1093/eurheartj/ehz939, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publishers. For Permissions, please email: journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint are those of the authors and contributors, and do not necessarily reflect those of the European Society of cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs and doses, the results of experimental work and clinical findings published in the Journal. The ultimate responsibility for the use and dosage of drugs mentioned in this reprint and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the Journal or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. **Karlo Golubić** and **Mario Ivanuša** are solely responsible for the translation and this reprint. ## Preamble Similar to previous years, (1–3) the current article reviews groundbreaking science published 2019 in the area of aortic and peripheral arterial diseases (PAD) as well as venous thromboembolic disease (VTE) that will affect our daily clinical practice. With the growing recognition of PAD, it will be necessary to consolidate imprecisions in terminology. Many are used to the acronym PAD for atherosclerotic disease of the lower extremity arteries. Others have used the same acronym to qualify atherosclerotic disease of the lower extremity arteries and carotid arteries. In the current article and in line with the European Society of Cardiology (ESC) guidelines, (4) we have stringently used the specific terms lower extremity arterial disease (LEAD) and reserved PAD as the umbrella term encompassing all arterial diseases other than aorta and coronaries. ## Vascular biology/translational research The extent to which genetic factors contribute to PAD development and if they are shared or distinct between LEAD, cerebral, and coronary arteries are largely unknown. In a genome-wide association study in the Million Veteran Program, ~32 million DNA sequence variants were tested for PAD (31 307 cases, 211 753 controls) and combined with electronic health records. (5) The results were replicated in an independent sample from the UK Biobank. They identified 19 LEAD loci (18 not previously reported): 11 loci were associated with disease in three vascular beds (coronary, cerebral, and lower extremity), including LDLR, LPL, and Lp(a) (**Figure A** – Take home figure); 4 loci appeared to be specific for LEAD, including F5 p.R506Q (Factor V Leiden variant), highlighting the pathogenic role of thrombosis in LEAD and supporting Factor Xa inhibition as a therapeutic strategy. FIGURE A. Please see the original article (Eur Heart J. 2020 Jan 21;41(4):501-508b.). Despite the fact that numerous long non-coding RNAs (lncRNA) have been identified, only a few of them have been studied with respect to endothelial cell homeostasis or vascular disease development. One of them, the pro-angiogenic lncRNA MANTIS, may be clinically relevant in carotid disease. (6) In fact, the protective effects of laminar flow and statins are, at least in part, attributed to the expression of MANTIS. The mechanisms involve epigenetic rearrangements and the transcription factors Krüppel-like factor 2 and 4. As induction of MANTIS mimics the beneficial effects of statins on endothelial function, the authors proposed that strategies to increase MANTIS might improve vascular function in patients not responding to statin therapy. The transcriptional activity of nuclear receptors that regulate key pathophysiological processes in atherosclerosis development is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Oppi et al**.**(7) investigated the role of NCOR1 in atherogenesis. Myeloid cell-specific deletion of NCOR1 in LDL receptor knockout mice aggravated atherosclerosis development. Macrophage NCOR1-deficiency led to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 were mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized LDL uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 was reduced, whereas the PPARγ signature was increased, and this signature was more pronounced in ruptured compared with non-ruptured carotid plaques. The data suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression. Radiotherapy-induced cardiovascular disease (CVD) is an emerging problem in a growing population of cancer survivors where traditional vascular treatments have limited benefits. Using a translational approach, it was now shown that human irradiated blood vessels exhibit elevated levels of inflammation signals associated with inflammasome activation long after radiotherapy, and similar changes occurred in a mouse model of localized irradiation to the heart and carotids. (8) In the model, the localized inflammatory response was ameliorated by an interleukin (IL)-1 receptor antagonist. Clinical studies in humans now need to evaluate IL-1 blockade as a potential treatment of radiotherapy-induced CVD. Subjects with Lp(a) elevation have increased arterial wall inflammation and cardiovascular risk. Stiekema et al. (9) evaluated whether evolocumab, which as opposed to statins lowers both LDL-cholesterol and Lp(a), attenuates arterial wall inflammation in the index vessel (carotid or thoracic aorta) in patients with elevated Lp(a) (>200 mg/dL). In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-cholesterol by 60.7% [95% confidence interval (CI) 65.8–55.5] and Lp(a) by only 13.8% (95% CI 19.3–8.5). Importantly, arterial wall inflammation [assessed by [(positron emission tomography with 2-deoxy-2-[fluorine-18]-fluoro-D-glucose integrated with computed tomography)] 18F-FDG PET/CT] was not significantly altered with evolocumab at Week 16. This supports that, beyond economic issues, statins remain the first pillar of lipid-lowering therapies, which ties in with current lipid guidelines. (10) Another large study characterized serum metabolic signatures associated with atherosclerosis in the carotid and coronary arteries and subsequently their association with incident CVD among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. (11) They showed that 30 1H NMR (proton nuclear magnetic resonance spectroscopy) measured metabolites were associated with coronary artery calcium and/or carotid intima-media thickness. Metabolites associated with atherosclerosis were largely consistent between the carotid and coronary vascular beds and predominantly tag pathways that overlap with the known cardiovascular risk factors: disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. ## Vascular biomarkers and cardiovascular risk Multimodality vascular assessment enables to evaluate the atherosclerotic process and the cardiovascular risk. In a population-based study (12) using hybrid 18F-FDG PET and magnetic resonance imaging (MRI), arterial inflammation was detected in 48% of participants of 40–54 years of age, increasing steadily by the number of risk factors. Aortic, carotid, and/or iliofemoral plaques were present in 90% of cases, but most inflammation was depicted in the plaque-free zones. Inflammation was present only in 11% of plaques, suggesting arterial inflammation in early stage of atherosclerosis process. An experimental study went one step further and developed a integrative multiparametric PET/MRI protocol that allows non-invasive assessment of different processes relevant to atherosclerosis progression. (13) Using clinically approved nanobody radiotracers, they were able to study different biomarkers of atherosclerosis progression, namely vascular cell adhesion molecule-1, lectin-like oxidized low-density lipoprotein receptor-1, and macrophage mannose receptor, that correlated with histopathological findings in mice and rabbits. Atherosclerosis is even identifiable in adolescence, especially in case of unhealthy lifestyle: in an observational study (14) including 1266 young participants aged 13–17 years, aortic stiffness, estimated by carotid-femoral pulse-wave velocity (cfPWV) was proportionally increased by the tobacco smoking and alcohol drinking intensities, with a strong potentiation when both were combined (**Figure 1**). At these ages, smoking and drinking cessation lead to normalization of cfPWV. In the other lifespan tip, vascular markers could be useful to downgrade the estimated risk in elderly people who would have an indication for statins based on risk scores, highly affected by age. In a cohort of 5805 healthy elderly participants (mean age 69 years), normal (40 years attending a screening programme; the control group received regular risk factors screening and guidelines-based management but the results of carotid ultrasound were not disclosed, while the intervention group received, along with their general practitioners, a pictorial presentation of the carotid ultrasound results, including colour-scaled presentations of vascular age based on intima-media thickness, and plaque identification. A nurse called 2–4 weeks later to reassure participants and provide any information needed. The same pictorial information was repeated after 6 months. The baseline Framingham risk score (FRS) and SCORE were respectively at 12.9 and 1.28. At 1 year, both scores were significantly lower in the intervention group (−1.07, P = 0.0017 for FRS and −0.16, P = 0.001 for SCORE), with more striking results in the high-risk group (−2.16 and −2.85, respectively). The persistence of these results and their consequences on CVD events need further evaluation. ## Cerebrovascular disease Excessive arterial pulsatility may contribute to cognitive decline and risk of dementia via damage to the fragile cerebral microcirculation. As part of the Whitehall II study, (17) peak forward-travelling compression wave intensity (FCWI) was assessed using Duplex ultrasound within the common carotid arteries in 3191 individuals (mean age = 61 years; 75% male) and serial measures of cognitive function were taken at baseline and almost 10 years later. Higher FCWI at baseline was associated with accelerated cognitive decline during follow-up and this association was largely driven by cognitive changes in individuals with the highest FCWI. Compared to other participants, this group was approximately 50% more likely to exhibit cognitive decline, even after adjustments for multiple potential confounding factors. While intensive lipid lowering is recommended after transient ischemic attack (TIA) and ischaemic stroke the target level for LDL to reduce cardiovascular events after stroke has not been well studied. In a parallel group trial, 2860 patients with recent ischaemic stroke or TIA and evidence for cerebrovascular and coronary artery atherosclerosis were randomized to either LDL target of 1.4 mm in diameter. (19) Patients received aspirin/clopidogrel for 3 months, and aspirin thereafter. In three centres, 25 patients with atrial fibrillation, with CHA2DS2-VASc ≥2, who were unsuitable for OACs and had no carotid stenosis >30% were enrolled. The procedure success was 92%; 1 patient had unilateral deployment. There were no device/procedure-related major adverse events. After 6-month mean follow-up, asymptomatic thrombi were detected in four patients (one bilateral, four unilateral) and the thrombi dissolved with subcutaneous heparin. Permanent carotid filter placement for stroke prophylaxis seems technically feasible and safe. Larger studies and a comparison with the use of left atrial appendage occluders are necessary. ## Aortic disease A common challenge in the emergency room is to distinguish patients with symptoms suggestive of acute aortic syndrome (AAS) requiring a computed tomography scan, from others. In a study of 839 patients attending the emergency room with suspected AAS, focused cardiac ultrasound, integrated into a strategy including clinical assessment and (for low-risk patients) D-Dimer testing, enabled the correct identification of all patients with aortic dissection (AD), although the upper border of the 95% CI was 1.2%. (20) These findings confirm the importance of transthoracic chocardiography in the diagnostic strategy of AAS as suggested in the last ESC guidelines. (21) The term AAS has become commonplace, but constitutes a range of disease entities, which may not have the same pathophysiological mechanisms, responses to treatment or outlook. Among 1012 patients, those with intra-mural haematoma (IMH) (n = 340) had a much better short- and long-term mortality than those patients with AD (n = 672). (22) Taking the Type B IMH in-hospital mortality, estimated at 1.5%, as reference, the overall crude in-hospital mortality of Type A AD was 15.0% with an adjusted hazard ratio (aHR) of 30.4; compared to Type A IMH mortality of 8.0% (aHR 4.85) and Type B AD mortality of 5.0% (aHR 3.51). Identifying patients with Marfan syndrome at particular risk of AD is currently based on the absolute diameter of the aorta, the growth rate, and the presence/absence of a family history of AD. A novel additional approach may be the evaluation of the longitudinal strain of the proximal aorta by MRI (**Figure 2A**). (23) Higher strain rates were associated with more rapid aortic expansion and appeared to predict clinical outcomes. If proximal aortic strain is reproducible and if these findings are replicated in larger cohorts, this may help to inform the need for, and timing of, surgery in these patients. FIGURE 2. New imaging techniques for risk stratification in patients with aortic diseases (**A**) methods for proximal longitudinal strain measurement by magnetic resonance imaging,23 (**B**) Doppler approach to flow in aortic dissection. Reproduced with permission from Ref. (24) Complex flow patterns are identified in the true and often the false lumen after AD. A better understanding of these flow dynamics may explain the differing behaviour of ADs over the long term. Recent insights into this process have become available from detailed study categorizing flow patterns using echo Doppler. The potential for prognostic implications is discussed (**Figure 2B**). (24) The optimal management of descending thoracic aortic aneurysms is controversial. A retrospective study on a propensity-adjusted population of Medicare beneficiaries found lower perioperative and overall mortality in patients undergoing thoracic endovascular aortic repair (TEVAR) compared to open repair, but with a higher risk of reintervention. (25) The odds of perioperative mortality were greater for open surgical repair and depended on the centre volume: high-volume centre, odds ratio (OR) 1.97 (95% CI 1.5–2.6); low-volume centre, OR 3.62 (95% CI 2.9–4.5). The restricted mean survival time difference favoured TEVAR at 9 years, −209 days (95% CI −299 to −120 days) for open surgical repair. The risk of reintervention was lower for open surgical repair, HR 0.40 (95% CI 0.34–0.60). In the last ESC guidelines on the management of aortic diseases, (21) both open surgery and endovascular aneurysm repair (EVAR) of abdominal aneurysms received Class I recommendation, based on several head-to-head trials enrolling patients with suitable anatomy for both options. While, in the short term, EVAR was associated with lower mortality, this difference was gradually annihilated over time, while in turn, EVAR requested repeated X-ray exposure and reinterventions for endoleaks. The results of very long-term follow-up (14 years) of the Open vs. Endovascular Repair (OVER) trial (26) are interesting in that they show no mortality or secondary procedure difference beyond the first years. These results support current recommendations; importantly, mortality was largely not aneurysm-related (only 2.7%, mostly post-operative), and mostly due to cardiovascular causes, emphasizing the need for maximal preventive measures in these patients. Finally, gender-specific evidence is still lacking, as women constituted <10% of all participants. ## Lower extremity artery disease Lower extremity arterial disease is an increasing public health problem according to the latest global epidemiology report. (27) In 2010, LEAD, defined as ABI ≤0.9, affected 202 million subjects worldwide; this number increased by 22% to 237 million in 2015. The overall prevalence in subjects aged ≥25 years was 5.6% (95% CI 3.8–8.6), higher in high-income countries than in low- and middle-income countries (LMIC) (7.4% vs. 5.1%), although the vast majority of patients (73%) lived in LMIC. This prevalence was similar between sexes, with higher rates of young (<50 years) patients in LMIC. The association of LEAD with major adverse cardiovascular events (MACE) is well documented, whereas its association with limb events is less clear. In the Veterans Aging Cohort Study, including 125 674 subjects without history of prior amputation, the incidence of amputation over a median of 9.3 years of follow-up was 1.2 per 1000 person-years. (28) The presence of LEAD conferred a 13.9-fold increase in amputation risk, but microvascular disease (MVD), defined as retino-, neuro-, and/or nephropathy, was also associated with a 3.7-fold risk increase, and the combination of LEAD and MVD lead to a 22.7-fold increased risk. Importantly, MVD alone was associated with 15% of all below-the-knee amputations. Among the 13 885 patients with an ABI ≤0.8 or prior lower extremity revascularization (LER) randomized to ticagrelor vs. clopidogrel in the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, the rate of acute limb ischaemia (ALI) requiring hospitalization was 0.8 per 100 patient-years, with no difference between treatment arms. (29) Acute limb ischaemia was strongly associated with subsequent MACE (aHR 1.4, 95% CI 1.0–2.1), all-cause mortality (aHR 3.3, 95% CI 2.4–4.6), and major amputation (aHR 34.2, 95% CI 9.7–20.8). Previous LER, baseline atrial fibrillation, and baseline ABI ≤0.60 were independent predictors of ALI. In this trial, a second analysis showed that 12.5% of patients experienced LER during the trial. (30) Independent predictors of post-randomization LER were prior history and type of prior LER (P < 0.0001), living in North America or Europe (P < 0.0001), presence of limb symptoms at baseline (HR 1.3; 95% CI 1.2–1.5), diabetes (HR 1.3; 95% CI 1.1–1.4), and smoking (HR 1.2; 95% CI 1.1–1.4). Cardiac and limb events were numerically higher in patients undergoing surgical procedures, but surgical patients experienced fewer LERs after the index LER. A growing proportion of ALI hospitalizations occurs in cancer patients who experience arterial thromboembolism. In the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, 374 331 patients ≥67 years with primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma were identified. (31) The risk of arterial thromboembolic events began to increase 150 days before the date of cancer diagnosis in older patients and peaked in the 30 days before cancer diagnosis, when 0.62% of patients suffered an arterial thromboembolic event vs. 0.11% in control subjects (OR 5.63; 95% CI 5.07–6.25). Lipid lowering is a key element of LEAD treatment. (4) The 2019 ESC guidelines recommend a LDL-cholesterol reduction of ≥50% and a goal of <55 mg/dL (1.4 mmol/L) for LEAD patients, to be achieved with statins, plus ezetimibe and PCSK9 inhibitors if needed. (10) A recent pre-specified analysis of the Evaluation of CV Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trial further supports these recommendations. (32) After a median follow-up of 2.8 years, the 1554 patients with atherosclerotic disease in two or three vascular beds (coronary, lower limb, and/or cerebrovascular) showed a significantly larger absolute risk reduction with alirocumab, as compared to patients with isolated coronary artery disease (CAD). The absolute risk reduction regarding MACE was 1.9% (95% CI −2.4% to 6.2%) and 13.0% (95% CI −2.0% to 28.0%) for two and three vascular beds, respectively, whereas regarding all-cause mortality was 1.3% (95% CI −1.8% to 4.3%) and 16.2% (95% CI 5.5–26.8%), respectively. Another pillar of the medical treatment of LEAD is optimal control of arterial hypertension. (4, 33) A recent analysis from the Atherosclerosis Risk in Communities (ARIC) study evaluated the impact of different stages of hypertension on the development of LEAD. (34) During a median follow-up of 25.4 years, a systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg was associated with higher rate of incident LEAD diagnosis (HR 2.40; 95% CI 1.72–3.34), independent of the use of anti-hypertensive medications. Higher BP categories showed significant associations with incident LEAD starting from 120 to 129 mmHg for systolic BP and ≥90 mmHg for diastolic BP. These data emphasize the need for BP control to prevent the development of LEAD. While supervised exercise training is a mainstay of the management of claudication, (4) low adherence rates limit its clinical application. In a randomized study, 156 participants were allocated to supervised treadmill exercise, supervised resistance training, or oral advice about nutrition and training. (35) After 6 months, the 6‐min walk distance improved only in the treadmill exercise group (36.1 m, 95% CI 13.9–58.3), but at 12 months neither treadmill nor resistance significantly differed from baseline or control (walking distance: +7.5 m and +6.1 m). These results highlight the need for long-term supervised exercise programmes to maintain benefits. Additionally, a systematic review of 84 studies reported that alternative training modalities (circuit exercise, low-pain and pain-free walking, resistance training, upper/lower limb ergometry, and pole striding) had significantly higher adherence and completion rates vs. traditional exercise training (85.5% vs. 77.6%, and 86.6% vs. 80.8%, respectively). (36) In lack of randomized controlled trials (RCTs), a large gap in evidence regards the best revascularization strategy in chronic limb threatening ischaemia (CLTI). In a retrospective analysis, 16 800 patients with CLTI who had first surgical LER (36%) were compared to those with first endovascular LER (64%). (37) The endovascular group was younger, but suffered from more comorbidities, including renal failure (36% vs. 24%), CAD (34% vs. 32%), heart failure (19% vs. 15%), and diabetes (65% vs. 58%; all P < 0.05). In a propensity-matched analysis, a surgery-first strategy was associated with worse amputation-free survival (HR 1.16, 95% CI 1.13–1.20), while an endovascular-first strategy was associated with higher reintervention rates (HR 1.19, 95% CI 1.14–1.23) after 80 months of follow-up. Mortality was similar between groups (HR 0.94, 95% CI 0.89–1.11). These results suggest that an endovascular-first approach might be preferable regarding amputation-free survival. Several trials have shown the superiority of drug-eluting stents (DES) and drug-coated balloons (DCBs) vs. plain balloon angioplasty (PTA) in patients with femoropopliteal disease. (1–3) The 5-year results of the IN.PACT SFA trial showed the persistence of clinical benefits, with 74.5% freedom from clinically driven target lesion revascularization with DCBs vs. 65.3% with PTA (P = 0.020), although this benefit was non-significant in diabetics (70.3 vs. 64.4%, P = 0.24). (38) The clinical use of paclitaxel-eluting devices was dramatically interrupted in November 2018 by the unexpected results of a meta-analysis including 28 RCTs with a total of 4432 patients. (39) The study described a two-fold increase in all-cause mortality between 2 and 5 years of follow-up with paclitaxel-eluting DES/DCBs (HR 1.93, 95% CI 1.27–2.93), and a causal link between paclitaxel dose and mortality was hypothesized. These findings raised great concern, halted enrolment in RCTs on paclitaxel-eluting devices, and prompted a worldwide call for high-quality data collection and analysis. Most recently, a confutation of the above-mentioned study came from a large analysis of German health claims data, investigating long-term mortality with paclitaxel-eluting devices from 2007 until present in 64 771 patients undergoing 107 112 endovascular procedures. (40) The use of paclitaxel-eluting devices was not associated with any signal of increased mortality up to 10 years of follow-up (**Figure 3**). FIGURE 3. Long-term mortality after use of paclitaxel-based drug eluting devices (DED) in lower extremity arterial disease. A multivariable Cox regression analysis was developed including numerous comorbidities and all devices that were applied in each treated patient. For each distinct device, the analysis accounted for its type [drug-eluting stents (DES), drug coated balloon (DCB), bare metal stents (BMS), and plain old balloon angioplasty (POBA)] and application date. The model took also concern of any non-constant time dependent effects: thus, a potentially detrimental effect of DED in the later course of time would become verifiable despite a potentially beneficial effect in the early years, or also any potential aggregation of subsequently applied devices. Combined hazard ratios for any scenario including multiple devices that were applied various years ago can be determined as the product of elementary hazard ratios. In summary, there was no signal that paclitaxel DCBs or DESs were associated with increased mortality up to 11 years of follow-up. Reproduced with permission from Ref (40) ## Venous thromboembolism In 2019, the ESC issued updated guidelines for management of patients with acute pulmonary embolism (PE). (41) Key points include use of age-adjusted D-dimer cut-off in preclinical risk assessment. Furthermore, categorization of PE events in ‘provoked’ and ‘unprovoked’ is no longer suggested. Rather, occurrence of index event in presence of ‘reversible risk factor’, or in absence of any ‘identifiable risk factor’ is suggested for patient stratification and guidance of treatment duration. For the first time, direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists for PE treatment in eligible patients as for patients with atrial fibrillation. A reduced dose of apixaban or rivaroxaban for extended anticoagulation should be considered after the first 6 months of treatment. Edoxaban or rivaroxaban should be considered as an alternative to low molecular weight heparin in patients with non-gastrointestinal cancer who experience VTE. A new recommendation (class IIa, level A) proposes that carefully selected, low-risk PE patients should be considered for early discharge and home treatment, as long as proper outpatient care and anticoagulant therapy are possible (**Figure 4**). A recent prospective multicentre single-arm trial further corroborates this recommendation. Low-risk PE patients (no HESTIA criteria present, and absence of right ventricle enlargement/dysfunction) were early discharged (maximum of two nights in hospital) for home treatment with rivaroxaban. The study was prematurely terminated because of low symptomatic VTE recurrence and PE-related death rates (0.6%; one-sided upper 99.6% CI 2.1%), and low bleeding episodes (1.2%) at 3 months from diagnosis. (43) Careful selection of low-risk PE patients is key in successful home treatment; in this regard, clinical severity scores alone may not be sufficient to identify such low-risk group especially with regard to subclinical right ventricular dysfunction exclusion. Therefore, combining right ventricular assessment to clinical criteria further allow proper risk stratification as recently suggested by Barco et al. (44) FIGURE 4. Pulmonary embolism management algorithm. Reproduced with permission from Ref. (42) The diagnosis of PE during pregnancy is challenging with wide pregnancy-related and PE suspicion symptoms overlap. Overall PE prevalence is however low thus exposing patients to unnecessary imaging tests. The 2019 ESC PE guidelines propose a dedicated diagnostic algorithm for suspected PE in pregnancy using stratification tools based on clinical presentation, D-Dimer testing, and compression ultrasonography of lower extremities. The pregnancy adapted YEARS algorithm, which takes into account these three parameters, was recently shown to safely rule out PE across all trimesters of pregnancy avoiding a significant number of imaging tests. (45) Management of vein thrombosis at unusual sites is challenging in practice. Whether patients with isolated distal deep vein thrombosis (IDDVT) should be systematically treated with anticoagulation is still questioned. It is suggested to stratify patients with IDDVT in high- and low-risk of recurrence. (46) Those at high risk should be anticoagulated as for proximal deep vein thrombosis. (47) With this regard, recent prospective registries suggested that patients with IDDVT may be treated with DOACs although data from clinical trials are still missing. (48, 49) ## Perspectives Exciting new scientific data published in 2019 shed more light on the nuances of atherosclerosis among the different peripheral vascular territories. The year 2020 is highly awaited for vascular specialists, with the completion of the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD) study, evaluating the efficacy and safety of rivaroxaban 2.5 mg b.i.d. together with aspirin in reducing the risk of major thrombotic vascular events in subjects with symptomatic LEAD undergoing surgical or endovascular revascularization (NCT02504216). Additionally, further data will become available addressing the safety of paclitaxel-coated technology for LEAD revascularization. In the field of VTE, data from the CARAVAGGIO study (NCT03045406), comparing apixaban to dalteparin, for the treatment of acute VTE in cancer patients, are awaited.

Zdravko Babić, Eduard Margetić, Davor Miličić

The authors would like to thank their colleagues from Iraq for their reaction to article published in the Cardiologia Croatica journal (1). A trend of significant reduction in the number of patients with acute myocardial infarction (AMI) who are admitted and hospitalized during the COVID-19 pandemic is being reported across Europe and the United States. The STENOS registry of percutaneous coronary interventions shows similar results for ST-elevated myocardial infarction in most centres in the Republic of Croatia (**Figure 1**). Most foreign authors explain this condition as primarily due to fear, even in critically ill patients, of arriving at hospitals during the COVID-19 pandemic and risking infection, and to a lesser extend as resulting from the reduced availability of emergency medical services as well as substituting AMI symptoms for COVID-19 infection. Consequences of quarantine and self-isolation such as less exposure to psychological stressors, less air pollution, better adherence to drug therapy, lower blood pressure, less smoking because of fear of COVID-19 respiratory infection, more rest, and less exertion are some of the additional mechanisms which the cardiac community considered as potentially reducing the incidence AMI during this pandemic. However, during the COVID-19 pandemic, a higher incidence of some otherwise less common AMI complications such as mechanical complications (e.g., myocardial rupture) or cardiogenic shock (2) has been reported. Furthermore, the decrease in the number of patients with acute coronary syndrome treated in Austrian hospitals in March this year, lead the Austrian authors (3) to estimate that the number of deaths in these patients could be higher than that of COVID-19 infection at the same time. We therefore agree with colleagues from Iraq that it is time for health professionals, even in public, to point out this problem and the danger of avoiding emergency treatment for conditions such as AMI. FIGURE 1. The number of patients with acute ST-elevation myocardial infarction treated with primary percutaneous coronary intervention – data from the Croatian STENOS PCI Registry.

Firas AL Obaidi, Mohammed Al-Ali, Hasan AL Farhan

The effects of COVID-19 pandemic have overwhelmed health care systems globally, both in developed and developing countries. Medical facilities are struggling to overcome the pandemic and at the same time to provide care for patients with other emergency medical conditions. The unprecedented situation with the large number patients and limited resources has resulted in reduced presentation of other patients to hospitals during the crisis. Reports indicated a decline in the number of patients with acute ST-elevation myocardial infarction (STEMI) presenting to hospitals. In Spain, the rate of primary percutaneous coronary intervention (pPCI) declined by 40% (1), and in the United States pPCI was reduced by 38% (2). One of the possible reasons for that is the idea of contracting the infection from hospitals is currently prevalent among people, so patients are avoiding calling emergency services despite major events. Another reason, but likely to a lesser extent, is increasing use of fibrinolytic therapy for STEMI patients, especially those suspected of COVID-19 infection (3). In Iraq, the COVID-19 pandemic is less prevalent in comparison with other affected countries such as China, Iran, Italy, Spain, and others. At the peak of the pandemic, the authorities decided to limit medical resources for emergency conditions and defer elective cases for later appointments across the country. The data from two tertiary cardiac centers in the south of Iraq showed a 20% reduction in the rate of pPCI procedures performed during March-April 2020 in comparison with the proceeding months. Possible explanations are patient anxiety towards admission to hospitals, the total lockdown of the cities causing difficult access to hospitals, adoption of pharmacotherapy to treat STEMI patients in hospitals with no catheterization laboratories, and to a lesser extent the possibility of reduced STEMI incidence during the pandemic. The most important point here how well patients understand the current situation. We need to educate patients with STEMI and other acute events that hospitals are safe and that they have to call for help immediately to save their lives. It is our responsibility as medical professionals to keep an eye on all aspects of our field to minimize losses as much as possible.

Jadranka Šeparović Hanževački, Vlatka Rešković Lukšić

The coronavirus pandemic caused by SARS-CoV-2 (COVID-19) has created new and unforeseen challenges for modern medicine and healthcare systems around the world. Since COVID-19 has direct and indirect effects on the cardiovascular system and cardiovascular patients are at risk of increased mortality from this disease, the work of cardiology departments has also been affected. Additionally, the fact that the severe acute respiratory syndrome caused by this virus is capable of airborne droplet human-to-human transmission has resulted in the need for special protection for medical and non-medical staff caring for these patients. Echocardiography fellows and echocardiographic laboratories in Croatia have found themselves exposed to this sudden and unknown danger. Since echocardiography fellows are in close and extended contact with patients, they have increased risk of contracting the infection. Echocardiographic laboratories faced increased demands for echocardiography in critical patients and those suspected for COVID-19, which is understandable given that echocardiography is a basic cardiologic diagnostic procedure. In order to reduce the risk of transmitting the infection for patient to patient, from patient to echocardiography fellow, and vice-versa, it was necessary to carefully evaluate the indications for echocardiography and select only those that always effect the treatment and course of the disease. The demanding and unprecedented conditions created by the pandemic, the limited number of trained echocardiography fellows available, and the risk of periprocedural transmission have become significant challenges in the organization of echocardiographic laboratories. As a result, the Working Group for Echocardiography and Imaging Modalities in Cardiology of the Croatian Cardiac Society has, based on the example of the EACVI guidelines (1), published a set of protocol recommendations for echocardiography during the COVID-19 pandemic (**Figure 1** in Croatian, **Figure 2**) (2). The protocol, which is adapted to the specific conditions in Croatia, provides detailed recommendations on categorizing patients based on COVID-19 status, indications for echocardiography examinations, and protective measures for staff (personal protective equipment, organization of echocardiographic laboratories, choice and protection of devices). The greatest emphasis is placed on establishing the indications for an echocardiographic examination, which will remain topical even after the epidemic has subsided – an echocardiographic examination is indicated if it answers the crucial clinical question and if echocardiographic findings directly influence the course and/or outcome of patient treatment. FIGURE 1. Preporuke Radne skupine za ehokardiografiju i slikovne metode u kardiologiji Hrvatskoga kardiološkog društva za ehokardiografiju u vrijeme COVID-19 pandemije. FIGURE 2. The Working Group on Echocardiography and Cardiac Imaging Modalities of the Croatian Cardiac Society recommendations for echocardiography during COVID-19 pandemic. Core members of the Working Group for Echocardiography and Imaging Modalities in Cardiology of the Croatian Cardiac Society presented the protocol at the first web seminar titled “Echocardiography during the COVID-19 pandemic” that was held on April 30, 2020. During the web seminar, a previously recorded video was shown that presented detailed recommendations and instructions, after which representatives of regional centers exchanged their practical experiences with COVID-19 patients and organizing echocardiographic laboratories and had a live online discussion. The web seminars were received with great interesting and had a good response, so the first one was followed with five more web seminars under the overarching topic of “Echocardiography during the COVID-19 pandemic” that addressed the sub-topics “Pulmonary ultrasound” and “FoCUS echocardiography” (2). Educational video materials were made available on the “Armchair Echo” platform in order to make them accessible for on-demand viewing to as many physicians as possible (3). The Working Group for Echocardiography and Imaging Modalities in Cardiology will continue to implement various educational projects, such as the multi-year “Echo on Wheels” project with in-person workshops, while also continuing the “Armchair Echo” project through web seminars available both live and on-demand from their educational platform.

Dudley Pennell, Victoria Delgado, Juhani Knuuti, Pàl Maurovich-Horvat, Jeroen J. Bax

Reproduced from: Pennell D, Delgado V, Knuuti J, Maurovich-Horvat P, Bax JJ. The year in cardiology: imaging. Eur Heart J. 2020 Feb 1;41(6):739-747. https://doi.org/10.1093/eurheartj/ehz930, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publishers. For Permissions, please email: journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint are those of the authors and contributors, and do not necessarily reflect those of the European Society of cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs and doses, the results of experimental work and clinical findings published in the Journal. The ultimate responsibility for the use and dosage of drugs mentioned in this reprint and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the Journal or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. **Sandra Makarović**, **Marko Boban** and **Mario Ivanuša** are solely responsible for the translation and this reprint. ## Introduction Multimodality imaging and artificial intelligence applied to imaging techniques have been a major interest in this year. The pathophysiological insights that various imaging modalities have provided in numerous clinical scenarios (heart failure, coronary artery disease, and valvular heart disease) influence the way we evaluate and manage patients. Conventional imaging to assess cardiac structure and function is still the first approach to evaluate patients and decide the management. However, advanced echocardiography with strain imaging techniques, tissue characterization with cardiovascular magnetic resonance (CMR), and assessment of biological processes with nuclear imaging techniques have helped to understand that early intervention may be needed in order to prevent or halt the progression of the disease. By applying machine learning techniques to all these imaging modalities, we are able to generate algorithms that can identify certain patterns of disease or risk and develop decisions in a more personalized way. This Year in Cardiology review articles summarize the most relevant studies in the field of imaging published in the last year. This year, artificial intelligence and machine learning applied to cardiac imaging has been one of the main novelties. Other advances in non-invasive cardiac imaging published in 2019 are summarized in this Year in Cardiology review article (**Figure A** – Take home figure (1, 2)). FIGURE A. *Take home figure:* Multimodality imaging and artificial intelligence in cardiac imaging. The use of the different imaging modalities should be based on a clinical question. Selecting the most appropriate imaging techniques and integrate them to answer that specific question will be key to improve the outcomes of patients (**A**). In the future, many of the process the clinicians are used to do to integrate all the information gathered from the imaging modalitiesmay be automated by using artificial intelligence techniques. How artificial intelligence interacts with medical research, clinical practice and statistics will be the focus of ongoing research (**B**). Reproduced with permission from Fox et al. (1) and Krittanawong et al. (2). ## Echocardiography Early detection of left ventricular (LV) dysfunction in various populations has been the focus of numerous publications in 2019. Left ventricular diastolic function usually precedes LV systolic dysfunction and is associated with cardiovascular morbidity and mortality. From the Copenhagen City Heart Study, a population-based study including 6238 individuals, Lassen et al. (3) evaluated the association between LV filling pressures measured on tissue Doppler imaging (E/E′) and speckle tracking echocardiography (E/E′sr) with the occurrence of cardiovascular death, admission for incident heart failure or myocardial infarction (MI). Of 1238 participants, 140 (11.3%) reached the primary endpoint during a median follow-up of 11 years. After adjusting for various clinical and echocardiographic parameters, E/E′sr was independently associated with the endpoint [hazard ratio (HR) 1.08, 95% confidence interval (CI) 1.02–1.13 per each 10 cm increase; P = 0.003] whereas E/E′ was not. In addition, E/E′sr provided incremental prognostic value over the SCORE risk chart, currently used to evaluate the risk of cardiovascular morbidity and mortality in the general population. Increased LV filling pressures may reflect the ageing process of the heart characterized by increased fibrosis. This fibrosis may lead to conduction abnormalities that influence the contractile function of the LV. Modin et al. (4) evaluated in 1138 participants of the Copenhagen City Heart Study the prognostic value of LV mechanical dispersion which is measured as the standard deviation from time to peak longitudinal strain of the three LV apical views. The mean value of LV mechanical dispersion in the general population was 45 ± 38 ms and increased with age, hypertension, body mass index, and presence of MI. Large LV mechanical dispersion was associated with worse LV systolic and diastolic function. Each 10 ms increase in LV mechanical dispersion was independently associated with increased risk of cardiovascular death (HR 1.04, 95% CI 1.01–1.06; P = 0.004). Despite the growing evidence on the diagnostic and prognostic value of strain derived measures of LV systolic and diastolic function, LV ejection fraction (EF) remains the mainstay parameter for risk stratification in clinical practice. The association between physician-reported LVEF and survival was assessed in 403 977 echocardiograms performed in 203 135 patients from USA. (5) Fifty percent of the population had an LVEF between 55% and 65%. Over a median follow-up of 4 years, 23% of patients died. A U-shaped relationship between LVEF and all-cause mortality was observed with the nadir at the 60–65% LVEF category. These results were reproduced in an independent dataset from New Zealand including 45 531 echocardiograms from 35 976 patients. The U-shaped relationship was also observed in men and women, inpatients and outpatients with heart failure, and deviations from LVEF of 60–65% were associated with greater multiplicative increase in risk for younger patients as compared to old patients. Left ventricular ejection fraction is also the parameter to classify heart failure patients. Ten to 20% of patients with heart failure with reduced LVEF (≤40%) may improve in LVEF. However, the evidence on the frequency and outcomes of patients with heart failure and recovered LVEF is based on selected cohort of patients or randomized clinical trials. Of 3124 heart failure patients with reduced LVEF at baseline treated with contemporary heart failure medications, 37.6% presented improvement in LVEF from 26% to 46% over a median follow-up of 17 months. (6) Patients with heart failure and recovered LVEF had lower rates for all-cause mortality, all-cause hospitalizations, cardiac transplantation, or LV assist device implantation than the patients who remained with reduced LVEF. Not less important is the characterization of the right ventricular (RV) remodelling in heart failure patients. In 271 patients with heart failure and preserved LVEF (HFpEF), RV fractional area change reduced by 10% and RV diastolic area increased by 21% over a median follow-up of 4 years. (7) These changes exceeded the corresponding changes in the LV. In addition, the prevalence of tricuspid regurgitation increased by 45%. Atrial fibrillation, higher body weight, coronary artery disease, higher pulmonary pressures and LV filling pressures and RV dilation were associated with development of RV dysfunction (**Figure 1**). (7) Patients with HFpEF developing RV dysfunction had two-fold increased risk of death. In this group of heart failure patients, assessment of left atrial function has provided important new insights. In 308 patients with HFpEF, Freed et al. (8) showed that impaired left atrial reservoir strain (stiff left atrium) was associated with increased pulmonary vascular resistance and decreased peak oxygen consumption and was independently associated with the composite outcome of cardiovascular hospitalization or death. It should be noted that the study did not correct the association between left atrial reservoir strain and the composite outcome for neuro-hormonal markers and as acknowledged by the authors, the studies stablishing the reference values of normal left atrial strain values across the echocardiographic systems and analysis platforms are scarce. FIGURE 1. Development of right ventricular dysfunction (RVD) over time in patients with heart failure and preserved ejection fraction. Increased left ventricular (LV) filling pressures and associated comorbidities characterize the initial phase of isolated left ventricular dysfunction (LVD) and lead to right ventricular (RV) remodelling, right ventricular dysfunction. Patients with incident right ventricular dysfunction have worse outcome as compared to patients with preserved RV function. Reproduced with permission from Obokata et al. (7). In patients with asymptomatic severe aortic stenosis and preserved LVEF, LV global longitudinal strain (GLS) on speckle tracking echocardiography is more sensitive than LVEF to identify early changes in LV systolic function during the follow-up. An LV GLS of >−18.2% (more impaired) is associated with higher risk of developing symptoms and needing aortic valve intervention as compared to more preserved values of LV GLS (≤−18.2%). (9) Echocardiography is the imaging technique of first choice to assess valvular heart disease. Secondary mitral regurgitation quantification remains challenging. In 423 heart failure patients, Bartko et al. (10) developed a unifying algorithm combining effective regurgitant orifice area (EROA), regurgitant volume, and regurgitant fraction that had better discrimination power to identify patients with increased mortality risk than current guideline-based definitions. Low-risk patients were characterized by an EROA of 2 and a regurgitant volume of 2 and a regurgitant volume of ≥45 mL. Intermediate-risk patients (with an EROA between 20 and 29 mm2 and a regurgitant volume of 30–44 mL) were reclassified as high risk if the regurgitant fraction was ≥50%. However, this algorithm had a rather modest discrimination power (area under the curve 0.63). The use of transthoracic focused cardiac ultrasound (FoCUS) is gaining popularity at the emergency department and intensive care units. Among 839 patients with suspected acute aortic syndrome, an aortic dissection detection risk score of ≤1 and a negative FoCUS could rule out an acute aortic syndrome with a sensitivity of 94% and a failure rate of 1.9%. (11) Finally, elevated carotid artery wave intensity measured on Duplex Doppler ultrasound was independently associated with faster cognitive decline among 3191 individuals enrolled in the Whitehall II study, (12) highlighting the relevance of ultrasound imaging outside the heart. ## Cardiovascular magnetic resonance The ICELAND-MI study is providing significant new data in the understanding of MI and fibrosis in elderly adults. In the first report by Shanbhag et al., (13) 397 patients aged 72–81 years were studied using CMR incorporating late gadolinium enhancement (LGE) imaging which identifies myocardial fibrosis due to MI (subendocardial) and other causes (other patterns). During the follow-up of 5.8 years, 192 events were recorded. The authors found that major non-ischaemic fibrosis was the only independent predictor of outcome (**Figure 2**). (13) FIGURE 2. Inverse propensity adjusted prognosis of ischaemic and non-ischaemic myocardial fibrosis. Reproduced with permission from Shanbhag et al. (13). In the second report from the ICELAND-MI trial, Acharya et al. (14) report on the long-term predictive value of unrecognized MI (UMI) in an elderly cohort of 935 subjects aged 67–93 years. Previous reports have suggested a poor short-term prognosis but this study extends follow-up to 13.3 years. The authors showed that all-cause mortality in UMI patents was lower than recognized MI for at least 5 years, but similar at 10 years. At all time-points UMI had a higher mortality than patients with no MI. It is not known whether secondary prevention would be useful in UMI patients. Cardiovascular magnetic resonance has made an enormous contribution to the diagnosis and management of the cardiomyopathies through the presence and patterns of myocardial fibrosis from LGE imaging, tissue characterization through T1, T2, and T2* mapping, and accurate measures of ventricular function and mass. Gutman et al. (15) studied 452 patients with non-ischaemic dilated cardiomyopathy (DCM) stratified by the presence or absence of non-ischaemic myocardial fibrosis by LGE. In patients with fibrosis, the mortality was reduced by an implantable cardioverter-defibrillator (ICD) with HR 0.45 (P = 0.003), but in patients without fibrosis there was no improvement in mortality with ICD (HR 1.22, P = 0.64). The authors conclude that in non-ischaemic DCM, the presence of fibrosis may allow for improved selection of patients requiring ICD. Galan-Arriola et al. (16) used serial CMR to identify the early stages of anthracycline-induced cardiotoxicity in a pig study. The earliest detectable abnormality was increased T2 relaxation which was correlated on histology with intramyocyte oedema, without change in the extracellular space. Changes in T1 and the extracellular volume on T1 mapping occurred much later and coincided with wall motion abnormalities. Stopping doxorubicin upon detection of T2 abnormality resolved intramyocyte vacuolization, indicating that the early T2 findings are at a stage when reversibility is still possible. These findings have important clinical implications for cancer therapy. Scally et al. (17) studied 55 patients with takotsubo cardiomyopathy using CMR including ultrasmall paramagnetic particles of iron oxide (USPIO) which localize in inflammatory macrophages. During the acute presentation, USPIO signal was reduced in the ballooning zone by 27% (P 82rubidium positron emission tomography (PET) imaging in 34 high-risk patients. The CT-derived global myocardial blood flow values correlated highly with those measured on PET (r = 0.92; P 18F-fluoride PET imaging is gaining increasing interest in various conditions as an indicator of tissue microcalcification, which is occurring in atherosclerosis. Creager et al. (29) investigated in an ex vivo study if 18F-fluoride accumulation on atherosclerotic plaques are related to the development of microcalcifications that are not visible on CT. In this complex study, 18F-fluoride signal in tissue analysis of human and mouse specimens was found to be clearly linked with small microcalcifications, which were not detected on CT. These results confirm that plaque mineralization is an active process and that 18F-fluoride PET imaging detects coronary and carotid plaques with high-risk features. In the study by Cartlidge et al., (30) the degeneration of bioprosthetic aortic valve was investigated using 18F-fluoride PET. In ex vivo analyses, the 18F-fluoride uptake colocalized with tissue degeneration on histology. In patients with aortic bioprostheses, increased valve 18F-fluoride uptake in PET imaging was associated with more rapid deterioration in valve function at 2-year follow-up. Aortic bioprosthesis dysfunction was detected in 10 patients and all of them showed 18F-fluoride uptake at baseline when still the valve haemodynamics were normal. On multivariable analysis, 18F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction. Although a larger patient cohort is needed, 18F-fluoride PET imaging appears promising method in predicting dysfunction of bioprosthetic valves. Infection and inflammation imaging using molecular imaging methods is an established technique in prosthetic valve endocarditis and device infections. Swart et al. (31) investigated the possible confounders that may impact on the accuracy of 18F-fluoro-deoxyglucose (FDG) PET/CT. In a multicentre study, 160 patients with suspected prosthetic valve endocarditis and 77 control patients were scanned. The authors found that low inflammatory activity (C-reactive protein 0 statin therapy was associated with reduced risk of major adverse cardiovascular events (adjusted sub-HR 0.76; 95% CI 0.60–0.95; P = 0.015). The effect of statin use on major adverse cardiovascular events was significantly related to the severity of CAC (P 100). A recent post hoc analysis of the SCOT-HEART trial demonstrated that coronary heart disease death or non-fatal MI was three times more frequent in patients with high-risk plaque features (positive remodelling or low attenuation plaque) and was twice as frequent in those with obstructive CAD. (34) However, these associations were not independent of CAC score, a surrogate measure of atherosclerosis burden. The investigators of the PROMISE Trial assessed the prevalence and clinical predictors of high-risk CAD (defined as left main stenosis or either ≥50% stenosis or ≥70% stenosis of 3 vessels or 2-vessel CAD involving the proximal left anterior descending artery). (35) High-risk CAD was identified in 6.6% (≥50% stenosis) and 2.4% (≥70% stenosis) of patients. Variables predictive of high-risk CAD included family history of premature CAD, age, male sex, lower glomerular filtration rate, diabetes mellitus, elevated systolic blood pressure, and angina. High-risk CAD was associated with more frequent invasive interventions and adverse events as compared to non-high-risk CAD. An intriguing study has investigated the prognostic value of combined information of lesion-specific ischaemia (FFR) and adverse plaque features by CCTA. (36) The authors evaluated 772 vessels (299 patients) by both CCTA and invasive FFR measurement. Interestingly, the presence of ≥3 high-risk plaque features was independently associated with clinical events in the FFR > 0.80 group, but not in the FFR ≤0.80 group. It seems that the integration of both lesion-specific ischaemia and CT plaque features may provide better prognostic stratification than either individual component alone, especially in patients with n FFR >0.80. Using computational fluid dynamics simulations CT is now capable to provide non-invasive FFR measurements. A study by Norgaard et al. (37) assessed real-world clinical outcomes following a diagnostic strategy including first-line coronary CTA with selective FFRCT testing. The study reviewed the results of 3674 consecutive patients with stable chest pain evaluated with CTA and FFRCT testing. The presence of intermediate-range CAD and FFRCT >0.80 was associated with favourable clinical outcomes similar to the prognosis in patients without or with minimal evidence of CAD. Beyond FFRCT simulation stress CT perfusion has emerged as a potential strategy to acquire anatomic and functional evaluation of CAD. Whole heart coverage CT scanners have become readily available, which allow a more robust stress CT MPI (CTP). The diagnostic accuracy of latest scanner generation was tested by Pontone et al. (38) in 100 intermediate- to high-risk symptomatic patients with suspected CAD. CCTA alone demonstrated a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 98%, 76%, 99%, 63%, and 83%, respectively. Combining CCTA with stress CTP, these values were 91%, 94%, 96%, 86%, and 93%, respectively, with a significant improvement in specificity, positive predictive value, and accuracy. The mean effective radiation dose for CCTA and stress CTP were 2.8 ± 1.4 mSv and 2.5 ± 1.1 mSv. Patients with diabetes are a high-risk patient cohort for adverse cardiovascular outcomes. The PROMISE Trial investigators assessed whether a diagnostic strategy based on CCTA is superior to functional stress testing in reducing cardiovascular death or MI among symptomatic patients with diabetes [n = 1908 (21%)] vs. patients without diabetes [n = 7058 (79%)]. (39) Patients with diabetes who underwent CCTA had a lower risk of cardiovascular death or MI compared with functional stress testing [CCTA: 1.1% (10 of 936) vs. stress testing: 2.6% (25 of 972); adjusted HR 0.38; 95% CI 0.18–0.79; P = 0.01]. Another study including also individuals with diabetes, investigated the rate and extent of plaque progression, changes in plaque features, and clinical predictors of plaque progression. (40) A total of 1602 patients who underwent serial CCTA (median scan interval 3.8 years) were enrolled and analysed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. (41) Diabetes was an independent risk factor for plaque progression (OR 1.526, 95% CI 1.100–2.118; P = 0.011). A more precise risk assessment that incorporates the detection of coronary inflammation would allow personalized medical interventions. Novel analytical techniques such perivascular fat attenuation index or plaque-based radiomics may facilitate the detection and quantification of pericoronary inflammation and atherosclerotic plaque activity. (42, 43) An innovative study by Oikonomou et al. (44) demonstrated that artificial intelligence powered pericoronary fat radiomic profile (FRP) analysis significantly improved major adverse cardiovascular events prediction beyond traditional risk stratification that included risk factors, CAC, coronary stenosis, and high-risk plaque features on CCTA in the SCOT-HEART trial (**Figure 4**). The authors conclude that FRP leads to a significant improvement of cardiac risk prediction over and above the current state-of-the-art, which might help to identify patients with elevated residual risk for cardiovascular events. FIGURE 4. Radiomic phenotyping of coronary perivascular adipose tissue. (**A**) The perivascular adipose tissue (PVAT) of the right (RCA) and left (LCA) coronary was segmented and used to calculate a number of shape-, attenuation-, and texture-related statistics. (**B**) Correlation plot of all 1391 stable radiomic features in the SCOT-HEART population (n= 1575 patients), with hierarchical clustering revealing distinct clusters of radiomic variance. (**C**) Heatmap of scaled radiomic features in the SCOT-HEART population revealing between-patient variance across the cohort. Reproduced with permission from Oikonomou et al. (44). ## Advanced imaging, fusion imaging, and applied artificial intelligence in imaging Cardiovascular (invasive and non-invasive) imaging is developing at ultrafast pace and the clinician of today gets daily confronted with different imaging modalities, with major technological developments, but also fusion imaging and introduction of artificial intelligence and machine learning. From a clinical perspective, the cardiovascular imager of tomorrow needs to be familiar with the different modalities, when to apply which technique in which clinical scenario. A dedicated task force of The European Association of Cardiovascular Imaging (part of the ESC) has published a statement on the organization of multimodality imaging services in cardiology, the use of the different modalities as well as training and research in the multimodality era. (1) Ramos et al. (45) used an animal (mice) model to study myocardial healing after infarction using serial imaging (7 days and 21 days post-infarction) with 3 T magnetic resonance imaging (MRI) and a 19F/1H surface coil. Injected 19F-perfluorocarbon nanoparticles were used to evaluate recruitment of inflammatory cells (e.g. macrophages), and an injected gadolinium-based elastin-binding contrast agent was used to assess elastin content. The combination of these imaging techniques enabled assessing the time course of the remodelling and healing process, as well as scar development. Engel et al. (46) evaluated 25 patients with either stable CAD or presenting with suspected ACS using a non-invasive albumin-binding probe gadofosveset-enhanced CMR, as well invasive coronary angiography and optical coherence tomography (OCT). CMR was performed twice: prior to baseline examination and 24 h after gadofosveset-trisodium administration. The patients with suspected ACS revealed significantly higher signal enhancement on CMR following gadofosveset-trisodium application on the segments containing a culprit lesion as compared to patients with stable CAD. On OCT, these patients presented with thin-cap fibroatheroma. The novel CMR approach may enable early detection of patients with potential ACS. Several articles in the field of multimodality and fusion imaging are worth to highlight. Mitral annular calcification is observed in patients with mitral regurgitation/stenosis and is important when transcatheter valve replacement is considered. To better understand pathophysiology, Massera et al. (47) performed CT calcium score of the mitral annulus, as well as PET with 18F-fluoride (calcification activity) and 18F-FDG (inflammation activity) in 104 patients. Mitral annular calcification was noted in 35 patients who exhibited increased 18F-fluoride uptake and FDG uptake, suggesting increased local calcification and inflammation. Fernandez-Friera et al. (48) used hybrid FDG PET/MRI to assess arterial vascular plaques in middle-aged individuals (n = 755). With this sophisticated imaging technology, the authors evaluated multi-territorial atherosclerosis (carotid, aortic, and ilio-femoral arteries); plaques were present on MRI in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids), whereas inflammation was observed on PET in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs). The authors concluded that arterial inflammation is noted in 50% of arterial plaques in middle-aged individuals. The current status of artificial intelligence and machine learning was elegantly reviewed by Al’Aref et al. (49) With the increasing digitization of data making big datasets available and easier to process, machine learning has enabled to autonomously acquire knowledge by the extraction of patterns from these large datasets. Particularly in cardiology machine learning has been rapidly adopted in various fields, to permit automated analysis of electrocardiograms and imaging (echocardiography, nuclear perfusion imaging, and CCTA) (**Figure 5**). FIGURE 5. Machine learning algorithms applied to echocardiography. Echocardiographic data are post-processed to automate many processes performed in clinical practice by cardiologists and sonographers such as view classification and image segmentation that will lead to the interpretation of the data and the diagnosis. Reproduced with permission from Al’Aref et al. (49). Another excellent review was published by Krittanawong et al. (2) providing further insight in deep learning. This is a branch of artificial intelligence, which combines computer science, statistics and decision theory to discover patterns in complex and big data. Casaclang-Verzosa et al. (50) applied machine learning to advanced network analysis to demonstrate automated assessment of LV (hypertrophy) in response to aortic valve stenosis from echocardiographic images. Finally, Zhang et al. (51) published original research on the use of deep learning to analyse echocardiographic data (n = 14 035 echocardiograms), in a fully automated fashion, including (i) view identification, (ii) image segmentation, (iii) quantification of structure and function, and (iv) disease detection. Specifically, convolutional neural networks were trained to detect hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension with respective C statistics of 0.93, 0.87, and 0.85.

Duška Glavaš

Heart failure represents one of the most significant diseases due to its high morbidity and mortality, despite the availability of various treatment methods that are being continuously improved. It is more common in older populations, and with the aging of the population it has become a growing global issue. On the other hand, many diseases, especially heart diseases, can manifest as heart failure (HF). Although those of us who work in the field might feel that the issues surrounding HF are well-known, we can still be surprised by (new) data. Over the last few months, we have witnessed the rise of the COVID-19 (COVID) virus pandemic, that has changed all of our lives and affected many people, in many cases with a lethal outcome. COVID infection primarily affects the respiratory system, but once it has spread it can influence the whole organism via different mechanisms, and HF can also be one of its manifestations, especially in the terminal phase. It should be noted that as many as 80% of patients can have mild or no symptoms while still transmitting the disease. The COVID pandemic has made us face new challenges and taught us or warned us of current problems or of issues that will arise in the near future with regard to both new and previously known infections and diseases. The working groups of the European Society of Cardiology and Heart Failure Association are continuously developing and implementing numerous activities in addition to providing guidelines and organizing congresses, trainings, and meetings, with the ultimate goal of improving the prognosis of patients with heart failure, and the Croatian Cardiac Society is part of this process. Notably, this participation includes the Heart Failure III Registry, the ATLAS project (with epidemiological data from individual countries), the Heart Failure Awareness Week (this year from May 4 to May 10), and an initiative for general practitioner patient care for patients with HF with the help of specialized medical nurses, and telemedicine support (which was especially useful during the pandemic). In the rest of this article, we will provide a review of the treatment of acute and chronic HF during the COVID-19 pandemic. Guidelines of the European Society of Cardiology for the diagnosis and treatment of cardiovascular diseases during the COVID-19 pandemic in relation to heart failure Patients with comorbidities are infected by COVID more often with a higher disease severity and mortality, especially if the comorbidity involves cardiovascular (CV), respiratory, renal, or malignant diseases, diabetes, and arterial hypertension (1). One study (n=8910) followed patients with COVID based on comorbidities. The mortality was 5.8%, and the risk was especially pronounced in the older age group (>65, 10%: 5.8%), in coronary artery disease (CAD, 10.2%: 5.2%), heart failure (15.3%: 5.6%), chronic obstructive pulmonary disease (COPD, 14,2%: 5,6%), arrhythmia (11.5%: 5.6%), and smoking (9.4%: 5.6%). CV diseases significantly increased mortality (2). In a meta-analysis of 6 studies, hypertension and CV diseases were present in 17.1% of those hospitalized for COVID, with up to 3 times higher risk of higher disease severity (3). COVID affecting the heart usually manifests as cardiac damage and heart failure, arrhythmia, and cardiac arrest. Different signs of infection can be prevalent in patients with COVID (high fever, muscle and joint pain, sore throat, headache, fatigue, skin changes, smell and taste disorders, and disorders of the digestive and urinary systems), and breathing problems accompanied by chest pain are common, which can resemble myocardial infarction. All known clinical methods must be used to establish a diagnosis. If performed, coronarography is usually normal. In a study on patients with COVID from China (1/2020; 552 hospitals, n=1099, average incubation – 4 dana, febrility 43%, lymphocytopenia 83.2%, typical changes observed on lung CT 56%), the severe form of the disease was observed in 6.1% of patients (5% were admitted to intensive care, 2.3% were placed on a respirator, and 1.4% died) (4). A fifth of the infected had signs of myocardial damage, in which case the mortality rate was several times higher. In the deceased, the heart was affected in about 40% of cases, 12% did not have prior CV diseases, whereas 25-50% of patients with pneumonia had comorbidities. Patients with COVID-19 infection can develop a new CV disease or present with progression of an existing disease (CAD, cardiomyopathies, various form of HF). Heart failure can be the consequence of acute viral myocarditis and a “cytokine storm”, but also the result of exacerbation of chronic HF. The high cardiometabolic burden during infection causes overwork of the heart, while cytokines can exacerbate shock and circulation changes, including the coronary vessels and microthrombosis. Respiratory infections accompanied by hypoxia lead to a higher incidence of mortal outcomes. Approximately one third of patients with the severe form of the infection can develop HF. ## Acute heart failure Acute heart failure is one of the possible complications in the clinical course of COVID infection, especially in more severe cases. The underlining condition can be acute myocardial ischemia, infarction, inflammation/myocarditis, stress-induced cardiomyopathy, tachyarrhythmia, acute respiratory distress syndrome (ARDS), acute kidney injury, and hypervolemia. COVID-induced pneumonia leads to deterioration of the patient’s condition due to hypoxemia, dehydration, and hypoperfusion. The patient’s clinical presentation, comorbidities, imaging methods, and elevated natriuretic peptides (NP) can indicate HF. Application of a bedside transthoracic echocardiogram (TTE) is important for the diagnosis (care should be taken not to transmit the infection to the staff and device). Data on acute HF with COVID infection are lacking. In one report, 23% of all hospitalized patients developed HF, and HF was a significantly prevalent diagnosis in mortal outcomes in comparison with those who survived the infection (52% vs. 12%, P< 0.0001) (5). There are several mechanisms that cause the development of acute HF in COVID infection, such as: 1. Acute myocardial injury (changes in troponin levels, ECG, TTE) manifests in 8% of patients (3). The causes can be ischemia, infarction, or myocarditis. In severe infections, damage to the myocardium was reported in 22.2-31.0% of patients (6). A meta-analysis of 4 studies (n=341) reported that troponin was already significantly elevated on hospital admission in patients with severe infection, that it remained higher in those who survived the infection, and that troponin levels increased as the disease became more severe (5). HF was more common in patients with acute myocardial damage (14.6% vs. 1.5%), with elevation of NT-proBNP levels (7). 2. Comorbid diseases can contribute to the development of HF (such as acute respiratory distress syndrome, hypoxemia, acute kidney injury, hypovolemia, stress-induced cardiomyopathy, systemic inflammatory activation – a “cytokine storm”, or severe infection with multi-organ dysfunction). 3. Arrhythmia can lead to deterioration of heart function. It has been reported in 16.7% of all hospitalized COVID patients and in 44.4% of those who required intensive care (6). The limited data we have indicate that SARS-CoV-2 infection can lead to fulminant myocarditis. This diagnosis can be suspected in case of acute onset of chest pain, ECG changes, arrhythmia, and hemodynamic instability. Dilatation of the left ventricle (LV) can usually be observed, along with global hypocontractility, significantly elevated troponin and NP values, but with no significant changes in the coronary arteries. Myocarditis should also be suspected in patients with COVID-19 and HF. Imaging using MSCT coronarography is desirable when we want to exclude CAD comorbidity. Magnetic resonance imaging (MR) can be used as an additional diagnostic tool. Endomyocardial biopsy is not recommended in patients with COVID. The exact mechanism of this myocarditis is still unclear (8). ## Chronic heart failure Risk of COVID-19 infection can be high in patients with HF, as well as those at an advanced age and with comorbidities. A number of tests are used in diagnosis: body temperature measurement (with non-contact devices), ECG (arrhythmia, myocardial ischemia, myocarditis), chest X-ray (cardiomegaly, COVID-induced pneumonia), and laboratory tests (elevated erythrocyte sedimentation rate, fibrinogen, CRP, and lymphocytopenia) can facilitate establishment of the diagnosis. Due to low chest X-ray sensitivity, chest MSCT scan is used to discover pneumonia. TTE is very important to show LV dysfunction and spot myocarditis. During all of the above, it is important to prevent virus transmission. Patients with chronic HF should adhere to protective measures (masks, medical gloves, hand hygiene, social distancing, disinfectants, self-isolation), and hospital checkups should be avoided during the stable phase. Telemedicine (internet, phone) should be used as much as possible. This helps reduce virus transmission while monitoring stable patients. Support from psychologists and home delivery of medication is recommended. SARS-CoV-2 uses ACE2 receptors to enter the cell, and some data indicate that angiotensin receptor blockers (ARB) and angiotensin-converting-enzyme inhibitors (ACE inhibitors) can increase the number of ACE2 receptors, which might hypothetically increase susceptibility to infection (9). A study on 12 patients with COVID-19 infection and ARDS showed that plasma angiotensin II was significantly increased with viral infection and damage to the lungs (10). Therefore, treatment with the ARB group of medications can have a beneficial effect on suppressing angiotensin II-mediated lung damage. Data available so far indicates that treatment in chronic patients with HF according to guideline recommendations (ACE inhibitors, ARB, beta-blockers, sacubitril/valsartan, aldosterone receptor antagonists) should be continued regardless of COVID infection (2, 11). Termination of chronic therapy can lead to HF deterioration (12). Further research on the role of ACE inhibitors and ARB in this disease is expected. Patients with a left ventricular assist device (LVAD) and with heart transplants are especially susceptible to infections, and strict adherence to preventive measures against virus transmission is necessary. There have been few publications on transplant patients with COVID-19 infection; some studies with SARS and MERS infection are available (13-16).

John G.F. Cleland, Alexander R. Lyon, Theresa McDonagh, John J.V. McMurray

Reproduced from: Cleland JGF, Lyon AR, McDonagh T, McMurray JJV. The year in cardiology: heart failure. Eur Heart J. 2020 Mar 21;41(12):1232-1248. https://doi.org/10.1093/eurheartj/ehz949, by permission of Oxford University Press on behalf of the European Society of Cardiology. ® The Authors(s) 2020. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission of the Publishers. For Permissions, please email: journals.permissions@oup.com The opinions expressed in the Journal item reproduced as this reprint are those of the authors and contributors, and do not necessarily reflect those of the European Society of cardiology, the editors, the editorial board, Oxford University Press or the organization to which the authors are affiliated. The mention of trade names, commercial products or organizations, and the inclusion of advertisements in this reprint do not imply endorsement by the Journal, the editors, the editorial board, Oxford University Press or the organization to which the authors affiliated. The editors and publishers have taken all reasonable precautions to verify drugs and doses, the results of experimental work and clinical findings published in the Journal. The ultimate responsibility for the use and dosage of drugs mentioned in this reprint and in interpretation of published material lies with the medical practitioner, and the editors and publisher cannot accept liability for damages arising from any error or omissions in the Journal or in this reprint. Please inform the editors of any errors. Oxford University Press, OPL., and the European Society of Cardiology are not responsible or in any way liable for the accuracy of the translated reprint, for any errors, omissions, or inaccuracies, or for any consequences arising therefrom. **Anita Jukić** and **Mario Ivanuša** are solely responsible for the translation and this reprint. ## Preamble The past year has brought many new concepts and an abundance of new data on the nature, management, and outcome of heart failure. The pace of change is accelerating. We look forward to an exciting new decade of research. The prognosis of cardiovascular disease is determined to a large extent by the ability to delay or prevent the development and progression of heart failure. (1) Accordingly, attention is shifting to earlier diagnosis of and intervention for heart failure. Patients with type-2 diabetes mellitus (T2DM) (2) or coronary artery disease (CAD) (3) have a relatively good prognosis unless plasma concentrations of natriuretic peptides are increased, indicating important cardiac or renal dysfunction. Adoption of a simple ‘Universal Definition’ of heart failure based on natriuretic peptides would facilitate early diagnosis and treatment but lead to an enormous increase in its prevalence and demand upon medical services. (4) We need to prepare for the impending shock. ## Epidemiology and prevention In cardiology, the term prevention is often used to mean delaying the onset of disease; in other words, procrastination. Failure to appreciate the difference between prevention and procrastination leads to problems in projecting future healthcare needs and costs. Older people have more co-morbid conditions that complicate management but may also offer more opportunities for intervention; consequently, more time and resources are required to manage older patients well. A detailed report on heart failure in the UK shows that the median age of onset has risen to about 80 years, consistent with improvements in the treatment of hypertension and other risk factors for atherosclerosis and better management of myocardial infarction. (5) Unfortunately, data on left ventricular ejection fraction (LVEF) were not available for this report. Analyses of the diagnostic pathway in primary care in the UK suggest that key investigations are often not done. (6-8) Similar data from other countries are urgently required. Several large epidemiological surveys (9, 10) and analyses of large trials (11, 12) have recently been published that allow the demographics, aetiology, and management of heart failure to be compared internationally. Mineralocorticoid receptor antagonists (MRAs) are effective anti-hypertensive agents that also improve the prognosis of patients with heart failure and a reduced (HFrEF) and possibly preserved (HFpEF) LVEF. (13) Whether MRAs have specific effects on reducing other potential drivers of the progression to heart failure such as inflammation and fibrosis is currently under investigation. (14, 15) Genetic propensity to greater body fat was associated with the risk of developing heart failure in an analysis on 367 703 UK Biobank participants. (16) However, the incidence of heart failure was only 1% (4803 patients), the diagnostic criteria were not robust, and the increase in risk was modest (odds ratio 1.22; 95% CI 1.06–1.41). Further analyses on this population showed a strong relationship between cardio-respiratory fitness and grip strength and future incidence of heart failure. (17) A study of 4403 people considered for bariatric surgery in Sweden and followed for 22 years, found that 188 (9%) of the 2003 who had surgery (25–35 kg weight loss; BMI 1 year after surgery 32 kg/m2) developed heart failure compared with 266 (13%) of 2030 who did not (BMI after 1 year observation 40 kg/m2). (18) Although these data suggest links between obesity and the risk of developing heart failure, it is possible that obesity just provokes similar symptoms. Once heart failure has developed, obesity is associated with a lower mortality, but this may also reflect earlier diagnosis rather than a protective effect. (19) Randomized controlled trials (RCTs) of effective interventions for obesity are required to demonstrate whether weight loss improves symptoms (likely) and clinical outcomes (less certain). A report from ‘the Atherosclerosis Risk in Communities’ (ARIC) study confirmed the association between influenza epidemics and hospitalizations for heart failure, reinforcing guideline-recommendations for vaccination (20); an RCT is underway. (21) Extended follow-up (median 18.9 years) of the Women’s Health Initiative Hormone Therapy trials, which randomized 27 347 women to various hormone replacement regimens, showed that they had no effect on the incidence of HFrEF or pEF. (22) The ISCHEMIA trial (presented at the American Heart Association 2019) compared strategies of early coronary revascularization, predominantly percutaneous, with conservative management for stable CAD, some of whom had mild symptoms of heart failure and/or a reduced LVEF. Revascularization did not reduce the risk of myocardial infarction or death but increased the risk of stroke almost four-fold and did not reduce new-onset heart failure over the following 4 years. ## Diagnosis The Heart Failure Association of the European Society of Cardiology has proposed a new scoring system for the diagnosis of HFpEF. (23) Its practical utility awaits confirmation. (24) Simpler approaches may be preferred. (4) ## Congestion Congestion lies at the heart of failure. (25–27) Imaging has long been used to identify dilation of the atria and venous system, which might be termed haemodynamic congestion, for which natriuretic peptides are a useful biomarker. (25) More recently imaging has been used to identify accumulation of fluid in tissues (tissue congestion), (25, 28–32) which may be associated with increases in the biomarker, (bio)-adrenomedullin. (33) Imaging and biomarkers in combination are both sensitive and specific for detecting a failing heart, a useful guide to the severity of congestion and prognosis and a potential therapeutic target indicating successful management. Imaging remains the preferred method for identifying the cause of heart failure. If congestion is central to the management of heart failure, then better monitoring (34) and more effective (diuretic) interventions (perhaps acetazolamide? (35)) should improve outcome (**Figure A** – Take home figure). FIGURE A. *Take home figure:* Two-year cause-specific mortality and non-fatal vascular events for patients with cardiovascular disease according to New York Heart Association (NYHA) class. Numbers and proportions are a conceptual representation of absolute and relative risk and are not strictly evidence-based. Note that for patients in NYHA Class 4, interventions for sudden arrhythmic death may be ineffective or fail to lead to a meaningful prolongation of life because the patient is likely soon to die of worsening heart failure. CRD, congestion-related death, otherwise called death due to worsening heart failure; NFVE, non-fatal vascular event (e.g. myocardial infarction and stroke; note that events are more likely to be suddenly fatal as heart failure progresses); non-CVD, non-cardiovascular death; RSAD, resuscitatable sudden arrhythmic death; SVD, sudden vascular death; TSAD, terminal (non-resucitatable) sudden arrhythmic death. Reproduced with permission from ref. (59) ## Age and prognosis Analysis of a large primary care database suggested that the cardiovascular (CV) prognosis of new-onset heart failure improved substantially between 2002 and 2014 [hazard ratio (HR): 0.73; 95% CI 0.68–0.80] for patients above and below the age of 80 years. (5) However, in those aged >80 years, the fall in CV mortality was entirely offset by non-CV mortality. In other words, treatment changed the way that elderly patients died but not overall mortality (**Figure 1**). Unfortunately, information on LVEF was not available; many patients will have had HFpEF and, therefore, caution should be exercised in attributing the reduction in CV mortality to treatment of heart failure. A systematic review of survey and registry data also suggested that the prognosis of heart failure had improved; important determinants of outcome were age and cardiology input to management. (36) Frailty, which might be considered a biological rather than chronological measure of age, may be an even more powerful predictor of disability and death. (37) FIGURE 1. Please see the original article (Eur Heart J. 2020 Mar 21;41(12):1232-1248.). Guideline-recommendations for the treatment of HFrEF do not discriminate by age. The Swedish Heart Failure Registry found that prescription of ACE inhibitors or beta-blockers to patients with HFrEF aged >80 years was associated with a lower mortality. (38, 39) However, observational associations have many explanations other than a therapeutic effect. (40) An individual patient-data meta-analysis of three RCTs of MRA (RALES, EMPHASIS, and TOPCAT-Americas) (13) suggested that MRAs exerted a similar reductions in mortality (by about 25%) for patients with HFrEF above and below age 75 years but benefit was less certain for HFpEF. ## The diversity of heart failure phenotypes Precision-medicine, which should also be accurate, requires patients to be classified in a way that informs management. For oncology, this has focused on the genetic cause, tumour location, and spread. For heart failure, a multi-system disorder, it is much more complex. (41–47) Current, therapeutically relevant classifications of heart failure include the severity of congestion (based on symptoms, signs, blood biomarkers, and imaging), CAD, heart rate and rhythm and QRS duration, blood pressure, serum potassium, renal function, indices of iron deficiency, mitral regurgitation, infiltrative myocardial disease (e.g. amyloid), and ventricular phenotype. (41, 48) Optimal management of heart failure, with a few rare exceptions, requires only a modest amount of information but this still creates many thousands of patient-subgroups or clusters that might have different therapeutic needs. (45, 46) Such subgroups will increase exponentially with the introduction of each new class of treatment. Despite this heterogeneity of substrate and wealth of interventions, precision-medicine is in its infancy in heart failure. One therapeutically relevant classification of heart failure is by LVEF, a surrogate for left ventricular (LV) dilation. Prior to the 1980s, imaging of cardiac function was available only in expert centres. Clinical trials relied on the chest X-ray rather than the echocardiogram to support a diagnosis of heart failure. The success of trials such as SOLVD, MERIT, and CHARM, which all had a reduced LVEF as an inclusion criterion, led to the adoption of LVEF 350 000 routinely collected echocardiograms suggested that the nadir of risk, whether or not the patient has a diagnosis of heart failure, lies in the range 60–65% both for men and women. Interestingly, an LVEF of >70% was associated with similar risk as an LVEF of 30–40% (**Figure 2**). (50) FIGURE 2. All-cause mortality according to left ventricular ejection fraction reported on >350 000 routine echocardiograms stratified by age and sex. HFmrEF, heart failure with mildly reduced ejection fraction; HFnEF, heart failure with normal ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFsnEF, heart failure with supra-normal ejection fraction. Reproduced with permission from ref. (50) The ESC Guidelines of 2016 introduced the concept of HFmrEF, for two main reasons. Firstly, because of imprecision, an echocardiographic measurement could not reliably distinguish between two measurements of LVEF within 10% of each other. Creating a buffer-zone between HFrEF and HFnEF meant that misclassification was less likely. This innovation meant that a trial of HFpEF could not claim benefit for all patients with an LVEF >40% based solely on an effect in those with an LVEF 40–49%. Secondly, the introduction of HFmrEF challenged the convention that an LVEF 40% or >45% with no upper limit. Analyses of recent trials have led some to suggest that, for patients with an elevated NT-proBNP, the upper limit of LVEF for HFmrEF should be increased to 55% or even 60% but this seems premature until consistency is demonstrated across multiple interventions and end-points and measurement precision for LVEF improves. ### TABLE 1: Evidence supporting or refuting the benefits of treatments for heart failure with a left ventricular ejection fraction in the “mid-range” (HFmrEF: 40–49%). | | **LVEF** | **Symptoms** | **Hospitalization for** **heart failurea** | **CV death or HFHa** | **CV mortality** | **All-cause mortality** | | --- | --- | --- | --- | --- | --- | --- | | Diuretics | | | | | | | | Perindopril | | **Improved** | | **0.38 (0.19–0.75)**b | | | | Candesartan | | **Improved** | **0.72 (0.55–0.95)∏** | **0.76 (0.61–0.96)** | 0.81 (0.60–1.11) | 0.79 (0.60–1.04) | | Irbesartan | | | | 0.98 (0.85–1.12)Δ | | | | ARNI (Sac/Val) vs. Valc | | **Improved** | 0.77 (0.58–1.02) | 0.81 (0.64–1.03) | 0.94 (0.69–1.28) | NYR | | MRA (overall)c | | | 0.76 (0.46–1.27) | 0.72 (0.50–1.05) | 0.69 (0.43–1.12) | 0.73 (0.49–1.10) | | MRA (Americas)c | | | 0.60 (0.32–1.10) | **0.55 (0.33–0.91)** | **0.46 (0.23–0.94)** | **0.58 (0.34–0.99)** | | ß-Blocker (SR) | **Improved** | | 0.95 (0.68–1.32) | 0.83 (0.60–1.13) | **0.48 (0.24–0.97)** | 0.59 (0.34–1.03) | | ß-Blocker (AF) | **Improved** | | 1.15 (0.57–2.32) | 1.06 (0.58–1.94) | 0.86 (0.36–2.03) | 1.30 (0.63–2.67) | | Ivabradine | | | | | | | | Digoxin | | | 0.80 (0.63–1.03) | 0.96 (0.79–1.17) | 1.24 (0.94–1.64) | 1.08 (0.85–1.37) | | Rivaroxaban *vs*. aspirin | | | 0.65 (0.40–1.05) | | | 0.75 (0.53–1.06) | | Rivaroxaban+Aspirin *vs*. aspirin | | | 0.87 (0.56–1.35) | | | **0.63 (0.44–0.90)** | | CRT | | | | | | | | ICD | | | | | | | | BNP-guided therapy | | | | **Reduction from 67% to 44% patients with an event** | | | [†] Statistically significant results are shown in bold on a blue background. Blank cells indicate no relevant information reported. Other data shown are not significant, although may not be heterogeneous with the effect in patients with a reduced left ventricular ejection fraction (HFrEF). Data for sacubitril/valsartan taken from reference for LVEF >42.5% to 52.5%. (98) AF, atrial fibrillation; ARNI, angiotensin receptor-neprilysin inhibitors; BNP, brain natriuretic peptide; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; MRA, Mineralocorticoid receptor antagonist; SR, sinus rhythm. aRecurrent event analyses used when available. bThe PEP-CHF trial specified inclusion of patients with LVEF 40–49% as was LVEF >49% but did not report effects in this subgroup. However, it did report effects in patients with a prior myocardial infarction who were more likely to have HFmrEF. cStronger effect in women. In a substantial observational study of patients with HFpEF and pulmonary hypertension, progression of right rather than left ventricular dysfunction was observed and was associated with an increased risk of atrial fibrillation (AF) and death. (52) Although right ventricular (RV) dysfunction is a powerful prognostic marker, remarkably few trials focusing on RV dysfunction have been done (SERENADE: https://clinicaltrials.gov/ct2/show/NCT03153111). ## Atrial fibrillation About a third of outpatients, perhaps more for those with HFpEF, (53) and more than half of those admitted with heart failure will be in AF, which is associated with an adverse prognosis even after correcting for age and other risk factors. (54) Controversy continues over whether medical management focused on rate control or restoration of sinus rhythm is the better strategy for AF and heart failure. In practice, the strategy needs to be tailored to the patient. When AF is the driver of symptoms and worsening cardiac function, restoration of sinus rhythm might be appropriate but when AF reflects the progression of underlying cardiac dysfunction, it may not. (55) For new-onset or paroxysmal AF associated with a clear deterioration in symptoms, restoration of sinus rhythm may be warranted to improve symptoms. For long-standing AF and heart failure with markedly dilated atria, sustained restoration of sinus rhythm and atrial contraction is less likely. Optimal pharmacological management includes anticoagulation, avoiding toxic anti-arrhythmic agents and lenient ventricular rate control. Beta-blockers are the agent of choice for rate control, a resting day-time ventricular rate of 70–90 b.p.m. is preferred, (49) which may require only modest doses; digoxin should be used sparingly, if at all. Unfortunately, RCTs of rate vs. rhythm control for AF have failed to optimize the rate control strategy in the above fashion. A meta-analysis of RCTs of rate vs. rhythm control included four trials (n = 2486) comparing pharmacological rhythm to rate control found no difference in mortality or thromboembolic events but an increase in hospitalizations, often due to recurrent AF, in the rhythm control group. (56) Six trials (n = 1112) comparing AF ablation with rate control reported reductions in mortality (0.51; 95% CI 0.36–0.74), hospitalizations (0.44; 95% CI 0.26–0.76), and stroke (0.59: 95% CI 0.23–1.51) and an improved quality of life. (56) However, none of the trials individually had a robust result, patients were highly selected and the rate control strategy was not optimal. As such, this meta-analysis should be considered hypothesis generating. Further trials are required with greater involvement of heart failure physicians. ## Implanted electrical devices The controversy over the role of high-energy devices for heart failure continues. Long-term follow-up of cardiac resynchronization therapy (CRT) in a French Registry showed a low rate of sudden death amongst patients who received CRT-Pacing (without a defibrillator). (57–59) A systematic review of observational studies and RCTs reported that differences in the rate of sudden death with CRT-Pacing and CRT-D were narrowing. (58) RCTs comparing CRT-Pacing and CRT-D are underway (59) (**Figure A** – Take home figure). Whether myocardial scar found on cardiac magnetic resonance imaging identifies patients with more to gain from an implantable cardioverter defibrillator (ICD) is also under investigation (60) (CMR_GUIDE; https://clinicaltrials.gov/ct2/show/NCT01918215). Retrospective analysis of SCD-HeFT found that patients with T2DM did not benefit from an ICD. (61) An individual patient-data meta-analysis confirmed a reduction in sudden death with MRA. (62) A systematic review identified 22 studies with post-mortem interrogation of ICDs; the analysis suggested that 24% of sudden deaths were not arrhythmic. (63) A substantial multi-point pacing trial failed, so far, to show improvements in the clinical or echocardiographic response to CRT. (64) ## Mitral regurgitation COAPT suggested that a percutaneously delivered mitral clip could reduce functional (secondary) regurgitation with a subsequent substantial improvement in morbidity and mortality that was moderately cost-effective in a US healthcare context (US$40 361 per life-year gained and $55 600 per quality-adjusted life year). (65–68) Two-year follow-up of MITRA.fr suggested no benefit. (69) A possible explanation for the apparent discrepancy could be the ratio of the severity of LV dysfunction to the severity of mitral regurgitation. When regurgitation is disproportionate to the severity of LV dysfunction it may drive disease progression and correction may improve outcome. (70, 71) When regurgitation is proportionate to the severity of LV dysfunction, fixing the mitral regurgitation may be less useful because myocardial dysfunction drives disease progression. The concept is simple and plausible but application in practice may be difficult. Mitral regurgitation offloads the LV and may mask dysfunction. It is also likely that there is a spectrum of primary and secondary mitral regurgitation, with some patients having a mixed picture. More experience and further data from RCTs may improve patient selection (RESHAPE-HF2: https://clinicaltrials.gov/ct2/show/NCT02444338). However, optimizing guideline-recommended therapy, including diuretic dose, may cause mitral regurgitation secondary to dilation of the LV and mitral ring to improve or resolve. Other technologies for secondary mitral (72) and tricuspid regurgitation (73, 74) are being developed. ## Coronary artery disease In COMPASS (n = 27 395), 5902 with CAD, in sinus rhythm and with a diagnosis of heart failure (predominantly HFpEF) were randomly assigned them to aspirin 100 mg/day, rivaroxaban 5 mg bd or aspirin and rivaroxaban 2.5 mg bd. (75, 76) The study was stopped early for benefit on the primary endpoint (a composite of CV death, stroke, or myocardial infarction) with the combination compared with aspirin alone. Further analysis suggested a reduction in all-cause mortality for patients with heart failure, especially HFpEF, assigned to combination therapy (HR: 0.63; 0.44–0.90) or rivaroxaban alone (HR: 0.75; 0.53–1.06) with an estimated 4% absolute difference at 2 years; rather similar to the magnitude of effect in HFrEF for sacubitril-valsartan (77) or dapagliflozin (78) (**Figure 3**). This suggests that coronary events might be an important driver of death in HFpEF (**Figure A** –Take home figure), although effects of rivaroxaban on endothelial function, inflammation, and fibrosis should not be discounted. The analysis also suggests that those who do not have heart failure have little to gain from additional treatment with rivaroxaban. FIGURE 3. Please see the original article (Eur Heart J. 2020 Mar 21;41(12):1232-1248.). However, for patients with HFrEF, CAD in sinus rhythm with a recent hospital discharge for worsening heart failure, addition of rivaroxaban 2.5 mg bd to background anti-platelet therapy did not improve overall prognosis, although a composite of vascular outcomes (stroke, myocardial infarction, and sudden death) was reduced, driven mainly by a reduction in stroke. (79, 80) This suggests that for patients with stable CAD and more advanced heart failure, hospitalizations, and deaths due to worsening heart failure are not greatly influenced by anti-thrombotic therapy (**Figure A** –Take home figure). ## Angiotensin receptor-neprilysin inhibitors ## Heart failure with reduced ejection fraction As experience in the implementation of angiotensin receptor-neprilysin inhibitors (ARNIs) grows, both in clinical trials and in clinical practice, there is a strong argument to consider them as first-line agents, rather than angiotensin converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), for the treatment of HFrEF. In PIONEER-HF, (81) 881 patients with an LVEF ≤40% who were hospitalized for worsening heart failure were randomly assigned, without a run-in period, to sacubitril/valsartan or enalapril prior to discharge and followed for 8 weeks to determine the effect on plasma concentrations of NT-proBNP; about one-third had new-onset heart failure. Sacubitril-valsartan exerted a greater reduction in NT-proBNP. Reductions in markers of myocardial injury or stress, high-sensitivity cardiac troponin-T and soluble ST2, were also observed. These effects appeared early after randomization (within 1–4 weeks). Moreover, patients assigned to sacubitril/valsartan were less likely to experience adverse outcomes within the first 8 weeks. TRANSITION (82) randomly assigned 1002 patients to pre- or post-discharge initiation of sacubitril/valsartan, showing no adverse consequences to earlier administration. EVALUATE (83) compared the effects of sacubitril/valsartan and enalapril on aortic stiffness in HFrEF most of whom were already chronically treated with an ACEi or ARB. After 24 weeks treatment, no differences in aortic stiffness were observed but slightly greater reductions in LV end-diastolic and systolic volumes were observed with sacubitril/valsartan compared with enalapril, although changes in LVEF were similar. Mitral E-velocity and left atrial volume declined, consistent with a fall in left atrial pressure. PROVE-HF, (84) an observational study, had similar findings and showed that most of the decline in NT-proBNP occurred within 14 days consistent with the rapid onset of clinical benefit observed with sacubitril/valsartan in trials and clinical practice. PRIME (85) was an RCT (n = 118) comparing the effects of sacubitril/valsartan or valsartan on functional mitral regurgitation in patients with an LVEF between 25% and 49% who were already receiving an ACEi or ARB. Those assigned to sacubitril/valsartan had greater reductions in mitral regurgitation and LV end-diastolic and left atrial volumes but LVEF increased by a similar small amount in each group (about 2.5%). Further reports from PARADIGM-HF suggest that, compared with enalapril, sacubitril/valsartan may improve markers of collagen metabolism, in particular, decreasing synthesis of type-I collagen, which makes an important contribution to myocardial stiffness. (86) In I-PRESERVE, irbesartan (an ARB) did not affect collagen biomarkers compared with placebo. (87) ## Heart failure with preserved ejection fraction PARAGON-HF investigated the effect of sacubitril/valsartan compared to valsartan alone on morbidity and mortality in patients with HFpEF (defined as an LVEF >45%). (88) It was the first RCT since PEP-CHF (89) to require patients to be treated with diuretics, the first-line treatment for the relief of symptoms and signs of congestion, and to have echocardiographic evidence of cardiac dysfunction. It was also the first large trial of HFpEF to require all patients to have raised plasma concentrations of natriuretic peptides, the most powerful, widely available prognostic marker in HFpEF. Sacubitril/valsartan was compared with valsartan rather than placebo because many patients eligible for PARAGON-HF had indications for ACE inhibitors and ARBs such as hypertension and CAD. The only trial comparing valsartan to placebo in HFpEF was of modest size and neutral. (90) Previous RCTs of other ARBs, including candesartan (CHARM-Preserved) and irbesartan (I-PRESERVE) failed to show substantial benefit for HFpEF. (88) Patients had to tolerate, sequentially, both valsartan and sacubitril/valsartan at half the intended target dose before randomization. This simulates clinical practice (doctors do not usually prescribe medicines to patients unwilling or unable to take them) and reduces the risk of a neutral trial-outcome due to low adherence. Of 10 539 patients screened, 4822 were randomized. PARAGON-HF was neutral for its primary endpoint (CV death or the total number of recurrent hospitalizations for heart failure (91); **Figure 4**). Some have argued that the P-value was very close to 0.05 and that it was ‘almost’ positive. This misses the point. The trial shows that the size of the potential benefit of sacubitril/valsartan for HFpEF is modest, regardless of the P-value and that the treatment is, overall, unlikely to be cost-effective. Accordingly, we should look for more effective treatments or, more controversially, subgroups that obtain greater benefit. After a median follow-up of 35 months, 23% of patients experienced a primary event but the annual incidence of CV and all-cause mortality were, respectively, only about 3% and 5%, which is similar to those for previous trials of HFpEF and for elderly patients with resistant hypertension assigned to placebo in HYVET. (92) Although 50%. Many of these patients probably had undiagnosed HFpEF prior to randomization. Higher rates of hospitalization for heart failure in trials of HFpEF compared to hypertension may well reflect ascertainment bias, as clinicians who are interested or expert in the management of heart failure are more likely to diagnose or report heart failure events. Overall, these trials suggest that the mortality rate and possibly the rates of cardiovascular and all-cause hospitalization may be similar in patients with and without a diagnosis of HFpEF, if they have a similar burden of co-morbidities. However, it is also likely that many patients with hypertension, CAD and T2DM have undiagnosed heart failure. FIGURE 4. Please see the original article (Eur Heart J. 2020 Mar 21;41(12):1232-1248.). Subgroup analysis suggested that the effect of sacubitril/valsartan on the primary endpoint was greater for patients with an LVEF below the median (57%), but this was driven almost entirely by an effect on hospitalization for heart failure rather than on CV death. (93) The effect of sacubitril/valsartan on the primary endpoint was also greater for women and this was true throughout the studied range of LVEF, but again this was driven by a difference in hospitalization for heart failure and not CV mortality. (94) Reductions in NT-proBNP were similar for each sex. Sacubitril/valsartan appeared to have a favourable effect on quality of life for men but not for women. Patients with a recent heart failure hospitalization may also have benefited more. (95) These observations should be interpreted in the light of a trial that was neutral for its primary endpoint. No effect was observed on mortality and the benefits of treatment on quality of life and hospitalizations for heart failure according to sex were inconsistent. In PARADIGM-HF, no difference in treatment effect according to sex was observed. A further sizeable RCT in HFpEF, PARALLAX-HF, investigating the effects of sacubitril/valsartan on quality of life and exercise capacity will provide more evidence in 2020 (https://clinicaltrials.gov/ct2/show/NCT03066804). ## Do women and men respond differently to treatment? An analysis of 12 058 patients with HFrEF in two large trials found that women had more severe symptoms, similar LVEF but a substantially better prognosis than men, even after adjusting for key prognostic variables including aetiology and NT-proBNP (HR: 0.68; 0.62–0.89). (96) A combined analysis of PARAGON-HF and PARADIGM-HF suggested that patients with HFrEF and HFpEF had similarly impaired quality of life but that women generally reported a worse quality of life than men. (97) In an observational analysis of patients with HFrEF, the BIOSTAT survey also found that women generally had a better prognosis than men despite being prescribed lower doses of beta-blockers and ACE inhibitors. (98) Interestingly, men and women had the same heart rate, the pharmacodynamic marker of beta-blocker dose. For patients with HFpEF in the TOPCAT trial, reductions in mortality, but not hospitalizations for heart failure, were greater for women, although the interaction was statistically significant only for all-cause mortality. (99) In the PARAGON-HF trial (HFpEF), women obtained greater benefit than men throughout the studied range of LVEF but the difference was driven by differences in the rate of hospitalization for heart failure rather than mortality. (94) One obvious difference between men and women, on average, is size. Cardiac resynchronization therapy is reputed to be more effective in women than men, but differences disappear once adjusted for height. (100) Many medicines are cleared by the kidney. Estimated glomerular filtration rate (eGFR) is indexed to body surface area (BSA) but doses of treatment are usually not. A woman (or small man) weighing 64 kg and 160 cm tall has BSA of 1.67 m2 using the Dubois formula and a man (or large woman) weighing 85 kg and 180 cm tall has a BSA 2.05 m2. If both have an eGFR of 60 mL/kg/m2, then the woman (or small man) has an un-indexed eGFR of 100 mL/min and the man (or large woman) has an un-indexed eGFR of 123 mL/min. If a medicine is cleared by the kidney then perhaps smaller people require lower doses to achieve the same plasma therapeutic concentration and clinical benefit? ## Sodium-glucose cotransporter-2 inhibitors Sodium-glucose cotransporter protein-2 (SGLT2) is found mainly in the proximal renal tubule and to a lesser extent in other organs. SGLT1 is abundant in the intestine and myocardium. SGLT2 inhibitors (SGLT2i) cause glycosuria, improving glycaemia, which led to their development for the treatment of T2DM, and an osmotic diuresis, leading to a contraction of plasma volume. (101, 102) SGLT1 inhibitors reduce intestinal glucose absorption, which can cause diarrhoea but might have favourable effects on myocardial energy-utilization. (103) Most SGLT2i are highly selective, including dapagliflozin and empagliflozin, but sotagliflozin is less selective. (103) EMPA-REG enrolled 7020 patients with T2DM, about 10% of whom had heart failure (LVEF was not measured) and showed that empagliflozin reduced the risk of hospitalization for heart failure and mortality. (104) Within a few weeks of initiating empagliflozin, body weight, and blood pressure fell and haematocrit rose, consistent with a diuretic effect. Subsequent RCTs of other SGLT2i in T2DM had similar findings. Meta-analyses suggested that SGLT2i were the hypoglycaemic agents most likely to reduce incident heart failure, (105–107) whilst observational data raises concerns about insulin therapy. (108) A meta-analysis of RCTs of empagliflozin, canagliflozin, and dapagliflozin for T2DM, including >30 000 patients, showed benefit, at least for those with established CV disease. (109) For the outcome of hospitalization for heart failure or CV death, the annual rate was about 0.6% for the 13 672 patients with multiple risk factors but without established CV disease, about 3% for the 20 650 patients with established atherosclerotic disease and about 6% for 3891 patients with heart failure at baseline; the relative risk reductions with SGLT2i in these populations were 16%, 24%, and 29%, respectively, without evidence of heterogeneity amongst agents. The largest of these trials, DECLARE, (110) included 17 160 patients of whom 671 had HFrEF and 1316 had HFpEF or an unspecified LVEF. In a subgroup analysis, (111) dapagliflozin reduced hospitalizations for heart failure and CV mortality for HFrEF but not for other patient-groups (**Figure 5**). FIGURE 5. Please see the original article (Eur Heart J. 2020 Mar 21;41(12):1232-1248.). DAPA-HF (78, 112) enrolled 4744 patients and followed them for a median of 18.3 months, demonstrating that addition of dapagliflozin to guideline-recommended therapy for HFrEF-reduced hospitalizations for heart failure by 30% and mortality (mainly cardiovascular) by 18%, preventing 3–5 hospitalizations and 1–2 deaths per 100 patients treated per year (**Figure 6**). Patients were somewhat less likely to experience serious adverse events, especially renal, with dapagliflozin compared with placebo. The benefits appeared consistent across subgroups, although patients with evidence of more severe congestion (worse NYHA class or higher NT-proBNP) may have received less benefit. Importantly, benefits were similar for those with and without T2DM and regardless of age. (113) Dapagliflozin also improved quality of life, (114) an effect that was confirmed in a smaller RCT (DEFINE) (115) that followed 263 patients for 12 weeks; about one in six patients got a meaningful benefit, either prevention of worsening or an improvement in symptoms, compared with placebo. FIGURE 6. Please see the original article (Eur Heart J. 2020 Mar 21;41(12):1232-1248.). In DAPA-HF, the placebo-corrected decline in weight between baseline and 8 months was 0.87 kg and this was associated with a small fall in NT-proBNP and systolic blood pressure and a small increase in haematocrit and serum creatinine. These findings are again consistent with the belief that SGLT2i exert at least some of their benefits by enhancing diuresis, either through an osmotic effect of glycosuria or by interfering with sodium-hydrogen exchange in the nephron. (116) The effects of SGLT2i appear early, consistent with an immediate haemodynamic effect. However, alternative or additional explanations for the effect of SGLT2i have been proposed. A small RCT suggested that empagliflozin stimulated production of erythropoietin leading to a rise in haematocrit and a fall in ferritin, a marker of inflammation and iron deficiency, although not transferrin saturation, a marker of iron deficiency alone. (117) However, administration of exogenous erythropoietin did not reduce morbidity or mortality in the RED-HF trial. (118) Others have suggested that SGLT2i increase the production of ketones, which may be a more efficient myocardial energy substrate, or block myocardial sodium–hydrogen exchanger-3, which may improve myocardial function and reduce fibrosis. (119, 120) An RCT of empagliflozin in patients with T2DM but not heart failure (121) suggested little effect on cardiac function or remodelling; RCTs of the effects of SGLT2i on cardiac function in patients with HFrEF and HFpEF are awaited. Future trials will confirm whether the benefit observed in DAPA-HF is a class effect and whether they are effective for HFpEF or when congestion is severe. (122, 123) ## Acute heart failure Two large RCTs of serelaxin failed to confirm the results of the original RELAX-AHF trial. RELAX-AHF-EU, (124) an openlabel RCT (n = 2688), reported a similar and low rate for mortality (≤2%) and re-admissions for heart failure (+ve breast cancer; about 60% of interruptions are for cardiotoxicity. (132) An observational study showed that of 30 women receiving HER2-targeted therapies who developed an LVEF of 40–49% and were treated prospectively with beta-blockers and ACE inhibitors, only three went on to develop severe heart failure or a LVEF <35%. (133) Cardiac function rarely returned to normal after completion of treatment, challenging the view that trastuzumab-related LV dysfunction is usually reversible. A recent study reported high rates of CV events, especially heart failure, amongst patients with multiple myeloma receiving potent proteasome inhibitors, such as carfilzomib and bortezomib, (134) which were associated with much poorer survival. Risk factors for developing a CV event included elevated pre-treatment NT-proBNP or an increase during treatment. A systematic review of prophylactic use of renin–angiotensin–aldosterone antagonists and beta-blockers identified 22 relevant RCTs, of which the largest had only 206 patients, (135, 136) but found no convincing evidence of clinical efficacy ## Implementation of therapy Analyses of administrative data from primary care in the UK suggest that implementation of therapy has improved substantially over the last decade, with 72% now prescribed a beta-blocker, although many patients remain on less than target doses. (6) Amongst hospital discharges in England and Wales, 89% of those with HFrEF were discharged on a beta-blocker (https://www.nicor.org.uk/wp-content/uploads/2019/09/Heart-Failure-2019-Report-final.pdf), which is very similar to that observed in patients with HFrEF selected for enrolment in the ESC-EURObservational Heart Failure Long-Term Registry. (137) However, an analysis of Medicare beneficiaries in the USA found that only 51% of patients with HFrEF were prescribed a beta-blocker after a first or recurrent hospitalization for heart failure and only 12% received at least ≥50% of the target dose by 1 year. (138) This suggests that the organization of care for HFrEF makes an important difference to treatment and, consequently, outcome. However, a cluster RCT (n = 2494) of service redesign aiming to improve hospital-to-home transition, which included self-care education, a structured hospital discharge summary, family physician follow-up within 1 week, and, for high-risk patients, home-visits, did not substantially improve patient well-being or outcome. (139) An RCT (n = 110) showed that frequent (several times per month) visits to participating community pharmacies could improve medication adherence and well-being. (140) An RCT of 450 patients found benefits of e-Health intervention on self-care behaviour and quality of life in the first 3 months after initiation but not thereafter, (141) with no effect on hospitalizations or mortality. There are many reasons why RCTs of complex interventions fail including inadequate power, suboptimal trial design, already excellent or unintended improvements in care for the control group, lack of long-term engagement and motivation of staff and patients, inclusion of patients for whom pharmacological intervention is largely ineffective (e.g. HFpEF) but sometimes we just have to admit that what should work does not. More evidence is required; learning from past experience. (142) ## Rehabilitation Systematic reviews suggest that exercise-based rehabilitation can improve patients’ well-being and exercise capacity and reduce heart failure-related and all-cause hospitalization but may not reduce mortality, despite potentially improving adherence to treatment. (143–147) The best and most cost-effective service-model is a topic of active research. (148, 149) ## Palliative care Morphine relieves chronic breathlessness in patients with chronic lung disease but data for heart failure are sparse. An RCT of 45 patients failed to demonstrate important clinical benefits of morphine administration to patients with HFrEF or HFpEF predominantly in NYHA functional class III. (150) ## Withdrawing treatment for heart failure after recovery Withdrawing treatment from patients with idiopathic or genetically determined dilated cardiomyopathy who have experienced full recovery of ventricular function should be done with great caution if at all. (151) Although patients with a recovered LVEF (HFrcEF) may have a better prognosis, it may still not be good. (152) Further research is required for peripartum and other specific types of cardiomyopathy. A recent report from an old trial (DIG), suggested that withdrawal of digoxin was associated with an increased risk of hospitalization for heart failure but did not affect mortality. (153) An RCT of 188 patients with stable heart failure from Brazil suggested that 75% of patients could be withdrawn from loop diuretics for at least 90 days without deterioration in symptoms, need for reinstitution of diuretic therapy, or a rise in plasma NT-proBNP. (154) This is in stark contrast to a smaller RCT from the UK, where withdrawal of diuretics and other therapies for 48 h led to a doubling of plasma concentrations of NT-proBNP, an increase in LV and left atrial volumes and worsening symptoms. (155) ## Conclusion Great progress in the understanding and management of heart failure has been made over the last year. New controversies and new evidence challenge many old assumptions. As ever, some will resist progress and others will embrace it. You, the reader, must help our professions and patients find the correct balance between reckless enthusiasm and diagnostic and therapeutic inertia.

Duška Glavaš, Mario Ivanuša

This article is a translated and abridged version of a Cochrane Review previously published in the: - The Cochrane database of systematic reviews, vol. 10,10 CD013015. 15 Oct. 2019, doi:10.1002/14651858.CD013015.pub2 - The Cochrane database of systematic reviews, vol. 6,6 CD012721. 28 Jun. 2018, doi:10.1002/14651858.CD012721.pub2 - The Cochrane database of systematic reviews vol. 1,1 CD002752. 8 Jan. 2019, doi:10.1002/14651858.CD002752.pub4 (see www.cochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review. Heart failure (HF) is currently one of the leading healthcare problems in the world. This clinical syndrome at the end of the cardiovascular continuum is important not only as a significant cause of morbidity, mortality, and large economic burden, but also represents a challenge in the optimal application of diagnostic methods, risk stratification, and evidence-based application of effective medication (especially from the neurohormonal antagonist group) or electronic implantable heart devices. (1, 2) Over the last decades, a number of studies and activities have been conducted all around the world with the goal of achieving optimal patient care, improving quality of live, and improving awareness of HF. The members of the Croatian Cardiac Society also continuously work to raise awareness on the importance of early recognition of HF symptoms, establishing the correct diagnosis, and implementing optimal treatment. In addition to the Croatian Heart Failure Registry (3) and scientific and professional articles and meetings, the Heart Failure Awareness Day is to be held in May 2020. (4) We have therefore selected developments related to HF as the leading topic of this issue of the Cardiologia Croatica journal, this time in cooperation with two professional societies. The main body of this article features a translation of the summaries of three meta-analyses recently published by the Cochrane Heart group, which also wants to share these insights with the members of the Croatian Cardiac Society. This group has been an integral part of the Cochrane Collaboration since 1998. (5) The first Cochrane systematic review featured in this article discusses how effective natriuretic peptide-guided treatment is as a preventive strategy in patients with cardiovascular risk factors. (6) The subject to the second Cochrane review is the application of neurohormonal antagonists (beta-blockers and inhibitors of the renin-angiotensin aldosterone system) for chronic HF in patients with preserved left ventricular systolic function. (7) The topic of the third review are individual and multidisciplinary interventions by healthcare workers in patients with HF. (8) In the rest of this issue, we also present traditional review articles from the “The Year in Cardiology” series that were published by the European Heart Journal in early 2020. We received these articles for republication as part of the activity of the Editors’ Network of the European Society of Cardiology. Our previous issue featured articles that focused on acute coronary syndrome (9), coronary interventions (10), and arrhythmias and pacemakers (11). This issue brings three new articles focusing on heart failure (12), imaging (13), and diseases of the aorta and the peripheral arteries (14). All of these articles were translated by the Editorial Board of the Cardiologia Croatica journal. ## Natriuretic peptide-guided treatment for the prevention of cardiovascular events in patients without heart failure: a Cochrane systematic review (translation of the Cochrane systematic review abstract published in: Sweeney C, Ryan F, Ledwidge M, Ryan C, McDonald K, Watson C, et al. Natriuretic peptide-guided treatment for the prevantion of cardiovascular events in patients without heart failure. Cochrane Database Syst Rev. 2019 Oct 15;10:CD013015. https://doi.org/10.1002/14651858.CD013015.pub2) (6) Natriuretic peptides (NPs), including B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), are well-established biomarkers for the detection and diagnostic evaluation of heart failure. They are of interest for CVD prevention because they are secreted by the heart as a protective response to cardiovascular stress, strain, and damage. Therefore, measuring NP levels in patients without heart failure may be valuable for risk stratification, to identify those at highest risk of CVD who would benefit most from intensive risk reduction measures. ## Objectives To assess the effects of natriuretic peptide (NP)-guided treatment for people with cardiovascular risk factors and without heart failure. ## Search methods Searches of the following bibliographic databases were conducted up to 9 July 2019: CENTRAL, MEDLINE, Embase, and Web of Science. Three clinical trial registries were also searched in July 2019. ## Selection criteria We included randomized controlled trials enrolling adults with one or more cardiovascular risk factors and without heart failure, which compared NP-based screening and subsequent NP-guided treatment versus standard care in all settings (i.e. community, hospital). ## Data collection and analysis Two review authors independently screened titles and abstracts and selected studies for inclusion, extracted data, and evaluated risk of bias. Risk ratios (RRs) were calculated for dichotomous data, and mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous data. We contacted trial authors to obtain missing data and to verify crucial study characteristics. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, two review authors independently assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a ‘Summary of findings’ table. ## Main results We included two randomized controlled trials (three reports) with 1674 participants, with mean age between 64.1 and 67.8 years. Follow-up ranged from 2 years to mean 4.3 years. For primary outcome measures, effect estimates from a single study showed uncertainty for the effect of NP-guided treatment on cardiovascular mortality in patients with cardiovascular risk factors and without heart failure (RR 0.33, 95% CI 0.04 to 3.17; 1 study; 300 participants; low-quality evidence). Pooled analysis demonstrated that in comparison to standard care, NP-guided treatment probably reduces the risk of cardiovascular hospitalization (RR 0.52, 95% CI 0.40 to 0.68; 2 studies; 1674 participants; moderate-quality evidence). This corresponds to a risk of 163 per 1000 in the control group and 85 (95% CI 65 to 111) per 1000 in the NP-guided treatment group. When secondary outcome measures were evaluated, evidence from a pooled analysis showed uncertainty for the effect of NP-guided treatment on all-cause mortality (RR 0.90, 95% CI 0.60 to 1.35; 2 studies; 1354 participants; low-quality evidence). Pooled analysis indicates that NP-guided treatment probably reduces the risk of all-cause hospitalization (RR 0.83, 95% CI 0.75 to 0.92; 2 studies; 1354 participants; moderate-quality evidence). This corresponds to a risk of 601 per 1000 in the control group and 499 (95% CI 457 to 553) per 1000 in the NP-guided treatment group. The effect estimate from a single study indicates that NP-guided treatment reduced the risk of ventricular dysfunction (RR 0.61, 95% CI 0.41 to 0.91; 1374 participants; high-quality evidence). The risk in this study’s control group was 87 per 1000, compared with 53 (95% CI 36 to 79) per 1000 with NP-guided treatment. Results from the same study show that NP-guided treatment does not affect change in NP level at the end of follow-up, relative to standard care (MD -4.06 pg/mL, 95% CI -15.07 to 6.95; 1 study; 1374 participants; moderate-quality evidence). ## Authors’ conclusions This review shows that NP-guided treatment is likely to reduce ventricular dysfunction and cardiovascular and all-cause hospitalization for patients who have cardiovascular risk factors and who do not have heart failure. Effects on mortality and natriuretic peptide levels are less certain. Neither of the included studies were powered to evaluate mortality. Available evidence shows uncertainty regarding the effects of NP-guided treatment on both cardiovascular mortality and all-cause mortality; very low event numbers resulted in a high degree of imprecision in these effect estimates. Evidence also shows that NP-guided treatment may not affect NP level at the end of follow-up. As both trials included in our review were pragmatic studies, non-blinding of patients and practices may have biased results towards a finding of equivalence. Further studies with more adequately powered sample sizes and longer duration of follow-up are required to evaluate the effect of NP-guided treatment on mortality. As two trials are ongoing, one of which is a large multicenter trial, it is hoped that future iterations of this review will benefit from larger sample sizes across a wider geographical area. ## Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction: a Cochrane systematic review (translation of the Cochrane systematic review abstract published in: Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT. Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Database Syst Rev. 2018 Jun 28;6:CD012721. https://doi.org/10.1002/14651858.CD012721.pub2) (7) Beta-blockers and inhibitors of the renin-angiotensin aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction. There is uncertainty whether these treatments are beneficial for people with heart failure with preserved ejection fraction and a comprehensive review of the evidence is required. ## Objectives To assess the effects of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction. ## Search methods We searched CENTRAL, MEDLINE, Embase and two clinical trial registries on 25 July 2017 to identify eligible studies. Reference lists from primary studies and review articles were checked for additional studies. There were no language or date restrictions. ## Selection criteria We included randomized controlled trials with a parallel group design enrolling adult participants with heart failure with preserved ejection fraction, defined by a left ventricular ejection fraction of greater than 40 percent. ## Data collection and analysis Two review authors independently selected studies for inclusion and extracted data. The outcomes assessed included cardiovascular mortality, heart failure hospitalization, hyperkalemia, all-cause mortality and quality of life. Risk ratios (RR) and, where possible, hazard ratios (HR) were calculated for dichotomous outcomes. For continuous data, mean difference (MD) or standardized mean difference (SMD) were calculated. We contacted trialists where necessary to obtain missing data. ## Main results 37 randomized controlled trials (207 reports) were included across all comparisons with a total of 18,311 participants. Ten studies (3087 participants) investigating beta-blockers (BB) were included. A pooled analysis indicated a reduction in cardiovascular mortality (15% of participants in the intervention arm versus 19% in the control arm; RR 0.78; 95% confidence interval (CI) 0.62 to 0.99; number needed to treat to benefit (NNTB) 25; 1046 participants; 3 studies). However, the quality of evidence was low and no effect on cardiovascular mortality was observed when the analysis was limited to studies with a low risk of bias (RR 0.81; 95% CI 0.50 to 1.29; 643 participants; 1 study). There was no effect on all-cause mortality, heart failure hospitalization or quality of life measures, however there is uncertainty about these effects given the limited evidence available. 12 studies (4408 participants) investigating mineralocorticoid receptor antagonists (MRA) were included with the quality of evidence assessed as moderate. MRA treatment reduced heart failure hospitalization (11% of participants in the intervention arm versus 14% in the control arm; RR 0.82; 95% CI 0.69 to 0.98; NNTB 41; 3714 participants; 3 studies; moderate-quality evidence) however, little or no effect on all-cause and cardiovascular mortality and quality of life measures was observed. MRA treatment was associated with a greater risk of hyperkalaemia (16% of participants in the intervention group versus 8% in the control group; RR 2.11; 95% CI 1.77 to 2.51; 4291 participants; 6 studies; high-quality evidence). Eight studies (2061 participants) investigating angiotensin converting enzyme inhibitors (ACEI) were included with the overall quality of evidence assessed as moderate. The evidence suggested that ACEI treatment likely has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalization, or quality of life. Data for the effect of ACEI on hyperkalaemia were only available from one of the included studies. Eight studies (8755 participants) investigating angiotensin receptor blockers (ARB) were included with the overall quality of evidence assessed as high. The evidence suggested that treatment with ARB has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalization, or quality of life. ARB was associated with an increased risk of hyperkalaemia (0.9% of participants in the intervention group versus 0.5% in the control group; RR 1.88; 95% CI 1.07 to 3.33; 7148 participants; 2 studies; high-quality evidence). We identified a single ongoing placebo-controlled study investigating the effect of angiotensin receptor neprilysin inhibitors (ARNI) in people with heart failure with preserved ejection fraction. ## Authors’ conclusions There is evidence that MRA treatment reduces heart failure hospitalization in heart failure with preserved ejection fraction, however the effects on mortality related outcomes and quality of life remain unclear. The available evidence for beta-blockers, ACEI, ARB and ARNI is limited and it remains uncertain whether these treatments have a role in the treatment of HFpEF in the absence of an alternative indication for their use. This comprehensive review highlights a persistent gap in the evidence that is currently being addressed through several large ongoing clinical trials. ## Disease management interventions for heart failure: a Cochrane systematic review (translation of the Cochrane systematic review abstract published in: Takeda A, Martin N, Taylor RS, Taylor SJ. Disease management interventions for heart failure. Cochrane Database Syst Rev. 2019 Jan 8;1:CD002752. https://doi.org/10.1002/14651858.CD002752.pub4) (8) Despite advances in treatment, the increasing and ageing population makes heart failure an important cause of morbidity and death worldwide. It is associated with high healthcare costs, partly driven by frequent hospital readmissions. Disease management interventions may help to manage people with heart failure in a more proactive, preventative way than drug therapy alone. This is the second update of a review published in 2005 and updated in 2012. ## Objectives To compare the effects of different disease management interventions for heart failure (which are not purely educational in focus), with usual care, in terms of death, hospital readmissions, quality of life and cost-related outcomes. ## Search methods We searched CENTRAL, MEDLINE, Embase and CINAHL for this review update on 9 January 2018 and two clinical trials registries on 4 July 2018. We applied no language restrictions. ## Selection criteria We included randomized controlled trials (RCTs) with at least six months’ follow-up, comparing disease management interventions to usual care for adults who had been admitted to hospital at least once with a diagnosis of heart failure. There were three main types of intervention: case management; clinic-based interventions; multidisciplinary interventions. ## Data collection and analysis We used standard methodological procedures expected by Cochrane. Outcomes of interest were mortality due to heart failure, mortality due to any cause, hospital readmission for heart failure, hospital readmission for any cause, adverse effects, quality of life, costs and cost-effectiveness. ## Main results We found 22 new RCTs, so now include 47 RCTs (10,869 participants). Twenty-eight were case management interventions, seven were clinic-based models, nine were multidisciplinary interventions, and three could not be categorized as any of these. The included studies were predominantly in an older population, with most studies reporting a mean age of between 67 and 80 years. Seven RCTs were in upper-middle-income countries, the rest were in high-income countries. Only two multidisciplinary-intervention RCTs reported mortality due to heart failure. Pooled analysis gave a risk ratio (RR) of 0.46 (95% confidence interval (CI) 0.23 to 0.95), but the very low-quality evidence means we are uncertain of the effect on mortality due to heart failure. Based on this limited evidence, the number needed to treat for an additional beneficial outcome (NNTB) is 12 (95% CI 9 to 126). Twenty-six case management RCTs reported all-cause mortality, with low-quality evidence indicating that these may reduce all-cause mortality (RR 0.78, 95% CI 0.68 to 0.90; NNTB 25, 95% CI 17 to 54). We pooled all seven clinic-based studies, with low-quality evidence suggesting they may make little to no difference to all-cause mortality. Pooled analysis of eight multidisciplinary studies gave moderate-quality evidence that these probably reduce all-cause mortality (RR 0.67, 95% CI 0.54 to 0.83; NNTB 17, 95% CI 12 to 32). We pooled data on heart failure readmissions from 12 case management studies. Moderate-quality evidence suggests that they probably reduce heart failure readmissions (RR 0.64, 95% CI 0.53 to 0.78; NNTB 8, 95% CI 6 to 13). We were able to pool only two clinic-based studies, and the moderate-quality evidence suggested that there is probably little or no difference in heart failure readmissions between clinic-based interventions and usual care (RR 1.01, 95% CI 0.87 to 1.18). Pooled analysis of five multidisciplinary interventions gave low-quality evidence that these may reduce the risk of heart failure readmissions (RR 0.68, 95% CI 0.50 to 0.92; NNTB 11, 95% CI 7 to 44). Meta-analysis of 14 RCTs gave moderate-quality evidence that case management probably slightly reduces all-cause readmissions (RR 0.92, 95% CI 0.83 to 1.01); a decrease from 491 to 451 in 1000 people (95% CI 407 to 495). Pooling four clinic-based RCTs gave low-quality and somewhat heterogeneous evidence that these may result in little or no difference in all-cause readmissions (RR 0.90, 95% CI 0.72 to 1.12). Low-quality evidence from five RCTs indicated that multidisciplinary interventions may slightly reduce all-cause readmissions (RR 0.85, 95% CI 0.71 to 1.01); a decrease from 450 to 383 in 1000 people (95% CI 320 to 455). Neither case management nor clinic-based intervention RCTs reported adverse effects. Two multidisciplinary interventions reported that no adverse events occurred. GRADE assessment of moderate quality suggested that there may be little or no difference in adverse effects between multidisciplinary interventions and usual care. Quality of life was generally poorly reported, with high attrition. Low-quality evidence means we are uncertain about the effect of case management and multidisciplinary interventions on quality of life. Four clinic-based studies reported quality of life but we could not pool them due to differences in reporting. Low-quality evidence indicates that clinic-based interventions may result in little or no difference in quality of life. Four case management programmes had cost-effectiveness analyses, and seven reported cost data. Low-quality evidence indicates that these may reduce costs and may be cost-effective. Two clinic-based studies reported cost savings. Low-quality evidence indicates that clinic-based interventions may reduce costs slightly. Low-quality data from one multidisciplinary intervention suggested this may be cost-effective from a societal perspective but less so from a health-services perspective. ## Authors’ conclusions We found limited evidence for the effect of disease management programmes on mortality due to heart failure, with few studies reporting this outcome. Case management may reduce all-cause mortality, and multidisciplinary interventions probably also reduce all-cause mortality, but clinic-based interventions had little or no effect on all-cause mortality. Readmissions due to heart failure or any cause were probably reduced by case-management interventions. Clinic-based interventions probably make little or no difference to heart failure readmissions and may result in little or no difference in readmissions for any cause. Multidisciplinary interventions may reduce the risk of readmission for heart failure or for any cause. There was a lack of evidence for adverse effects, and conclusions on quality of life remain uncertain due to poor-quality data. Variations in study location and time of occurrence hamper attempts to review costs and cost-effectiveness. The potential to improve quality of life is an important consideration but remains poorly reported. Improved reporting in future trials would strengthen the evidence for this patient-relevant outcome.