REVIEW

Advances in Clinical Cardiology 2016: A Summaryof the Key Clinical Trials

Alastair Gray . Conor McQuillan . Ian B. A. Menown

Received: April 10, 2017 / Published online: May 23, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Introduction: The findings of many new car-diology clinical trials over the last year havebeen published or presented at major interna-tional meetings. This paper aims to describe andplace in context a summary of the key clinicaltrials in cardiology presented between Januaryand December 2016.Methods: The authors reviewed clinical trialspresented at major cardiology conferences dur-ing 2016 including the American College ofCardiology (ACC), European Association forPercutaneous Cardiovascular Interventions(EuroPCR), European Society of Cardiology(ESC), European Association for the Study ofDiabetes (EASD), Transcatheter CardiovascularTherapeutics (TCT), and the American HeartAssociation (AHA). Selection criteria were trialswith a broad relevance to the cardiology com-munity and those with potential to changecurrent practice.Results: A total of 57 key cardiology clinicaltrials were identified for inclusion. Here wedescribe and place in clinical context the key

findings of new data relating to interventionaland structural cardiology including delayedstenting following primary angioplasty, con-trast-induced nephropathy, management ofjailed wires, optimal duration of dual anti-platelet therapy (DAPT), stenting vs bypass forleft main disease, new generation stents(BioFreedom, Orsiro, Absorb), transcatheteraortic valve implantation (Edwards Sapien XT,transcatheter embolic protection), and closuredevices (Watchman, Amplatzer). New preven-tative cardiology data include trials of bariatricsurgery, empagliflozin, liraglutide, semaglutide,PCSK9 inhibitors (evolocumab and alir-ocumab), and inclisiran. Antiplatelet therapytrials include platelet function monitoring andticagrelor vs clopidogrel for peripheral vasculardisease. New data are also presented in fields ofheart failure (sacubitril/valsartan, aliskiren,spironolactone), atrial fibrillation (rivaroxabanin patients undergoing coronary intervention,edoxaban in DC cardioversion), cardiac devices(implantable cardioverter defibrillator innon-ischemic cardiomyopathy), and electro-physiology (cryoballoon vs radiofrequencyablation).Conclusion: This paper presents a summary ofkey clinical cardiology trials during the pastyear and should be of practical value to bothclinicians and cardiology researchers.

Keywords: Ablation; Anticoagulant;Antiplatelet; Acute coronary syndrome; Atrial

Enhanced content To view enhanced content for thisarticle go to http://www.medengine.com/Redeem/0B18F0603C0130FD.

A. Gray � C. McQuillan � I. B. A. Menown (&)Craigavon Cardiac Centre, Southern Trust,Craigavon, Northern Ireland, UKe-mail: ian.menown@southerntrust.hscni.net

Adv Ther (2017) 34:1503–1527

DOI 10.1007/s12325-017-0560-5

fibrillation; Bioabsorbable polymer; Drugeluting balloon; Lipids; Prevention;Revascularization

INTRODUCTION

Over the past year, many trials with the poten-tial to change practice and impact on clinicalguidelines have been presented at internationalmeetings including the American College ofCardiology (ACC), European Association forPercutaneous Cardiovascular Interventions(EuroPCR), European Society of Cardiology(ESC), European Association for the Study ofDiabetes (EASD), Transcatheter CardiovascularTherapeutics (TCT), and the American HeartAssociation (AHA). In this paper the authorsdescribe new clinical data placed in the contextof acute coronary syndrome (ACS), interven-tional cardiology, heart failure, atrial fibrilla-tion, electrophysiology, and coronaryprevention.

METHODS

The results of major clinical trials in cardiologypresented at major conferences in 2016 werereviewed by the authors in addition to a searchof PubMed, Medline, Cochrane library, andEmbase. Search terms included ‘‘acute coronarysyndrome,’’ ‘‘atrial fibrillation,’’ ‘‘coronary pre-vention,’’ ‘‘electrophysiology,’’ ‘‘heart failure,’’and ‘‘interventional cardiology.’’ Trials wereselected on the basis of relevance to the cardi-ology practice and the potential to guide furtherphase 3 research. This article is based on previ-ously conducted studies and does not involveany new studies of human or animal subjectsperformed by any of the authors.

ADVANCES IN INTERVENTIONALCARDIOLOGY

Coronary revascularization via primary percu-taneous coronary intervention (PCI) is the goldstandard treatment for patients with ST eleva-tion myocardial infarction (STEMI) but may be

complicated by slow or no-reflow. Registry datahave suggested that delayed stent implantation,after restoration of antegrade flow, may reducedistal embolization thereby potentiallyimproving clinical outcomes. The DANAMI 3-DEFER (Deferred versus conventional stentimplantation in patients with STEMI) trial ran-domized 1215 patients with STEMI to standardPCI (612) or deferred stent implantation (603)after 48 h [1]. There was no difference in pri-mary endpoint (composite of all-cause mortal-ity, hospital admission for heart failure,recurrent infarction, and unplanned target ves-sel revascularization) with deferred vs conven-tional stent implantation (17% vs 18%;p = 0.92). Thus while stenting at the time ofprimary PCI remains appropriate for themajority of patients (avoiding the need for asecond procedure), deferred PCI in certain set-tings such as high thrombus burden appearsreasonable.

Contrast-induced nephropathy (CIN)remains a frequent complication of coronaryangiography [2]. The CARIN (Safety and Efficacyof CMX-2043 for Periprocedural Injury Protec-tion in Subjects Undergoing Coronary Angiog-raphy at Risk of Radio-contrast InducedNephropathy) trial assigned 3503 patientsundergoing coronary angiography to threeincremental doses of CMX-2043 (an a-lipoicacid analogue aimed at reducingischemia–reperfusion injury) vs placebo [3].However, no significant reduction in the inci-dence of the primary endpoint (acute kidneyinjury at 4 days) was observed with CMX-2043.Thus preventative strategies continue to focuson optimization of preprocedure hydration andwithholding of nephrotoxic medications [2].

For decades, PCI fellows have been taughtthat hydrophilic guidewires should not be‘‘jailed’’ in side branches behind main vesselstent struts because of concerns that theirpolymer coating might be stripped off on wireremoval. At EuroPCR 2016, this dogma wasdebunked by a study of 235 patients undergoingbifurcation PCI who were randomized to eithera polymer-coated (PC) or non-polymer-coated(non-PC) guidewire for side-branch access andjailing [4]. Initial side branch wiring was sig-nificantly faster with PC wires (19 vs 42 s;

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p = 0.05). In subsequent wire evaluation bystereomicroscopy, PC wires had markedly lessdamage (1.7% PC wires damaged [all onlymildly damaged vs 55% non-PC wires damaged,41% of which were moderately to severelydamaged]; p = 0.001). Contributing factors towire damage included main vessel lesion lengthand jailed wire length. This small but importanttrial has been tipped to change worldwide PCIpractice.

Radial access popularity continues to growworldwide given its lower bleeding risk. How-ever, interim data at EuroPCR from a study of191 patients undergoing racial access PCIreported upper extremity dysfunction in theintervention arm (as defined by a combinationof Doppler, volumetry, and sensory testing) in74.9% of cases. Those with upper extremitydysfunction were more likely to have radialartery occlusion (9.8% vs 0%; p\0.001) and tobe younger (63.4 vs 67.5 years; p = 0.01) [5].Final data from 500 patients are expected inmid-2017.

The pathophysiology of saphenous vein graft(SVG) atherosclerosis appears different to nativecoronary artery disease. BASKET-SAVAGE(Drug-eluting vs bare metal stents in saphenousvein grafts) assessed the efficacy and safety ofdrug-eluting stents (DES) vs bare metal stents(BMS) in SVG PCI [6]. Despite the trial stoppingearly because of slow enrollment, those ran-domized to DES (n = 89) vs BMS (n = 84) hadmarkedly lower primary endpoint of majoradverse cardiac events (MACE) at 12 months(2.3% vs 17.9%; p\0.001) which was main-tained at 3 years (12.4% vs 28.9%; p = 0.0012).These differences were largely driven by targetlesion revascularization (TLR) and non-fatal MI,with no significant difference in mortality.

It is recognized that the improved clinicaloutcomes with newer compared with oldergeneration stents may be related to improvedstent design as well as polymer/drug factors [7].It is thus of interest that the NORSTENT (Nor-wegian Coronary Stent Trial) randomized 9013patients (1:1) undergoing PCI to DES (82.9%everolimus, 13.1% zotarolimus) or contempo-rary BMS [8]. Of note, two-stent bifurcation PCIwas excluded. There was no difference in theprimary outcome of death or MI at 6 years

(16.6% vs 17.1%; p = 0.66) in keeping withBASKET-PROVE results [9]. However, DES wasassociated with reduced TLR (5.3% vs 10.3%;p\0.001) and, interestingly, a reduced inci-dence of definite stent thrombosis (0.8% vs1.2%; p = 0.0498). Thus contemporary DESimprove overall PCI outcomes although con-temporary BMS remain a reasonable option incertain clinical settings.

Given the potential benefits of 30 months’dual antiplatelet therapy (DAPT) seen in theDAPT trial [10], optimal duration of DAPT was aprominent discussion point at the EuropeanSociety Congress (ESC). The NIPPON (NoboriDual Antiplatelet Therapy as AppropriateDuration) trial randomized patients undergoingPCI with the Nobori� bioabsorbable ablumi-nal-coated stent to short (6 months) vs long(18 months) duration of DAPT (primarilyclopidogrel) [11]. Interim analysis from 2772 of3775 patients showed no significant differencein incidence of NACCE (net adverse clinical andcerebral events) (1.92% [n = 1355] vs 1.45%[n = 1371] for 6 and 18 months, respectively),bleeding, or stent thrombosis, although resultsmust be interpreted with caution until full trialdata are available especially given the open-la-bel design and lower than expected events ratewhich is likely to have reduced statistical power.

Provisional main vessel PCI is the recom-mended technique for most bifurcation lesions[12]. However, when a two-stent strategy isrequired, opinion is divided on the optimaltechnique. In the BBK-II (Bifurcations BadKrozingen II) angiographic trial, 300 patientsundergoing bifurcation stenting with DES wererandomized (1:1) to culotte vs TAP (T-and-Pro-trude) stenting [13]. Culotte was superior withrespect to the primary endpoint of 9-monthpercentage diameter stenosis (21% vs 27%;p = 0.038) and binary restenosis (6.5% vs 17%;p = 0.006). In keeping with previous data [14](which showed culotte to be superior to crush),the BBK-II trial suggests that if a two-stentstrategy is required, culotte should be the pre-ferred technique in most patients.

While N-acetylcysteine (NAC) was ultimatelydisappointing in trials of prevention of contrastnephropathy, its potential antioxidant proper-ties were evaluated in the new setting of infarct

Adv Ther (2017) 34:1503–1527 1505

size reduction during primary PCI for STEMI.The NACIAM trial (N-AcetylCysteine in AcuteMyocardial infarction) randomized 112 patientsto 48 h of intravenous (IV) NAC administrationvs placebo. All patients also received glyceryltrinitrate intravenously. Use of NAC was asso-ciated with reduction in infarct size by cardiacmagnetic resonance (CMR) (mean infarct size5% vs 10% of myocardium; p = 0.02), reducedtransmural infarct (54% vs 79%; p = 0.02), andimproved myocardial salvage (60% vs 27%;p = 0.001) [15]. Given these interesting results,a larger trial is planned.

Invasive diagnostic coronary angiography,when undertaken according to conventionalreferral pathways in patients with suspectedangina, typically only demonstrates significantcoronary disease in around one-third of cases.New 2016 trial data suggests that greater use ofCT coronary angiography (CTCA) or CMR mayenable improved triage and reduce unnecessaryinvasive angiography [16, 17].

Routine CTCA (Fig. 1) has previously beenfound to be superior to standard non-invasiveprotocols for chest pain assessment and triage[18]. The CONSERVE (COronary ComputedTomographic ANgiography for SElective Car-diac Catheterization Relation to CardioVascularOutcomes and Economics) trial randomized1503 stable patients who had suspected coro-nary artery disease and guideline indications for

angiography either directly to invasive coronaryangiography (ICA) or to initial CTCA (only fol-lowed by ICA if the CTCA was positive). Theconservative approach (initial CTCA) was asso-ciated with a 78% reduction in referral for ICAand a 50% reduction in cost. Despite the loweruse of ICA in the conservative group, there wasno significant difference in MACE (death, MI,unstable angina, stroke, urgent revasculariza-tion, or CV hospitalization) between the twoapproaches (each 4.6%) [16].

CMR has been shown to have superior sen-sitivity and negative predictive valve comparedwith myocardial perfusion scintigraphy (MPS)for detection of angiographically significantcoronary disease [19]. In the CE-MARC 2(Clinical Evaluation of Magnetic ResonanceImaging in Coronary Heart Disease 2) trial, 1202stable patients with clinically suspected anginaand pretest probability score of 10–90% wererandomized (1:2:2) to conventional guidelines(based on National Institute for Health and CareExcellence), CMR, or MPS to guide need forinvasive angiography. By 12 months, angiogra-phy was undertaken in 43%, 18%, and 16% ofconventional, CMR and MPS groups, respec-tively. Significant angiographic findings (re-quiring intervention) were observed in 12.1%,9.8%, and 8.7% of the three groups, respec-tively, although there was no significant differ-ence in MACE events between groups [17].Unnecessary angiography (absence of signifi-cant stenosis measured by fractional flowreserve or quantitative coronary angiography)occurred in 28.8%, 7.5%, and 7.1% of the threegroups, respectively.

Coronary Artery Bypass vs PCIRevascularization

Treatment of unprotected left main coronaryartery disease by PCI has increased significantlyon the basis of findings from small studies,subgroup analyses, and observational data, butadequately powered studies were awaited. AtTCT 2016, findings of two key trials werepresented.

EXCEL (Evaluation of Xience versus Cor-onary Artery Bypass Surgery for Effectiveness of

Fig. 1 Computed tomography coronary angiographyshowing a left anterior descending (LAD) artery stenosis

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Left Main Revascularization) randomized 1905patients with significant left main disease(Syntax 32 or lower) to PCI with Xienceeverolimus-eluting stents or to CABG (voronaryartery bypass grafting) [20]. The incidence of theprimary composite endpoint of death, MI, andstroke at a median of 3 years was similar withPCI and CABG (15.4% vs 14.7%; p = 0.02 fornon-inferiority). PCI was associated with lowerdeath, MI, or stroke at the earlier time point of30 days (4.9% vs 7.9%; p = 0.008 for superiority)and a lower incidence of bleeding, arrhythmia,renal failure, and infection. Ischemia-drivenrevascularization was more common with PCIat 3 years (12.6% vs 7.5%; p\0.001) butthrombosis (definite stent thrombosis or graftocclusion) was less common with PCI (0.7% vs5.4%; p\0.001).

The NOBLE (Nordic-Baltic-British left mainrevascularisation) study randomized (1:1) 1201patients with significant left main disease andno more than three non-left main, non-com-plex lesions to PCI (n = 598) or CABG (n = 603).The incidence of the primary endpoint of death,MI (excluding procedural MI), stroke, andrevascularization up to 5 years (median 3 years)was higher in PCI than CABG [121 (29%) vs81(19%) patients; p = 0.0066] but there was nosignificant difference in mortality [21]. Need forrevascularization was more common with PCIthan CABG (16% vs 10%; p = 0.032) but thiswas driven by de novo, non-left main lesions.Unlike the Syntax trial left main subset [22], inNOBLE, the baseline Syntax score did not pre-dict outcome for those undergoing PCI and anunexpectedly high event rate was seen in thoseundergoing PCI in the low (1–22) Syntax sub-group. Further detailed analysis is planned toevaluate if this finding was due to specific ana-tomic subsets, specific PCI strategies, or otherfactors [23].

Although EXCEL and NOBLE outcomesappear disparate, this is likely due to differencesin trial design. EXCEL included large proceduralMI (creatine kinase MB greater than ten timesupper normal) within the definition of MI,whereas NOBLE excluded procedural MI.EXCEL had a shorter follow-up than NOBLEwhich may be relevant since differences favor-ing CABG emerge between 3 and 5 years. EXCEL

implanted only second-generation DES,whereas NOBLE included 11% of patients withfirst-generation DES before the new generationBiomatrix stent was mandated. After adjustingfor these differences, the trial outcomes appearsimilar and in keeping with prior CABG vs PCItrial data.

A criticism of some studies is that patientsundergoing study CABG have higher than usualrates of bilateral internal thoracic [mammary]artery (ITA) grafting which might be associatedwith better patency. The Arterial Revasculariza-tion Trial (ART) enrolled 3102 patients andrandomly assigned (1:1) to single (n = 1554) orbilateral (n = 1548) ITA grafting. At 5 years, therate of death (8.7% vs 8.4%; p = 0.77) andcomposite of death from any cause, MI, orstroke (12.2% vs 12.7%; p = 0.69) did not differ,but rates of sternal wound complications werehigher with bilateral ITA grafts (3.5% vs 1.9%;p = 0.005) [24]. However, longer follow-up isneeded to evaluate the effect of presumedlong-term patency of ITA vs vein grafting onclinical outcomes and 10-year follow-up isplanned.

New Generation Stents

A short duration of DAPT post PCI is desirablein many patients including those at highbleeding risk. The BioFreedom stent facilitates ashort 1-month course of DAPT since, instead ofhaving a polymer layer, it has a novel microp-orous abluminal surface (Fig. 2) which enablescontrolled release of Biolimus A9 achievingtherapeutic local tissue concentrations for28 days post implantation [25]. The LEADERS--FREE trial randomized 2466 high-bleeding-riskpatients to receive the BioFreedom drug-coatedstent (DCS) or a bare metal stent (BMS) followedby 1-month DAPT. At 2-year follow-upBioFreedom was associated with a 46% reduc-tion in the primary efficacy endpoint of clini-cally driven TLR (6.8% vs 12.0% patients,respectively; hazard ratio 0.54; 95% CI0.41–0.72; p\0.0001) and a 20% reduction inthe primary safety endpoint of cardiac death,stent thrombosis, or MI (12.6% DCS vs 15.3%BMS patients; HR 0.80; 95% CI 0.64–0.99;

Adv Ther (2017) 34:1503–1527 1507

p = 0.039) (Fig. 3) [26]. Current use of BMS isnow largely confined to patients thought likelyto require short courses of DAPT and LEADERSFREE suggests that drug-coated stents will likelyreplace BMS for this indication also. The LEA-DERS FREE II registry is ongoing evaluatingoutcomes of BioFreedom in a combined US andglobal cohort.

For stents requiring a polymer for drug elu-tion, use of a biodegradable polymer mayreduce risk of very late stent thrombosis vs apermanent polymer [27]. The ultra-thin strut(60 lm) cobalt-chromium Orsiro stent (Bio-tronik, Berlin, Germany) which has a passivesilicon carbide layer overlaid by a biodegradablePLLA polymer releasing sirolimus was previ-ously found to have similar overall clinicaloutcomes vs Xience (Abbott, Illinois, USA) andsuperior outcomes in the STEMI subgroup [28].PCI in chronic total occlusion (CTO) is anotherchallenging subgroup, typically associated withlonger stent length and higher TLR. PRISON IV(Bioresorbable polymer-based sirolimus-elutingstent versus a durable polymer-basedeverolimus-eluting stent in patients with coro-nary artery chronic total occlusions)

randomized 330 patients with successfullycrossed chronic total occlusions to Orsiro vsXience. Surprisingly, Orsiro was associated withgreater in-segment late lumen loss (0.13 vs0.02 mm; primary non-inferiority endpoint notmet) and more frequent binary restenosis (8.0%vs 2.1%; p = 0.028) at 9 months [29]. However,PRISON IV was underpowered to evaluate inci-dence of very late stent thrombosis and furtherstudies are warranted.

The Absorb stent, a bioresorbable vascularscaffold (BVS), fully resorbs in 3 years. It washoped the absence of a permanent stent wouldbe associated with improved coronary vasomo-tion (reported to be impaired after first-genera-tion DES) [30] and reduced risk of very late stentthrombosis. Significant expectation thus awai-ted findings of ABSORB II (Comparison of aneverolimus-eluting bioresorbable scaffold withan everolimus-eluting metallic stent) in which501 patients with one to two non-complexlesions undergoing PCI were randomized (2:1)to BVS vs Xience. At 3 years, disappointinglythere was no significant difference in theco-primary endpoint of vasomotor reactivityafter nitroglycerin, BVS had greater late lumenloss (0.37 vs 0.25 mm; pnon-inferiority = 0.78), andof concern in the BVS group were eight definitescaffold thromboses (one acute, one subacute,six very late) and one probable late scaffoldthrombosis vs zero with Xience (p = 0.0331)[31]. ABSORB II raised concerns that longduration (2–3 years) DAPT may be necessaryafter BVS and suggested that further designiteration and clinical study are required beforeBVS is considered suitable for widespread use.

Intracoronary Diagnostics

Diagnostic PCI is usually angiographicallyguided alone, although it is recognized thatintravascular ultrasound (IVUS) guidance maybe associated with decreased MACE. Whileoptical coherence tomography (OCT) producessuperior resolution (Fig. 4), equivocal or supe-rior data guiding PCI is lacking. ILUMIEN III(OPTIMIZE PCI) sought to clarify this by ran-domizing (1:1:1) 450 patients to OCT, IVUS, or

Fig. 2 BioFreedom stainless steel stent which incorporatesa novel microporous abluminal surface. Reproduced withpermission from Biosensors

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angiography with final OCT acquisitions forthe primary endpoint of post-PCI minimalstent area (MSA). OCT guidance was non-infe-rior to IVUS guidance but not superior to IVUSor angiography alone [32]. Efficacy of OCT-guided PCI to improve event-free survival after

DES will be evaluated in the upcoming ILU-MIEN IV trial.

Fractional flow reserve (FFR) is a guide-line-recommended technique for guiding theuse of PCI based on findings from multiple trialssuch as DEFER, FAME, and FAME II [33–35]. It

Fig. 3 Two-year follow-up of the LEADERS-FREE trialshowing the BioFreedom drug-coated stent vs bare metalstenting to be associated with significant reduction in a theprimary safety endpoint of cardiovascular death, stent

thrombosis, or myocardial infarction and b the primaryefficacy endpoint of clinically driven target lesion revascu-larization. RRR relative risk reduction. Reproduced withpermission from Dr. P Urban

Adv Ther (2017) 34:1503–1527 1509

was thus surprising that the FUTURE trial [36](Does FFR-guided treatment strategy in patientswith multivessel CAD improve prognosis com-pared to traditional treatment), which plannedto enroll 1728 patients, was halted prematurelyafter interim analysis suggested a higher12-month mortality in the FFR group (4% vs2%; p = 0.02). Subsequent follow-up of 797reaching 12-month follow-up showed a smallnumerical excess in all-cause mortality, but thiswas no longer significant (p = 0.07) andthought likely to be a spurious finding.

Calcified Lesion Preparation

With ever-older patients coming for PCI, strategiesto adequately prepare heavily calcified lesions areincreasingly needed. The novel technique oflithoplasty (high energy ultrasound waves) wasevaluated in 60 patients undergoing PCI in theDISRUPT CAD (Shockwave Coronary Rx Litho-plasty� Study trial). No angiographic complica-tions were reported and OCT confirmedcircumferential calcium fracture and luminal gain[37]. Larger studies with longer follow-up arerequired to assess the impact on clinical outcomes.

Advances in Structural Cardiology

Transcatheter aortic valve implantation (TAVI)is now an accepted treatment method for

patients with severe aortic stenosis who are athigh risk for surgical aortic valve replacement(SAVR) based on data from the Placement ofAortic Transcatheter Valves (PARTNER) study[38]. The PARTNER 2 trial aimed to evaluateTAVI in the setting of severe aortic stenosis andintermediate risk. In total, 2032 patients, ofwhom 81.3% had an STS [Society of ThoracicSurgeons] score between 4–8, were randomized(1:1 ratio) to TAVI (Edwards Lifesciences SapienXT) or SAVR [39]. TAVI was non-inferior toSAVR with regard to the primary endpoint ofdeath or disabling stroke at 2 years (19.3% vs21.1%; p = 0.001) and the transfemoral accessTAVI cohort had lower rate of death or disablingstroke than SAVR (hazard ratio 0.79; 95% CI0.62–1.00; p = 0.05).

While PARTNER 2 supports consideration ofTAVI as an alternative to SAVR for severe aorticstenosis and intermediate risk patients, carefulpatient selection is still required as highlightedby data from the German Aortic Valve Registry[40] where, among 5997 intermediate riskpatients (logistic EuroSCORE I of 10–20%)undergoing isolated valve treatment, highermortality rates were reported for TAVI vs SAVR,in hospital (3.8% vs 2.6%; p = 0.02), at 30 days(4.6% vs 3.2%; p = 0.01) and at 1 year 16.6% vs8.9%; p = 0.001). Confounding factors includ-ing frailty and other co-morbidities may nothave been fully accounted for, but intermediateto lower risk patient groups require furtherstudy.

As TAVI implant numbers increase, growingconcern surrounds the incidence of tran-scatheter heart valve thrombosis. At ESC 2016,data were presented from a cohort of 405intermediate risk patients (mean STS score 5.3)undergoing TAVI with Edwards Sapien XT orSapien 3 who were subsequently evaluated bycardiac CT 1–3 months later for evidence ofhypoattenuated leaflet thickening suggestingvalve thrombosis [41]. Overall, valve thrombo-sis was observed in 28 (7%) patients, of whomfive had clinically obstructive symptoms but 23were subclinical. Valve thrombosis was morecommon in those not receiving warfarin (10.7%vs 1.8%; risk ratio 6.09; 95% CI 1.86–19.84) andwith larger valves. Treatment with warfarineffectively resolved valve thrombosis and

Fig. 4 Coronary artery optical coherence tomography

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normalized function in 85% of patients. Dataregarding optimal antithrombotic therapy postTAVI is limited, but ongoing randomized trialssuch as the Global Study Comparing aRivaroxaban-based Antithrombotic Strategy toan Antiplatelet Strategy After TranscatheterAortic Valve Replacement to Optimize ClinicalOutcomes (GALILEO: NCT02556203) studymay guide preferred antithrombotic strategy.

Embolism of atherothrombotic debris iscommon following TAVI. The SENTINEL trialtested whether transcatheter embolic protec-tion (TCEP) during TAVI would decreaseperiprocedural neurological events and cerebralinfarction. In SENTINEL, 363 high risk patientsundergoing TAVI were randomized (2:1) toreceive TCEP or routine (non-TCEP) care. Evi-dence captured embolic debris in 99% ofpatients receiving TCEP. There was a small,non-significant increase in vascular complica-tions with TCEP placement (8.6% vs 5.9%). At30 days, numerically lower MACCE (7.3% vs9.9%) and numerically lower strokes (5.6% vs9.1%) were reported with TCEP, although thesedid not reach statistical significance [42]. In asubgroup undergoing brain MRI within 1 week,new lesion volume was numerically smallerwith TCEP (102.8 vs 178.0 mm3; p = 0.33) butthis did not reach statistical significance. Resultsare thus encouraging but further studies areneeded. The degree of confirmed embolismdetected also highlights the importance ofavoiding overly aggressive device manipulationwithin the aortic valvar complex.

Closure Devices

Extended follow-up from PROTECT AF(Watchman Left Atrial Appendage System forEmbolic Protection in Patients With AF) andPREVAIL (Prospective randomized evaluation ofthe Watchman Left Atrial Appendage Closuredevice in patients with atrial fibrillation vslong-term warfarin therapy) were presented atTCT 2016 as part of the CAP (Continued Accessto PROTECT AF) and CAP2 (Continued Accessto PREVAIL) registries [43] (Fig. 5). A total of 732device patients were followed up for 5 and3 years, respectively. Baseline predicted stroke

risk was 3.6% based on a median CHA2DS2-VASc score of 3.4. Procedural complicationsincluded major bleeding (2.3%), stroke (1.0%),and device embolization (0.5%). Risk ratios forischemic stroke, hemorrhagic stroke, and majorbleeding post-procedure were 1.35, 0.16, and0.62, respectively. The extended CAP follow-upsuggested that Watchman is associated with asimilar stroke risk reduction to that whichwould be expected with oral anticoagulants.

The significance and treatment of patentforamen ovale (PFO) in patients with crypto-genic stroke has been controversial. RESPECT(Closure of Patent Foramen Ovale vs MedicalTherapy after Cryptogenic Stroke) 10-year out-come data followed 980 patients with crypto-genic stroke, randomized 1:1 to AMPLATZERPFO Occluder device vs medical managementbetween 2003 and 2011 [44]. PFO closure usingthe AMPLATZER device was associated with a45% risk reduction (p = 0.046) in recurrentischemic stroke. There were no incidents ofdevice embolization or thrombosis, and majorvascular complications were low (0.9%). PFOclosure with the AMPLATZER device in appro-priate patients thus appears to be associatedwith superior long-term outcomes comparedwith medical management alone.

ADVANCES IN CARDIOVASCULARPREVENTION

Diabetes Strategies

The STAMPEDE (Surgical Therapy And Medica-tions Potentially Eradicate Diabetes Efficiently)

Fig. 5 Watchman left atrial appendage closure deviceReproduced with permission from Boston Scientific

Adv Ther (2017) 34:1503–1527 1511

trial (NCT00432809) has previously reportedshort-term improvement in outcomes for over-weight patients with poorly controlled diabetesrandomized to bariatric surgery plus medicaltherapy (n = 100) or to medical therapy alone(n = 50), but long-term results were awaitedwith interest [45].

At 5 years, bariatric surgery was associatedwith greater weight reduction in body weight(-23%, -19%, and -5% in the gastric bypass,sleeve gastrectomy, and medical therapygroups, respectively), triglyceride level (-40%,-29%, and -8%), and a greater achievement ofthe primary endpoint of normoglycemiadefined as HbA1C B6.0% (29%, 23%, and 5%).While such metabolic improvements wouldhopefully be associated with improved CV out-comes, STAMPEDE was not powered to assessthis and larger studies of this promising tech-nique are planned.

While older hypoglycemic treatments fordiabetes have failed to show clear CV benefit,The sodium–glucose cotransporter 2 inhibitorempagliflozin did show reduction in CV death,but the mechanism was unclear given theabsence of reduction in MI or stroke [25].

While it was hoped that GLP-1 receptoragonists would be beneficial, the previousEvaluation of Lixisenatide in Acute CoronarySyndrome (ELIXA) trial in patients with dia-betes and a recent ACS failed to show CV benefit[46]. The Liraglutide Effect and Action in Dia-betes: Evaluation of Cardiovascular OutcomeResults (LEADER) trial randomized 9340patients with diabetes (HbA1c C7%) and highCV risk to liraglutide 1.8 mg once daily or pla-cebo [47]. Liraglutide was associated with asignificant reduction in the primary outcome ofCV death, MI, or stroke (13.0% vs 14.9%, HR0.87, 95% CI 0.78–0.97; p = 0.01), all-causemortality (8.2% vs 9.6%; p = 0.02), CV death(4.7% vs 6.0%; p = 0.007), and MI (6.3% vs7.3%; p = 0.046). No increase in heart failurewas reported (unlike with some DPP-4 inhibi-tors). Subsequently, semaglutide, which has anextended half-life allowing once-weeklyadministration, was evaluated in the Trial toEvaluate Cardiovascular and Other Long-termOutcomes with Semaglutide in Subjects withType 2 Diabetes (SUSTAIN-6) which

randomized 2735 patients (1:1:1:1) to either0.5 mg or 1.0 mg of once-weekly subcutaneousadministration of semaglutide or vol-ume-matched placebo. Semaglutide was associ-ated with a significant reduction in the primaryoutcome of CV death, MI, or stroke [6.6% vs8.9%; hazard ratio 0.74; 95% CI 0.58–0.95;p = 0.02] and reduction in stroke (1.6% vs 2.7%;p = 0.04) [48]. There was only a trend toreduced non-fatal MI (2.9% vs 3.9%, p = 0.12)and no difference in CV death or all-causemortality, although follow-up was relativelyshort at 2 years.

In summary, given their favorable CV bene-fits, empaglifozin, liraglutide, or possiblysemaglutide should now be considered as sec-ond-line therapy in diabetic patients at high CVrisk.

New Lipid-Lowering Strategies

Previous trials have demonstrated that highdose statins may be associated with reduction incoronary atherosclerosis volume as quantifiedby IVUS. PCSK9 (proprotein convertase subtil-isin/kexin type 9) inhibitors when added tostatin therapy are associated with marked fur-ther reductions in LDL-C, but it was not knownif this would be associated with further reduc-tion in atherosclerosis volume. The GLAGOVtrial (Global Assessment of Plaque RegressionWith a PCSK9 Antibody as Measured byIntravascular Ultrasound) randomized 968patients (baseline mean LDL-C level 2.4 mmol/l) with angiographically moderate coronaryatheroma to monthly evolocumab 420 mg orplacebo for 76 weeks in addition to moder-ate–high intensity statins. Evolocumab reducedLDL-C to an average of 0.94 mmol/l. On repeatIVUS at 78 weeks, percentage atheroma volume(primary endpoint) was decreased by 0.95%with evolocumab vs an increase of 0.05% withplacebo (between group difference 1.0%;p\0.001). Overall, plaque regression occurredin significantly more evolocumab patients(64.3% vs 47.3%; p\0.001) [49]. In anexploratory subgroup analysis of patientsalready achieving the current ESC treatmentgoal of LDL-C less than 1.8 mmol/l, those

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receiving evolocumab achieved a mean LDL-Cof 0.6 mmol/l which was associated with aneven greater regression of atheroma (-1.97%change in percentage atheroma volume and81% of patients showing regression). Giventhese IVUS findings and post hoc clinical out-comes observed in phase 2 trials, results of thephase 3 outcome trial are eagerly awaited.

Patients with heterozygous familial hyperc-holesterolemia (HeFH) and LDL-C levels toohigh to be controlled by statin alone may cur-rently be treated with serial lipoproteinapheresis which entails significant expense,patient inconvenience, and often lengthy travelto a regional lipid center. Given the markedLDL-C reduction possible with PCSK9 treat-ment, ODYSSEY-ESCAPE (NCT02326220) ran-domized HeFH patients undergoing lipoproteinapheresis in blinded fashion to alirocumab150 mg twice monthly vs placebo. Apheresiswas deferred if LDL-C was at least 30% lowerthan the baseline (pre-apheresis) value. Use ofalirocumab significantly reduced requirementfor apheresis with 63.4% of patients on alir-ocumab avoiding all and 92.7% avoiding atleast half of the apheresis treatments [50]. Thishas significant implications for HeFH patientsand may offer potential cost savings.

A further indication for PCSK9 inhibitionmaybe use in patients with statin intolerance.GAUSS-3 (NCT01984424) randomized 218patients prospectively confirmed during run in ashaving atorvastatin intolerance to evolocumab420 mg once monthly or ezetimibe 10 mg daily.As expected, by 24 weeks evolocumab showedsignificantly greater reduction in LDL-C (-52.8%vs -16.7%; p\0.001) but importantly there wasno signal of excess myalgia with evolocumab;indeed the rate of discontinuation for musclesymptoms was numerically less (0.7% vs 6.8%)[51].Thus, PCSK9 inhibitorsoffer anewtreatmentoption in selected patients with statinintolerance.

A novel approach for reducing PCSK9 activ-ity is to inhibit liver synthesis of PCSK9 by useof small interfering RNAs (siRNAs) whichselectively silence the translation of PCSK9messenger RNA (mRNA). Inclisiran, a chemi-cally synthesized siRNA, has been shown toproduced sustained hepatocyte-specific,

PCSK9-specific RNA silencing in healthy vol-unteers up to 84 days after administration(Fig. 6).

Prespecified 90-day interim analysis(n = 497) from the phase II ORION 1 trial pre-sented at AHA 2016 reported that a single doseof inclisiran 300 mg achieved a mean 51%LDL-C reduction at day 60 and 45% LDL-Creduction by day 90. A double 300 mg injectionstrategy, the first on day 1 and the second onday 90, achieved a mean LDL-C reduction of57% at day 120 and 52% LDL-C reduction byday 180 [52]. These results support an attractive4–6 monthly injection dosing schedule. Com-plete ORION 1 results are expected in 2017 andwill help guide the phase 3 clinical outcometrial programme.

While interest mounts in methods to targetthe PCSK9 pathway, it continues to waneregarding the cholesteryl ester transfer protein(CETP) pathway. CETP inhibition is associatedwith favorable effects on HDL-C, LDL-C,lipoprotein(a), and cholesterol efflux, but pre-vious studies have failed to demonstrate reduc-tion in MACE. Evacetrapib, a potent CETPinhibitor but which lacks off-target aldosteroneeffect seen with torcetrapib, was tested in thelarge phase III ACCELERATE (NCT01687998)trial. A total of 12,072 patients at high vascularrisk were randomized with evacetrapib achiev-ing a 130% increase in HDL-C and 37% reduc-tion in LDL-C vs placebo [53]. However, the trialwas stopped early because of futility with nosignificant difference in clinical outcomesdemonstrated.

Multi-Risk Factor Reduction

The importance of amulti-risk factor approach toCV risk reduction is well recognized. HOPE 3(NCT00468923) aimed to determine the CVbenefit of antihypertensives, rosuvastatin, ortheir combination in an ethnically diverse pop-ulation without previous CV disease recruitedbased onoverall intermediateCV risk rather thanrequiring specific BP or LDL-C levels. In total,12,705 patientswith amean BP of 138/82 mmHgandmean LDL-C of 3.2 mmHg were randomizedin 2 9 2 factorial trial design into three arms.

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After 5.6 years follow-up, in the first arm, anti-hypertensive treatment (hydrochlorothiazide12.5 mg, candesartan 16 mg) vs placebo whichachieved a mean BP reduction of 6/3 mmHgshowed no overall difference in the CV death,stroke, or MI (4.1% vs 4.4%), although in thehighest BP tertile (systolic BP [143.5 mmHg),there was 27% reduction (HR 0.73; 95% CI

0.56–0.94). Symptomatic hypotension was 1.7times more common with antihypertensivetherapy (3.4% vs 2.0%; p\0.001). In the secondarm, rosuvastatin 10 mg vs placebo was associ-atedwith a 24% reduction inCVdeath, stroke, orMI (3.7% vs 4.8%, HR 0.76, 95% CI 0.64–0.91;p = 0.002). In the third arm rosuvastatin plusantihypertensive therapy vs placebo was

Fig. 6 Inclisiran mechanism of action: a small interferingRNA (siRNA) which selectively and catalytically silencesthe translation of its target PCSK9-encoding messenger

RNA (mRNA) through the formation of effectorRNA-induced silencing complexes Reproduced with per-mission from N Engl J Med 2017; 376:4–7

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associated with a 29% in CV death, stroke, or MI(3.6% vs 5.0%, HR 0.71, 95% CI 0.56–0.9;p = 0.005) [54]. In summary, primary preventionwith statin therapy in this intermediate riskpopulation was effective, whereas antihyperten-sive therapy was not of benefit in the absence ofelevated BP but was associated with adverseevents which thus calls into question the need toroutinely include antihypertensives in a polypillapproach.

Cardiac rehabilitation following a CV eventis associated with improved outcomes but theoptimum duration is unknown. In the OPTI-CARE trial (NCT01395095), following ACS anda standard 3 months of cardiac rehabilitation,914 patients were randomized to no furthertherapy, an additional 9 months of group ther-apy or an additional 9 months of telephonesupport. Overall, the prolonged programmeswere not associated with further improvementin CV risk markers. However, compliance withthe prolonged programmes was suboptimal andwhen only those attending more than 75% ofsessions were assessed, an additional 9 monthsof group therapy was associated with a 37%reduction in smoking (13.4% vs 21.3%;p\0.001) and a 9% reduction in total choles-terol (3.9 vs 4.3 mmol/L; p\0.001) [55]. Thissuggests that in motivated patients, a 1-yeargroup rehabilitation programme may be ofadditional CV benefit. In contrast, additionaltelephone support was of unclear benefit.

ANTIPLATELET THERAPY

Given the increased risk of gastrointestinal (GI)hemorrhage with antiplatelet therapy, protonpump inhibitors (PPI) are often co-prescribedbut there has been concern about possibleinteraction via CYP3A4 reducing antiplateletefficacy particularly in high risk subgroups fol-lowing PCI or ACS [56].

An updated analysis from the Clopidogreland the optimization of gastrointestinal eventstrial (COGENT) (NCT00557921), which ran-domized patients receiving DAPT to omeprazolevs placebo, reported outcomes from PCI(n = 2676) and post ACS ± PCI (n = 1573) sub-groups [57]. In those who underwent PCI,

omeprazole was associated with a 56% reduc-tion in GI bleed/ulcers/erosive disease at180 days (1.2% vs 2.7%; p = 0.02) but no clearincrease in CV events (5.4% vs 6.3%; HR 1.00;95% CI 0.67–1.50; p = 1.00). In those who hadan ACS ± PCI (n = 1573) omeprazole was asso-ciated with a 59% reduction in GI bleed/ulcers/erosive disease at 180 days (1.1% vs 2.7%;p = 0.05) but no increase in CV events (5.6% vs4.5%; HR 1.40; 95% CI 0.77–2.53; p = 0.27).While the CV outcome data appear encourag-ing, the wide confidence limits mean it is notpossible to exclude the possibility of a clinicallyimportant interaction and when combiningwith DAPT it may still be prudent to select PPIsassociated with lower CYP3A4 interaction.

Although titration of antiplatelet doseaccording to platelet function testing has notbeen shown to improve clinical outcome inprevious studies, optimizing antiplateletanti-ischemic/bleeding balance may be moreimportant in the elderly, given their increasedrisk of ischemic and bleeding events. TheANTARCTIC (Platelet function monitoring toadjust antiplatelet therapy in elderly patientsstented for acute coronary syndrome) trial(NCT01538446) randomized 877 elderlypatients aged 75 years and over with ACSundergoing stenting to dose-adjusted anti-platelet treatment guided by platelet functiontests vs conventional treatment. Dosageincreases occurred in 45% of patients in themonitoring group. However, there was no dif-ference in the primary endpoint of CV death,MI, stroke, stent thrombosis, urgent revascu-larization, or bleeding complications betweengroups (28% vs 28%; p = 0.98) or in rates ofbleeding [58]. Thus, even in elderly patientsplatelet function testing did not appear usefulfor guiding antiplatelet dose adjustment.

Current ESC guidelines regarding P2Y12blockers advocate the use of either thethienopyridine drug prasugrel or thecyclopentyltriazolopyrimidine drug ticagrelorin patients with acute MI. Despite their molec-ular differences, they display similarly fast onsetand greater inhibition of platelet activity thanclopidogrel and it is unclear if one has a clinicaladvantage over the other. The PRAGUE 18(Prasugrel vs ticagrelor in patients with acute MI

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treated with primary percutaneous coronaryintervention) trial (NCT02808767) randomizedpatients with acute MI to prasugrel vs ticagrelorin addition to aspirin therapy. The trial wasdiscontinued prematurely after only 1230 of theplanned 2500 patients were enrolled on thebasis of futility due to a lack of significant dif-ference in the primary endpoint of death, rein-farction, urgent TVR, stroke, or serious bleeding[59]. While results support continued use ofboth agents, the study was underpowered todraw firm conclusions.

Ticagrelor has previously been shown to besuperior to clopidogrel for reducing cardiacevents but it was unclear if its benefits extendedto peripheral arterial disease. The EUCLID trial(Examining use of ticagrelor in peripheral arterydisease; NCT01732822) randomized 13,885patients with symptomatic peripheral arterydisease to receive either ticagrelor (90 mg twicedaily) or clopidogrel (75 mg daily) [60]. Unlikein the ACS setting, ticagrelor was not superior toclopidogrel with no difference in the primaryefficacy endpoint of CV death, MI, ischemicstroke (10.8% vs 10.6%), acute limb ischemia(1.7% vs 1.7%), or major bleeding (1.6% vs1.6%). Thus EUCLID does not support anychange to the current management of thesepatients.

ADVANCES IN HEART FAILURE

Neurohormonal modulation is central to con-temporary heart failure management. Hyper-kalemia may be a more frequent concern whencombining mineralocorticoid receptor antago-nists (MRA) with renin–angiotensin–aldos-terone inhibitors such as ACE inhibitors orangiotensin receptor/neprilysin inhibitors(ARNI). Within the PARADIGM-HF trial(Prospective Comparison of ARNI With an ACEInhibitor to Determine Impact on Global Mor-tality and Morbidity in Heart Failure;NCT01035255) 4671 patients were receiving anMRA at baseline [61]. The combination of MRAplus ARNI vs MRA plus ACE inhibitor wasassociated with similar incidence of any hyper-kalemia (potassium [5.5 mmol/L) but a lowerincidence of severe hyperkalemia (potassium

[6.0 mmol/L) (2.2 vs 3.1 per 100 patient-years;p = 0.02). In patients who newly started takingMRAs during the trial, severe hyperkalemia wasalso less common in those combining MRAwith ARNI rather than ACE inhibitor (2.3 vs 3.3per 100 patient-years; p = 0.003) suggestingneprilysin inhibition may facilitate safer use ofMRAs in patients at risk of hyperkalemia.

The direct renin inhibitor aliskiren repre-sents one of the most recent targets forrenin–angiotensin system blockade. TheATMOSPHERE trial (Aliskiren Trial to MinimizeOutcomes in Patients with Heart Failure;NCT00853658) randomized 7016 patients withstable NYHA class II–III heart failure, LVEF lessthan 35%, and raised BNP/NT pro-BNP to one ofthree groups: aliskiren 300 mg once daily oraliskiren plus enalapril 5–10 mg twice dailycombination therapy vs enalapril alone (stan-dard care). As a result of later safety concernsregarding aliskiren use in diabetic patients, thetrial was amended to exclude diabetics. At amean of 36.6 months follow-up, neither aliski-ren monotherapy nor aliskiren/enalapril com-bination therapy was superior to enalapril alonefor the primary endpoint of CV death or hos-pitalization for heart failure (33.8% vs 32.9% vs34.6%). However, combination therapy wasassociated with a higher incidence of increasedcreatinine or potassium and of hypotension[62]. Thus, given previous trial data, aliskirenremains primarily reserved as an option forhypertension.

MRAs have been extensively studied inchronic heart failure, but less so in acute heartfailure. In patients with acute heart failure,intravenous loop diuretics are central to usualcare but their use intensifies secondary hyper-aldosteronism, enhancing proximal tubularsodium absorption and decreased distal sodiumdelivery, thereby contributing to diuretic resis-tance. While low doses of MRAs used in chronicHF are believed to benefit patients primarily byantifibrotic effects, higher doses of MRAs maycause significant natriuresis. The ATHENA-HFtrial (Aldosterone Targeted NeuroHormonalCombined with Natriuresis therapy in Heartfailure; NCT02235077) randomized 360patients hospitalized with acute heart failure tohigh dose spironolactone 100 mg od for 96 h vs

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placebo in addition to standard care. Althoughhigh dose spironolactone was well tolerated, nosignificant difference in reduction ofNT-proBNP was observed (-0.55 vs -0.49;p = 0.57) [63]. Whether benefit would be seenby using higher spironolactone doses or by tar-geting patients with more marked fluid reten-tion remains unclear.

In addition to renin–angiotensin systemapproaches, modulation of autonomic nervoussystem imbalance is central to contemporaryheart failure management. Previous small stud-ies have reported possible positive benefits ofvagal nerve stimulation on ECHO reverseremodeling and quality of life parameters. TheINOVATE-HF trial (Increase of vagal tone incongestive heart failure; NCT01303718) ran-domized 707 patients with heart failure (NYHAIII, EF \40%) to device-mediated vagal nervestimulation (Biocontrol Cardiofit�, BiocontrolMedical, Yehud, Israel) (Fig. 7) vs medical ther-apy. Disappointingly, at 16 months, vagal nervestimulation vs placebo showed no difference inthe primary endpoint of death or first eventheart failure (25.8% vs 30.3%; p = 0.37) andalthough improvements in NYHA symptomclass, quality of life, and 6-min walk test(p\0.05) were reported, there was no differencein LV end-systolic volume index by ECHO [64].

Invasive monitoring of pulmonary arterypressure using permanently implanted deviceshas been shown to reduce acute heart failure

admissions [65]. The clinical usefulness ofnon-invasive lung impedance measurement (asa marker for lung fluid content) was assessed inthe IMPEDANCE-HF trial (Non-Invasive LungIMPEDANCE-Guided Pre-emptive Treatment inChronic Heart Failure Patients; NCT101315223)which randomized 256 with heart failure(NHYA II–IV, EF\35%) to management guidedby non-invasive lung impedance (LI) measure-ment plus clinical assessment vs clinical assess-ment alone. Use of LI was associated withincreased medication adjustment, a markedreduction in acute heart failure admissions (67vs 158, p\0.001 at 1 year; 211 vs 386, p\0.001at study end), and reduction in all-cause mor-tality [66]. Importantly, decreases in LIappeared to precede hospitalizations. While theLI device needs further study and comparisonwith other implantable hemodynamic moni-toring devices, IMPEDANCE HF supports theemerging evidence base that early detection ofsubtle hemodynamic deteriorations in heartfailure in the outpatient setting may improveboth clinical outcomes and cost-effectiveness ofheart failure management.

By contrast, the REM-HF trial (Remote Man-agement of Heart Failure UsingImplantable Devices; ISRCTN96536028) [67],which randomized 650 heart failure patientswith CRT-P, CRT-D, and implantable car-dioverter defibrillator (ICD) devices to weeklyremote data downloads vs usual care (3–6 monthly clinic data downloads), failed todemonstrate any reduction in all-cause mortal-ity or acute hospital admissions despite 70% ofpatients in the weekly download group havingalterations to treatment plans.

Current American and European guidelinessupport the implantation of a prophylacticcardio-defibrillator for patients with severe LVsystolic dysfunction. While survival benefit hasclearly been demonstrated in patients withischemic heart failure it is less clear whether thisextends to the non-ischemic population. TheDefibrillator implantation in patients withnon-ischemic systolic heart failure (DANISH)study (NCT00542945) randomized 1116patients with non-ischemic systolic heart failure(EF\35%) to ICD vs medical therapy alone. Useof ICD was not associated with a reduction in

Fig. 7 Biocontrol Cardiofit�. Reproduced with permis-sion Biocontrol Medical, Yehud, Israel

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the primary outcome of all-cause mortality at amean of 67.6 months (21.6% vs 23.4%;p = 0.28) and there was no difference in CVdeath (13.8% vs 17%; p = 0.1, 95% CI0.57–1.05), although the incidence of suddencardiac death was halved (4.3% vs 8.2%;p = 0.005, 95% CI 0.31–0.82) [68]. As the resultsof this trial are at odds with the previouslypublished SCD-HeFT [69] and DEFINITE [70]trials, further studies within non-ischemic heartfailure patients are required to help clarify thosewho benefit or otherwise from ICD.

An evolving field in heart failure researchinvolves the use of cardiopoietic stem cells.Isolation of mesenchymal stem cells from apatient’s own bone marrow may be exposed to acardiogenic cocktail turning them into car-diopoietic cells which can then be injected intodamaged heart tissue. The CHART-1 trial(Congestive Heart Failure Cardiopoietic Regen-erative Therapy; NCT01768702) study random-ized 271 patients with ischemiccardiomyopathy (LVEF B35%) to stem cellinjection (n = 120) vs a sham procedure [71]. At39 weeks, there was no difference in the primaryefficacy endpoint (death, worsening heart fail-ure, quality of life score, 6-min walk distance,LV end-systolic volume and LVEF). However,stem cell injection in the subgroup with base-line LV dilatation (LV end-diastolic volume200–370 mL) was associated with benefit(p = 0.015) and a lower injection intensity alsoappeared helpful; these findings will help shapethe design of the CHART-2 US study.

Iron deficiency is present in approximately50% of patients with chronic heart failurewhich may lead to reduced hemoglobin and toimpaired oxygen utilization at a tissue level. IVadministration of iron has previously beenshown to improve NYHA status (FAIR-HF) and6-min walk (CONFIRM-HF) [72]. The effect onpeak VO2 was assessed in EFFECT-HF (Effect ofFerric Carboxymaltose on Exercise Capacity inPatients With Iron Deficiency and ChronicHeart Failure; NCT01394562), which random-ized 174 patients with stable heart failure andiron deficiency to IV administration of ferriccarboxymaltose vs standard care. At 24 weeks,IV administration of iron was associated with amarked increase in ferritin and mean peak VO2

improved by 1.04 ± 0.44 mL/kg/min (95% CI0.16–1.91) vs standard care [73]. These phase IItrials are highly encouraging and larger trials arenow planned to assess the effect of IV admin-istration of iron on clinical outcomes.

However, regular IV administration of ironposes logistical challenges and is expensive;hence, oral administration of iron has beenused by some clinicians as a substitute. TheIRONOUT HF trial (Oral Iron Repletion effectON oxygen Uptake in Heart Failure) trial(NCT02188784) randomized 225 patients withstable heart failure to oral administration ofiron polysaccharide (150 mg twice daily) vsplacebo. Unfortunately, oral administration ofiron only increased ferritin by 11% (in keepingits known poor absorption in heart failurepatients) and at 16 weeks there was noimprovement in exercise capacity [74].Although the trial duration was short, theminimal response suggests that regular oraladministration of iron is unlikely to be effective.

Whilst much progress has been made overthe last two decades in chronic management ofheart failure patients, there have been limitedadvances in the acute setting. It has been sug-gested that early treatment during acutedecompensation might reduce acute LV dis-tension and thus reduce myocardial micro-in-jury and potentially improve later clinicaloutcomes. TRUE-AHF (Trial of Ularitide Efficacyand Safety in Heart Failure; NCT01661634)randomized 2157 patients with acute heartfailure to early (less than 12 h) treatment withthe synthetic natriuretic peptide ularitide vsplacebo. In keeping with previous vasodilatortrials, ularitide vs placebo was associated with a47% reduction in BNP and reduction in earlyheart failure events (55 vs 87; p = 0.005). How-ever, this was not associated with any differencein troponin release or longer-term clinical out-come [75]. Thus, the current role of vasodilatortherapy therefore appears to be confined tosymptomatic relief in acute heart failure.

Previous 5-year data from the STICH trial(Surgical Treatment for Ischemic Heart Failure)failed to demonstrate a mortality benefit forCABG among 1212 patients with severeischemic cardiomyopathy (LVEF \35%) ran-domized to CABG plus medical therapy (610

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patients) vs medical therapy alone (602patients). However, long-term data at a medianfollow-up of 9.8 years (range 3.5–13.4) pre-sented at the ACC (from 98% of patients)reported a 16% reduction in the primary out-come of all-cause mortality vs medical therapy(58.9% vs 66.1%; HR 0.84, CI 0.73–0.97;p = 0.02) and median survival was 7.73 years inthe CABG group vs 6.29 years in the medicaltherapy group. Thus if clinically appropriate,CABG remains preferable to conservative ther-apy for complex coronary disease and ischemiccardiomyopathy [76].

ADVANCES IN ARRHYTHMIAAND ELECTROPHYSIOLOGY

Atrial Fibrillation Detection

ESC guidelines recommend opportunisticscreening for AF in patients over 65 (level 1B) bymeans such as pulse assessment or rhythm stripanalysis, although it is recognized that this mayfail to detect many paroxysmal episodes ofsubclinical AF. Previous trials in patients withpacemakers or ICDs have shown that subclini-cal AF (atrial high rate episodes) is common andis associated with increased incidence of subse-quent stroke but the prevalence in patients notrequiring a device has been unknown. TheASSERT II trial (Prevalence of Sub-Clinical AtrialFibrillation Using an Implantable CardiacMonitor; NCT01694394) recruited 256 patientsaged 65 years and over with at least one clinicalrisk factor (CHADS2VASC C2, obstructive sleepapnea, or BMI[30) and one echo or biochemi-cal risk factor (left atrial diameter C4.4 cm, leftvolume C58 mL, or NT-ProBNP C290 pg/ml).All patients received an implantable loopmonitor (Confirm DM2100; St Jude Medical) forbetween 9 and 18 months. The annualizedincidence of subclinical AF of at least 5 min wascommon—observed in 34.4% of patients peryear—and was almost twice as common inpatients with left atrial volume greater than73.5 mL (51.9% vs 27.4%; p = 0.015) but, ofinterest, it was not any more common in thefifth of patients with a prior history of stroke[77]. Thus, it remains unclear if all subclinical

AF patients require anticoagulation, and furtherstudies are investigating this key questionincluding ARTESiA (Apixaban for the Reductionof Thrombo-Embolism in Patients WithDevice-Detected Sub-Clinical Atrial Fibrillation;NCT01938248) and NOAH (Non-vitamin KAntagonist Oral Anticoagulants in PatientsWith Atrial High Rate Episodes; NCT02618577).

Non-Vitamin K Antagonists (NOACs)

The use of non-vitamin K antagonist oral anti-coagulants (NOAC) has revolutionized antico-agulation in atrial fibrillation. However, manyconcerns still exist over the place of these agentsfollowing major bleeding, PCI, and in plannedcardioversion. Several trials presented in 2016aimed to address these specific areas.

Despite landmark clinical trial data, the pre-vious lack of specific NOAC reversal agents posedconcern for some clinicians. Idarucizumab isnow approved for reversal of dabigatran [25].Andexanet, a factor Xa decoy protein, has pre-viously been shown, among healthy volunteers,to reduce anti-Xa activity and to restore throm-bin generation. ANNEXA-4 (Andexanet Alfa forAcute Major Bleeding Associated with Factor XaInhibitors; NCT02329327) evaluated 67 patientswho had acute major bleeding within 18 h afterthe administration of a factor Xa inhibitor (ri-varoxaban, apixaban, or enoxaparin) [78]. Allreceived a 30-min bolus followed by a 2-h infu-sionof adexanet.Dosewasdeterminedon timingof last administrationof factorXa inhibitor. Afterthe bolus dose median anti-factor Xa activitydecreased by 89–93% (with similar suppressionmaintained during the 2-h infusion). By 4 h afterthe infusion there was partial recovery ofanti-factor Xa activity (30–39% reduction frombaseline) but by 12 h, 79% of patients hadachieved clinical hemostasis (Fig. 8).

Of note, thrombotic events occurred in 12patients and 10 died (six due to cardiac cause)during 30-day follow-up. Overall, andexanetappears a useful option although given theshort plasma half-lives of the anticoagulantsstudied, the relatively long median 4.8-h delayfrom presentation to the administration ofandexanet, and the absence of a placebo arm, it

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cannot be determined how many patientswould have achieved hemostatic efficacy with-out andexanet. Further refinements in theadministration of andexanet could lead to morecomplete reversal of anti-factor Xa activity andimproved clinical outcomes.

An ongoing important area of uncertaintyrelates to patients with AF undergoing PCI. Inthe absence of definitive trial data, current ESCrevascularization guidelines for non-ST eleva-tion MI [79] suggest different treatment strategyoptions: (class IIa) triple therapy (anticoagulant,

Fig. 8 Anti-factor Xa activity following Andexanet Alfa. Reproduced with permission from [78]

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aspirin plus clopidogrel) for 6 months inlow-bleeding-risk patients or for 1 month inhigh-bleeding-risk patients and (class IIb)anticogulation plus clopidogrel only as analternative to triple therapy in selected patients(based on WOEST study data).

PIONEER-AF (Patients with atrial fibrillationundergoing coronary stent placement;NCT01830543) is the first study to compare aNOAC with warfarin in this setting and ran-domized 2124 patients (Fig. 9) to (group 1,‘‘WOEST-like’’) rivaroxaban 15 mg once dailywith a single P2Y12 inhibitor for 12 months;(group 2, ‘‘ATLAS ACS 2-like’’) rivaroxaban2.5 mg twice daily with DAPT for 1, 6, or12 months at the operators discretion then, asneeded, rivaroxaban 15 mg once daily plusaspirin until 12 months; or (group 3, ‘‘tripletherapy’’) warfarin with DAPT for 1, 6, or12 months at the operator’s discretion then, asneeded, warfarin plus aspirin until 12 months[80]. DAPT duration was 1 month in 16%,6 months in 35%, and 12 months in 49%.Clopidogrel was the P2Y12 inhibitor used in95% of cases. Clinically relevant bleeding wasreduced in patients receiving rivaroxaban vswarfarin (group 1, 16.8% and group 2, 18% vsgroup 3, 26.7%; p\0.001 for both). TIMI majorbleeding was numerically less but not

significant (2.1% vs 1.9% vs 3.3%). Stentthrombosis rates were similar (0.8% vs 0.9% vs0.7%) and were equivalent between groups.Although the composite of CV death, MI, orstroke was similar between groups (6.5%, 5.6%vs 6.0%) the study was not powered to testefficacy and wide confidence limits could notexclude an excess of events with rivaroxaban.Reduced all-cause re-hospitalization withrivaroxaban was described in post hoc analysis.

It would be helpful to have further trialspowered for efficacy and to include a warfarin‘‘WOEST arm’’ (warfarin plus clopidogrel for12 months since this was associated withreduced MACE in WOEST). However, given thereduction in bleeding and convenience of asimple double therapy for 12 months ratherthan triple therapy with stepdown to double,rivaroxaban 15 mg once a day plus single anti-platelet therapy may become the approach ofchoice once approved.

Following a major bleeding event cliniciansare faced with the dilemma of whether torecommence anticoagulants. A recent USobservational study has suggested improvedoutcomes in those who are restarted on anti-coagulants following a bleeding event. A largeDanish registry study identified 2662 patientswith AF who had suffered a hemorrhagic stroke

Fig. 9 PIONEER AF trial design. *If creatine clearance 30–49 mL/min dose reduced to 10 mg od; �singleantiplatelet = clopidogrel 85%, prasugrel, or ticagrelor; VKA vitamin K antagonist, INR international normalized ratio

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or traumatic intracranial bleed while on anti-coagulants [81]. In those that restarted oralanticoagulants there was an overall reduction inall-cause mortality at a mean of 2.1 years fol-low-up. In those with hemorrhagic stroke therewas a non-significant trend towards increasedrisk of recurrent intracranial hemorrhage but nosignal was seen for those with prior traumaticintracranial bleed. Findings thus support reini-tiation of anticoagulants following intracranialhemorrhage but further work is required todetermine optimum timing of reinitiation andpatient risk stratification.

The use of NOACs in place of warfarin tosupport cardioversion has, to date, been basedon retrospective analysis of the general AF trialsand a smaller prospective study with rivaroxa-ban. ENSURE-AF (Edoxaban vs enoxa-parin–warfarin in patients undergoingcardioversion of atrial fibrillation;NCT02072434), the largest prospective trial tocompare a NOAC with optimized warfariniza-tion (including bridging enoxaparin until INRwas therapeutic for more than 2 days) random-ized 2199 patients to edoxaban vs warfarin. Thewarfarin group received optimized treatment.There was a non-significant numerical reduc-tion in the composite of CV death MI, stroke,embolism, or major bleeding (0.7% vs 1.4%; OR0.50, 95% CI 0.19–1.25) although ENSURE AFwas not powered to fully test these outcomes[82]. Edoxaban appeared similarly useful whe-ther cardioversion was undertaken after a con-ventional 3-week course of anticoagulation ortransesphageal echocardiogram-guided car-dioversion within a few days. Overall, this studyadds to previous trial data suggesting that aNOACs-supported approach appears an effec-tive alternative to conventional VKA-basedanticoagulation for pericardioversion use.

AF Ablation

Pulmonary vein isolation using radiofrequency(RF) ablation has become an established treat-ment for AF refractory to pharmacologicalmanagement, although the previous complex-ity and duration of the procedure have limitedits availability. An alternative method using

cryogenic energy delivered via balloon (cry-oballoon) offers a significantly reduced proce-dural time. The FIRE AND ICE trial(NCT01490814) randomized 762 patients tocryoballoon vs RF ablation. Cryotherapy wasassociated with shorter procedural time (124 vs14 min; p\0.001) [83]. At a mean of 1.5 years,there was no difference in the primary endpointof recurrence of atrial arrhythmia, use ofanti-arrhythmic agent, or repeat procedure(34.6% with cryoballoon cohort vs 35.9% withRF, CI 0.76–1.22; p\0.001 for non-inferiority).Phrenic nerve injury was seen in 2.7% of cry-oballoon cases, although all but one resolved by12 months. This trial further supports the use ofcryoballoon ablation as an option for AF abla-tion. The second-generation cryoballoon hasalso shown improvement in long-term pul-monary vein isolation likely attributable to theextensive wide-area circumferential ablationthat is achieved.

CONCLUSION

In this paper we have highlighted and summa-rized numerous important studies in the field ofcardiology which have been published and/orpresented to major international cardiologymeetings throughout 2016. Many of thesestudies will contribute to updating of currentpractice guidelines and others will play anintegral role in the advancement and develop-ment of new therapeutic strategies.

ACKNOWLEDGEMENTS

No funding or sponsorship was received for thisstudy or publication of this article. All namedauthors meet the International Committee ofMedical Journal Editors (ICMJE) criteria forauthorship for this manuscript, take responsi-bility for the integrity of the work as a whole,and have given final approval for the version tobe published.

Disclosures. Ian B. A. Menown reportsgrants to institution, honoraria and/or

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conference sponsorship from Biosensors, Bos-ton Scientific, Sanofi Aventis, Meril Life,Menarini, Orbus Neich, Astra Zeneca, Bayer,Boehringer Ingelheim, Daichii Sankyo, Lilly,Bristol Myers Squibb, and Pfizer. Alastair Grayand Conor McQuillan have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no new datasets weregenerated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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