Imperial College London

ProfessorDarrelFrancis

Faculty of MedicineNational Heart & Lung Institute

Professor of Cardiology
 
 
 
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Contact

 

+44 (0)20 7594 3381d.francis Website

 
 
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Assistant

 

Miss Juliet Holmes +44 (0)20 7594 5735

 
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Location

 

Block B Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

578 results found

Cook CM, Ahmad Y, Howard JP, Shun-Shin MJ, Sethi A, Clesham GJ, Tang KH, Nijjer SS, Kelly PA, Davies JR, Malik IS, Kaprielian R, Mikhail G, Petraco R, Al-Janabi F, Karamasis GV, Mohdnazri S, Gamma R, Al-Lamee R, Keeble TR, Mayet J, Sen S, Francis DP, Davies JE, Cook CM, Ahmad Y, James H, Shun-Shin M, Sethi A, Clesham G, Tang K, Nijjer S, Kelly P, Davies J, Malik I, Kaprielian R, Mikhail G, Petraco R, Al-Janabi F, Karamasis G, Mohdnazri S, Gamma R, Al-Lamee R, Keeble T, Mayet J, Sen S, Francis D, Davies Jet al., 2018, Impact of percutaneous revascularization on exercise hemodynamics in patients with stable coronary disease, Journal of the American College of Cardiology, Vol: 72, Pages: 970-983, ISSN: 0735-1097

BACKGROUND: Recently, the therapeutic benefits of percutaneous coronary intervention (PCI) have been challenged in patients with stable coronary artery disease (SCD). OBJECTIVES: The authors examined the impact of PCI on exercise responses in the coronary circulation, the microcirculation, and systemic hemodynamics in patients with SCD. METHODS: A total of 21 patients (mean age 60.3 ± 8.4 years) with SCD and single-vessel coronary stenosis underwent cardiac catheterization. Pre-PCI, patients exercised on a supine ergometer until rate-limiting angina or exhaustion. Simultaneous trans-stenotic coronary pressure-flow measurements were made throughout exercise. Post-PCI, this process was repeated. Physiological parameters, rate-limiting symptoms, and exercise performance were compared between pre-PCI and post-PCI exercise cycles. RESULTS: PCI reduced ischemia as documented by fractional flow reserve value (pre-PCI 0.59 ± 0.18 to post-PCI 0.91 ± 0.07), instantaneous wave-free ratio value (pre-PCI 0.61 ± 0.27 to post-PCI 0.96 ± 0.05) and coronary flow reserve value (pre-PCI 1.7 ± 0.7 to post-PCI 3.1 ± 1.0; p < 0.001 for all). PCI increased peak-exercise average peak coronary flow velocity (p < 0.0001), coronary perfusion pressure (distal coronary pressure; p < 0.0001), systolic blood pressure (p = 0.01), accelerating wave energy (p < 0.001), and myocardial workload (rate-pressure product; p < 0.01). These changes observed immediately following PCI resulted from the abolition of stenosis resistance (p < 0.0001). PCI was also associated with an immediate improvement in exercise time (+67 s; 95% confidence interval: 31 to 102 s; p < 0.0001) and a reduction in rate-limiting angina symptoms (81% reduction in rate-limiting angina symptoms post-PCI; p < 0.001). CONCLUSIONS: In patients with SCD and severe single-vessel stenosis, objective physiological

Journal article

Kyriacou A, Rajkumar CA, Pabari P, Sohaib SMA, Willson K, Peters N, Lim P, Kanagaratnam P, Hughes A, Mayet J, Whinnett Z, Francis Det al., 2018, Distinct impacts of heart rate and right atrial-pacing on left atrial mechanical activation and optimal AV delay in CRT, Pacing and Clinical Electrophysiology, Vol: 41, Pages: 959-966, ISSN: 0147-8389

AbstractBackgroundControversy exists regarding how atrial activation mode and heart rate affect optimal AV delay in cardiac resynchronisation therapy. We studied these questions using high‐reproducibility haemodynamic and echocardiographic measurements.Methods20 patients were hemodynamically optimized using non‐invasive beat‐to‐beat blood pressure at rest (62±11 bpm), during exercise (80±6 bpm) and at 3 atrially‐paced rates: 5, 25 and 45 bpm above rest, denoted Apaced,r+5, Apaced,r+25 and Apaced,r+45 respectively. Left atrial myocardial motion and transmitral flow were timed echocardiographically.ResultsDuring atrial‐sensing, raising heart rate shortened optimal AV delay by 25±6 ms (p < 0.001). During atrial pacing, raising heart rate from Apaced,r+5 to Apaced,r+25 shortened it by 16±6 ms; Apaced,r+45 shortened it 17±6 ms further (p < 0.001).In comparison to atrial‐sensed activation, atrial pacing lengthened optimal AV delay by 76±6 ms (p < 0.0001) at rest, and at ∼20 bpm faster, by 85±7 ms (p < 0.0001), 9±4 ms more (p = 0.017). Mechanically, atrial pacing delayed left atrial contraction by 63±5 ms at rest and by 73±5 ms (i.e. by 10±5 ms more, p < 0.05) at ∼20 bpm faster.Raising atrial rate by exercise advanced left atrial contraction by 7±2 ms (p = 0.001). Raising it by atrial pacing did not (p = 0.2).ConclusionsHemodynamic optimal AV delay shortens with elevation of heart rate. It lengthens on switching from atrial‐sensed to atrial‐paced at the same rate, and echocardiography shows this sensed‐paced difference in optima results from a sensed‐paced difference in atrial electromechanical delay.The reason for the widening of the sensed‐paced difference in AV optimum may be physiological stimuli (e.g. adrenergic drive) advancing left atrial contraction during exercise but not with fast atrial pacing.

Journal article

Shun-Shin M, Arnold A, Keene D, Howard J, Sohaib A, Lim PB, Tanner M, Lefroy D, Peters N, Kanagaratnam P, Davies DW, Francis D, Whinnett Zet al., 2018, The magnitude of LV activation time reduction with His bundle pacing over biventricular pacing in LBBB predicts the incremental improvement in acute cardiac function, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 385-385, ISSN: 0195-668X

Conference paper

Ahmad Y, Gotberg M, Malik IS, Mikhail GW, Howard JP, Demir OM, Petraco R, Iglesias JF, Francis DP, Mayet J, Davies JER, Sen Set al., 2018, Coronary haemodynamics in patients with severe aortic stenosis and coronary artery disease undergoing TAVI: implications for clinical indices of coronary stenosis severity, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 22-23, ISSN: 0195-668X

Conference paper

Accad M, Francis D, 2018, Does evidence based medicine adversely affect clinical judgment?, BMJ, Vol: 362, Pages: k2799-k2799

Journal article

Al-Lamee R, Howard JP, Shun-Shin MJ, Thompson D, Dehbi H-M, Sen S, Nijjer S, Petraco R, Davies J, Keeble T, Tang K, Malik IS, Cook C, Ahmad Y, Sharp ASP, Gerber R, Baker C, Kaprielian R, Talwar S, Assomull R, Cole G, Keenan NG, Kanaganayagam G, Sehmi J, Wensel R, Harrell FE, Mayet J, Thom SA, Davies JE, Francis DPet al., 2018, Fractional flow reserve and instantaneous wave-free ratio as predictors of the placebo-controlled response to percutaneous coronary intervention in stable single-vessel coronary artery disease: physiology-stratified analysis of ORBITA, Circulation, Vol: 138, ISSN: 0009-7322

BACKGROUND : There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. METHODS : We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. RESULTS : Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and

Journal article

Francis DP, Al-Lamee R, 2018, Percutaneous coronary intervention for stable angina in ORBITA Reply, LANCET, Vol: 392, Pages: 28-30, ISSN: 0140-6736

Journal article

Broyd CJ, Rigo F, Nijjer S, Sen S, Petraco R, Al-Lamee R, Foin N, Chukwuemeka A, Anderson J, Parker J, Malik IS, Mikhail GW, Francis DP, Parker K, Hughes AD, Mayet J, Davies JEet al., 2018, Regression of left ventricular hypertrophy provides an additive physiological benefit following treatment of aortic stenosis: Insights from serial coronary wave intensity analysis., Acta Physiologica, Vol: 2018, Pages: e13109-e13109, ISSN: 1748-1708

AIM: Severe aortic stenosis frequently involves the development of left ventricular hypertrophy (LVH) creating a dichotomous haemodynamic state within the coronary circulation. Whilst the increased force of ventricular contraction enhances its resultant relaxation and thus increases the distal diastolic coronary "suction" force, the presence of LVH has a potentially opposing effect on ventricular-coronary interplay. The aim of this study was to use non-invasive coronary wave intensity analysis (WIA) to separate and measure the sequential effects of outflow tract obstruction relief and then LVH regression following intervention for aortic stenosis. METHODS: Fifteen patients with unobstructed coronary arteries undergoing aortic valve intervention (11 surgical aortic valve replacement [SAVR], 4 TAVI) were successfully assessed before and after intervention, and at 6 and 12 months post-procedure. Coronary WIA was constructed from simultaneously acquired coronary flow from transthoracic echo and pressure from an oscillometric brachial cuff system. RESULTS: Immediately following intervention, a decline in the backward decompression wave (BDW) was noted (9.7 ± 5.7 vs 5.1 ± 3.6 × 103  W/m2 /s, P < 0.01). Over 12 months, LV mass index fell from 114 ± 19 to 82 ± 17 kg/m2 . Accompanying this, the BDW fraction increased to 32.8 ± 7.2% at 6 months (P = 0.01 vs post-procedure) and 34.7 ± 6.7% at 12 months (P < 0.001 vs post-procedure). CONCLUSION: In aortic stenosis, both the outflow tract gradient and the presence of LVH impact significantly on coronary haemodynamics that cannot be appreciated by examining resting coronary flow rates alone. An immediate change in coronary wave intensity occurs following intervention with further effects appreciable with hypertrophy regression. The improvement

Journal article

Jackson T, Lenarczyk R, Sterlinski M, Sokal A, Francis D, Whinnett Z, Van Heuverswyn F, Vanderheyden M, Heynens J, Stegemann B, Cornelussen R, Rinaldi CAet al., 2018, Left ventricular scar and the acute hemodynamic effects of multivein and multipolar pacing in cardiac resynchronization, IJC Heart and Vasculature, Vol: 19, Pages: 14-19, ISSN: 2352-9067

BackgroundWe sought to determine whether presence, amount and distribution of scar impacts the degree of acute hemodynamic response (AHR) with multisite pacing.Multi-vein pacing (MVP) or multipolar pacing (MPP) with a multi-electrode left ventricular (LV) lead may offer benefits over conventional biventricular pacing in patients with myocardial scar.MethodsIn this multi-center study left bundle branch block patients underwent an hemodynamic pacing study measuring LV dP/dtmax. Patients had cardiac magnetic resonance scar imaging to assess the effect of scar presence, amount and distribution on AHR.Results24 patients (QRS 171 ± 20 ms) completed the study (83% male). An ischemic etiology was present in 58% and the mean scar volume was 6.0 ± 7.0%. Overall discounting scar, MPP and MVP showed no significant AHR increase compared to an optimized “best BiV” (BestBiV) site. In a minority of patients (6/24) receiver-operator characteristic analysis of scar volume (cut off 8.48%) predicted a small AHR improvement with MPP (sensitivity 83%, specificity 94%) but not MVP. Patients with scar volume > 8.48% had a MPP-BestBiV of 3 ± 6.3% vs. −6.4 ± 7.7% for those below the cutoff. There was a significant correlation between the difference in AHR and scar volume for MPP-BestBiV (R = 0.49, p = 0.02) but not MVP-BestBiV(R = 0.111, p = 0.62). The multielectrode lead positioned in scar predicted MPP AHR improvement (p = 0.04).ConclusionsMultisite pacing with MPP and MVP shows no AHR benefit in all-comers compared to optimized BestBiV pacing. There was a minority of patients with significant scar volume in relation to the LV site that exhibited a small AHR improvement with MPP.

Journal article

Whinnett Z, Sohaib SMA, Mason M, Duncan E, Tanner M, Lefroy D, Al-Obaidi M, Ellery S, Leyva-Leon F, Betts T, Dayer M, Foley P, Swinburn J, Thomas M, Khiani R, Wong T, Yousef Z, Rogers D, Kalra P, Dhileepan V, March K, Howard J, Kyriacou A, Mayet J, Kanagaratnam P, Frenneaux M, Hughes A, Francis Det al., 2018, Multicenter randomized controlled crossover trial comparing hemodynamic optimization against echocardiographic optimization of AV and VV delay of Cardiac Resynchronization Therapy: The BRAVO Trial, JACC: Cardiovascular Imaging, ISSN: 1936-878X

ObjectivesBRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method.BackgroundCardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform.MethodsThis study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro–B-type natriuretic peptide.ResultsA total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro–B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms.ConclusionsOptimization of cardiac resynchronization therapy

Journal article

Arnold AD, Shun-Shin MJ, Keene D, Howard J, Lefroy DC, Davies DW, Lim PH, Kanagaratnam P, Koa-Wing M, Wright IJ, Qureshi NA, Tanner MA, Muthumala AG, Linton N, Peters NS, Francis DP, Whinnett ZIet al., 2018, His bundle pacing can overcome left bundle branch block to produce greater improvements in acute haemodynamic function and ventricular activation than biventricular pacing, Heart Rhythm Society Scientific Sessions, Publisher: Elsevier, Pages: S40-S41, ISSN: 1547-5271

Conference paper

Kikuta Y, Cook CM, Sharp ASP, Salinas P, Kawase Y, Shiono Y, Giavarini A, Nakayama M, De Rosa S, Sen S, Nijjer SS, Al-Lamee R, Petraco R, Malik IS, Mikhail GW, Kaprielian RR, Wijntjens GWM, Mori S, Hagikura A, Mates M, Mizuno A, Hellig F, Lee K, Janssens L, Horie K, Mohdnazri S, Herrera R, Krackhardt F, Yamawaki M, Davies J, Takebayashi H, Keeble T, Haruta S, Ribichini F, Indolfi C, Mayet J, Francis DP, Piek JJ, Di Mario C, Escaned J, Matsuo H, Davies JEet al., 2018, Pre-Angioplasty Instantaneous Wave-Free Ratio Pullback Predicts Hemodynamic Outcome In Humans With Coronary Artery Disease Primary Results of the International Multicenter iFR GRADIENT Registry, JACC-CARDIOVASCULAR INTERVENTIONS, Vol: 11, Pages: 757-767, ISSN: 1936-8798

ObjectivesThe authors sought to evaluate the accuracy of instantaneous wave-Free Ratio (iFR) pullback measurements to predict post-percutaneous coronary intervention (PCI) physiological outcomes, and to quantify how often iFR pullback alters PCI strategy in real-world clinical settings.BackgroundIn tandem and diffuse disease, offline analysis of continuous iFR pullback measurement has previously been demonstrated to accurately predict the physiological outcome of revascularization. However, the accuracy of the online analysis approach (iFR pullback) remains untested.MethodsAngiographically intermediate tandem and/or diffuse lesions were entered into the international, multicenter iFR GRADIENT (Single instantaneous wave-Free Ratio Pullback Pre-Angioplasty Predicts Hemodynamic Outcome Without Wedge Pressure in Human Coronary Artery Disease) registry. Operators were asked to submit their procedural strategy after angiography alone and then after iFR-pullback measurement incorporating virtual PCI and post-PCI iFR prediction. PCI was performed according to standard clinical practice. Following PCI, repeat iFR assessment was performed and the actual versus predicted post-PCI iFR values compared.ResultsMean age was 67 ± 12 years (81% male). Paired pre- and post-PCI iFR were measured in 128 patients (134 vessels). The predicted post-PCI iFR calculated online was 0.93 ± 0.05; observed actual iFR was 0.92 ± 0.06. iFR pullback predicted the post-PCI iFR outcome with 1.4 ± 0.5% error. In comparison to angiography-based decision making, after iFR pullback, decision making was changed in 52 (31%) of vessels; with a reduction in lesion number (−0.18 ± 0.05 lesion/vessel; p = 0.0001) and length (−4.4 ± 1.0 mm/vessel; p < 0.0001).ConclusionsIn tandem and diffuse coronary disease, iFR pullback predicted the physiological outcome of PCI with a high degree of accuracy. Compared with angiography alone, availability of iFR pullback

Journal article

Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran Ket al., 2018, Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis, JAMA: Journal of the American Medical Association, Vol: 319, Pages: 1580-1591, ISSN: 0098-7484

Importance The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.Objective To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.Data Sources MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.Study Selection Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.Data Extraction and Synthesis Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.Main Outcomes and Measures The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.Results This network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors (absolute risk difference [RD], −1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, −0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, −0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, −0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11

Journal article

Rajkumar CA, Nijjer SS, Cole GD, Al-Lamee R, Francis DPet al., 2018, Moving the goalposts into unblinded territory: lessons of DEFER and FAME 2 and their implications for shifting end points in ISCHEMIA, Circulation: Cardiovascular Quality and Outcomes, Vol: 11, ISSN: 1941-7705

At its conception, a randomized controlled trial is carefully designed to detect a significant effect of an intervention on a prespecified primary end point. Each aspect of a trial is deliberately constructed to allow it to answer this principal question. From the moment the first patient is recruited, the primary end point is fixed, and all other outcomes are considered secondary.

Journal article

Khan HR, Kralj-Hans I, Haldar S, Bahrami T, Clague J, De Souza A, Francis D, Hussain W, Jarman J, Jones DG, Mediratta N, Mohiaddin R, Salukhe T, Jones S, Lord J, Murphy C, Kelly J, Markides V, Gupta D, Wong Tet al., 2018, Catheter ablation versus thoracoscopic surgical ablation in long standing persistent atrial fibrillation (CASA-AF): study protocol for a randomised controlled trial, Trials, Vol: 19, ISSN: 1745-6215

BACKGROUND: Atrial fibrillation is the commonest arrhythmia which raises the risk of heart failure, thromboembolic stroke, morbidity and death. Pharmacological treatments of this condition are focused on heart rate control, rhythm control and reduction in risk of stroke. Selective ablation of cardiac tissues resulting in isolation of areas causing atrial fibrillation is another treatment strategy which can be delivered by two minimally invasive interventions: percutaneous catheter ablation and thoracoscopic surgical ablation. The main purpose of this trial is to compare the effectiveness and safety of these two interventions. METHODS/DESIGN: Catheter Ablation versus Thoracoscopic Surgical Ablation in Long Standing Persistent Atrial Fibrillation (CASA-AF) is a prospective, multi-centre, randomised controlled trial within three NHS tertiary cardiovascular centres specialising in treatment of atrial fibrillation. Eligible adults (n = 120) with symptomatic, long-standing, persistent atrial fibrillation will be randomly allocated to either catheter ablation or thoracoscopic ablation in a 1:1 ratio. Pre-determined lesion sets will be delivered in each treatment arm with confirmation of appropriate conduction block. All patients will have an implantable loop recorder (ILR) inserted subcutaneously immediately following ablation to enable continuous heart rhythm monitoring for at least 12 months. The devices will be programmed to detect episodes of atrial fibrillation and atrial tachycardia ≥ 30 s in duration. The patients will be followed for 12 months, completing appropriate clinical assessments and questionnaires every 3 months. The ILR data will be wirelessly transmitted daily and evaluated every month for the duration of the follow-up. The primary endpoint in the study is freedom from atrial fibrillation and atrial tachycardia at the end of the follow-up period. DISCUSSION: The CASA-AF Trial is a National Institute for Health

Journal article

Ahmad Y, Demir O, Rajkumar CA, Howard J, Shun-Shin M, Cook C, Petraco R, Jabbour R, Arnold A, Frame A, Sutaria N, Ariff B, Kanaganayagam G, Francis D, Mayet J, Mikhail G, Malik I, Sen Set al., 2018, Optimal antiplatelet strategy after transcatheter aortic valve implantation: a meta-analysis, Open Heart, Vol: 5, ISSN: 2053-3624

Objective International guidelines recommend the use of dual antiplatelet therapy (DAPT) after transcatheter aortic valve implantation (TAVI). The recommended duration of DAPT varies between guidelines. In this two-part study, we (1) performed a structured survey of 45 TAVI centres from around the world to determine if there is consensus among clinicians regarding antiplatelet therapy after TAVI; and then (2) performed a systematic review of all suitable studies (randomised controlled trials (RCTs) and registries) to determine if aspirin monotherapy can be used instead of DAPT.Methods A structured electronic survey regarding antiplatelet use after TAVI was completed by 45 TAVI centres across Europe, Australasia and the USA. A systematic review of TAVI RCTs and registries was then performed comparing DAPT duration and incidence of stroke, bleeding and death. A variance weighted least squared metaregression was then performed to determine the relationship of antiplatelet therapy and adverse events.Results 82.2% of centres routinely used DAPT after TAVI. Median duration was 3 months. 13.3% based their practice on guidelines. 11 781 patients (26 studies) were eligible for the metaregression. There was no benefit of DAPT over aspirin monotherapy for stroke (P=0.49), death (P=0.72) or bleeding (P=0.91).Discussion Aspirin monotherapy appears to be as safe and effective as DAPT after TAVI.

Journal article

Petraco Da Cunha R, Dehbi H-M, Howard J, Shun-Shin MJ, Sen S, Nijjer S, Mayet J, Davies JE, Francis DFet al., 2018, Effects of disease severity distribution on the performance of quantitative diagnostic methods and proposal of a novel ‘V-plot’ methodology to display accuracy values, Open Heart, Vol: 5, ISSN: 2053-3624

Background Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test’s performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests.Methods and findings We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Cholrapid and Cholgold) by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V-plot of accuracies).Conclusion No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard.

Journal article

Panoulas VF, Francis DP, Ruparelia N, Malik IS, Chukwuemeka A, Sen S, Anderson J, Nihoyannopoulos P, Sutaria N, Hannan EL, Samadashvili Z, D'Errigo P, Schymik G, Mehran R, Chieffo A, Latib A, Presbitero P, Mehilli J, Petronio AS, Morice M-C, Tamburino C, Thyregod HGH, Leon M, Colombo A, Mikhail GWet al., 2018, Female-specific survival advantage from transcatheter aortic valve implantation over surgical aortic valve replacement: Meta-analysis of the gender subgroups of randomised controlled trials including 3758 patients, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 250, Pages: 66-72, ISSN: 0167-5273

Journal article

Cook CM, Jeremias A, Petraco R, Sen S, Nijjer S, Shun-Shin MJ, Ahmad Y, de Waard G, van de Hoef T, Echavarria-Pinto M, van Lavieren M, Al Lamee R, Kikuta Y, Shiono Y, Buch A, Meuwissen M, Danad I, Knaapen P, Maehara A, Koo B-K, Mintz GS, Escaned J, Stone GW, Francis DP, Mayet J, Piek JJ, van Royen N, Davies JEet al., 2017, Fractional Flow Reserve/Instantaneous Wave-Free Ratio Discordance in Angiographically Intermediate Coronary Stenoses: An Analysis Using Doppler-Derived Coronary Flow Measurements, JACC: Cardiovascular Interventions, Vol: 10, Pages: 2514-2524, ISSN: 1936-8798

ObjectivesThe study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR).BackgroundDiscordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels.MethodsBaseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFR+/iFR+ (108 vessels, n = 91), FFR–/iFR+ (28 vessels, n = 24), FFR+/iFR– (22 vessels, n = 22), FFR–/iFR– (208 vessels, n = 154), and an unobstructed vessel group (201 vessels, n = 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch-English] collaborators study).ResultsFFR disagreed with iFR in 14% (50 of 366). Baseline flow velocity was similar across all 5 vessel groups, including the unobstructed vessel group (p = 0.34 for variance). In FFR+/iFR– discordants, hyperemic flow velocity and CFR were similar to both FFR–/iFR– and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR–/iFR+ discordants, hyperemic flow velocity, and CFR were similar to the FFR+/iFR+ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all).ConclusionsFFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFR+/iFR– demonstrated similar coronary flow characteristics to angiographically unobstructed vessels.

Journal article

Al-Lamee R, Francis DP, 2017, Swimming against the tide: insights from the ORBITA trial, Eurointervention, Vol: 13, Pages: E1373-E1375, ISSN: 1774-024X

Journal article

Al-Lamee R, Thompson D, Dehbi H-M, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP, ORBITA investigatorset al., 2017, Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial., Lancet, Vol: 391, Pages: 31-40, ISSN: 0140-6736

BACKGROUND: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding

Journal article

Leong KMW, Ng FS, Roney C, Cantwell C, Shun-Shin M, Linton N, Whinnett Z, Lefroy D, Davies DW, Harding S, Lim PB, Francis D, Peters N, Varnava A, Kanagaratnam P, Leong KM, Ng FS, Roney C, Cantwell C, Shun-Shin MJ, Linton NW, Whinnett ZI, Lefroy DC, Davies DW, Harding SE, Lim PB, Francis D, Peters NS, Varnava AM, Kanagaratnam Pet al., 2017, Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts, Journal of Cardiovascular Electrophysiology, Vol: 29, Pages: 115-126, ISSN: 1045-3873

BACKGROUND: Models of cardiac arrhythmogenesis predict that non-uniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by non-invasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress. METHODS: ECGi was applied to 11 SCD survivors, 10 low-risk Brugada Syndrome patients (BrS) and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and > 1200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak-end intervals) were also calculated for all patients for comparison. RESULTS: Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13±8 ms vs 4±7 ms vs 4±5 ms; p = 0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarisation were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups. CONCLUSION: Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk-stratification techniques. This article is protected by copyright. All rights reserved.

Journal article

Mielewczik M, Francis D, Studer B, Simunek MVet al., 2017, Die Rezeption von Gregor Mendels Hybridisierungsversuchen im 19. Jahrhundert–Eine bio-bibliographische Studie, Nova acta Leopoldina : Abhandlungen der Kaiserlich Leopoldinisch-Carolinisch Deutschen Akademie der Naturforscher, Vol: 413, Pages: 83-134, ISSN: 0369-5034

Journal article

Gronda E, Francis D, Zannad F, Hamm C, Brugada J, Vanoli Eet al., 2017, Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction, Journal of Cardiovascular Medicine, Vol: 18, Pages: 641-649, ISSN: 1558-2027

Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.

Journal article

Sikkel MB, Francis DP, Howard J, Gordon F, Rowlands C, Peters NS, Lyon AR, Harding SE, MacLeod KTet al., 2017, Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies, Cardiovascular Research, Vol: 113, Pages: 1743-1752, ISSN: 1755-3245

AimsIt is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests).Methods and resultsCa2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF.Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF.ConclusionCa2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for relia

Journal article

Shun-Shin MJ, Francis DP, 2017, Is this muscle pain caused by my statin?, BMJ, Vol: 357, ISSN: 0959-8138

Journal article

Zaman S, Zaman S, Scholtes T, Shun-Shin MJ, Plymen CM, Francis DP, Cole GDet al., 2017, The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets, European Journal of Heart Failure, Vol: 19, Pages: 1401-1409, ISSN: 1879-0844

Aims: The prescription of optimal medical therapy for heart failure is often delayed despite compelling evidence of the reductions in mortality it may facilitate. We calculated the absolute risk resulting from delayed prescription of therapy. For comparison, we established the threshold applied by clinicians when discussing the risk for death associated with an intervention, and the threshold used in of ficial patient information leaflets.Methods and results:We undertook a meta-analysis of randomized controlled trials to calculate the excess mortality caused by deferral of medical therapy for 1 year. Risk ratios for angiotensin-converting enzyme inhibitors, beta-blockers and aldosterone antagonists were 0.80, 0.73 and 0.77, respectively. In patients who might achieve a 1-year survival rate of 90% if treated, a 1-year deferral of treatment reduced survival to 78% (i.e. an annual absolute increase in mortality of 12 in 100 patients). This corresponds to an additional absolute mortality risk per month of 1%. A survey of clinicians carried out to establish the risk threshold at which they would obtain written consent showed the majority (85%) sought written consent for interventions associated with a 12-fold lower mortality risk: one in 100 patients. A systematic review of UK patient information leaflets to establish the magnitude of risk considered sufficient to be stated explicitly showed that leaflets begin to mention death at a ∼18 000-fold lower mortality risk of just 0.0007 in 100 patients.Conclusions:Deferring heart failure treatment for 1 year carries far greater risk than the level at which most doctors seek written consent, and 18000 times more risk than the level at which patient information leaflets begin to mention death.

Journal article

Zolgharni M, Negoita M, Dhutia NM, Mielewczik M, Manoharan K, Sohaib SMA, Finegold JA, Sacchi S, Cole GD, Francis DPet al., 2017, Automatic detection of end-diastolic and end-systolic frames in 2D echocardiography, ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES, Vol: 34, Pages: 956-967, ISSN: 0742-2822

Background:Correctly selecting the end-diastolic and end-systolic frames on a 2D echocardiogram is important and challenging, for both human experts and automated algorithms. Manual selection is time-consuming and subject to uncertainty, and may affect the results obtained, especially for advanced measurements such as myocardial strain.Methods and Results:We developed and evaluated algorithms which can automatically extract global and regional cardiac velocity, and identify end-diastolic and end-systolic frames. We acquired apical four-chamber 2D echocardiographic video recordings, each at least 10 heartbeats long, acquired twice at frame rates of 52 and 79 frames/s from 19 patients, yielding 38 recordings. Five experienced echocardiographers independently marked end-systolic and end-diastolic frames for the first 10 heartbeats of each recording. The automated algorithm also did this. Using the average of time points identified by five human operators as the reference gold standard, the individual operators had a root mean square difference from that gold standard of 46.5 ms. The algorithm had a root mean square difference from the human gold standard of 40.5 ms (P<.0001). Put another way, the algorithm-identified time point was an outlier in 122/564 heartbeats (21.6%), whereas the average human operator was an outlier in 254/564 heartbeats (45%).Conclusion:An automated algorithm can identify the end-systolic and end-diastolic frames with performance indistinguishable from that of human experts. This saves staff time, which could therefore be invested in assessing more beats, and reduces uncertainty about the reliability of the choice of frame.

Journal article

Cook CM, Petraco R, Shun-Shin MJ, Ahmad Y, Nijjer S, Al-Lamee R, Kikuta Y, Shiono Y, Mayet J, Francis DP, Sen S, Davies JEet al., 2017, Diagnostic accuracy of computed tomography-derived fractional flow reserve a systematic review, JAMA Cardiology, Vol: 2, Pages: 803-810, ISSN: 2380-6591

Importance Computed tomography–derived fractional flow reserve (FFR-CT) is a novel, noninvasive test for myocardial ischemia. Clinicians using FFR-CT must be able to interpret individual FFR-CT results to determine subsequent patient care.Objective To provide clinicians a means of interpreting individual FFR-CT results with respect to the range of invasive FFRs that this interpretation might likely represent.Evidence Review We performed a systematic review in accordance with guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic search of MEDLINE (January 1, 2011, to 2016, week 2) and EMBASE (January 1, 2011, to 2016, week 2) was performed for studies assessing the diagnostic accuracy of FFR-CT. Title words used were computed tomography or computed tomographic and fractional flow reserve or FFR. Results were limited to publications in peer-reviewed journals. Duplicate studies and abstracts from scientific meetings were removed. All of the retrieved studies, including references, were reviewed.Findings There were 908 vessels from 536 patients in 5 studies included in the analysis. A total of 365 (68.1%) were male, and the mean (SD) age was 63.2 (9.5) years. The overall per-vessel diagnostic accuracy of FFR-CT was 81.9% (95% CI, 79.4%-84.4%). For vessels with FFR-CT values below 0.60, 0.60 to 0.70, 0.70 to 0.80, 0.80 to 0.90, and above 0.90, diagnostic accuracy of FFR-CT was 86.4% (95% CI, 78.0%-94.0%), 74.7% (95% CI, 71.9%-77.5%), 46.1% (95% CI, 42.9%-49.3%), 87.3% (95% CI, 85.1%-89.5%), and 97.9% (95% CI, 97.9%-98.8%), respectively. The 82% (overall) diagnostic accuracy threshold was met for FFR-CT values lower than 0.63 or above 0.83. More stringent 95% and 98% diagnostic accuracy thresholds were met for FFR-CT values lower than 0.53 or above 0.93 and lower than 0.47 or above 0.99, respectively.Conclusions and Relevance The diagnostic accuracy of FFR-CT varies markedly across the spectrum of disease. This ana

Journal article

Shun-Shin MJ, Zheng S, Cole G, Howard J, Whinnett Z, Francis Det al., Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials, European Heart Journal, Vol: 38, Pages: 1738-1746, ISSN: 1522-9645

AimsPrimary prevention implantable cardioverter defibrillators (ICDs) are established therapy for reducing mortality in patients with left ventricular systolic dysfunction and ischaemic heart disease (IHD). However, their efficacy in patients without IHD has been controversial. We undertook a meta-analysis of the totality of the evidence.Methods We systematically identified all RCTs comparing ICD versus no ICD in primary prevention. Eligible RCTs were those that recruited patients with left ventricular dysfunction, reported all-cause mortality, and presented their results stratified by the presence of IHD (or recruited only those with or without). Our primary endpoint was all-cause mortality.ResultsWe identified 11 studies enrolling 8567 participants with left ventricular dysfunction, including 3128 patients without IHD and 5439 patients with IHD. In patients without IHD, ICD therapy reduced mortality by 24% (HR 0.76, 95% CI 0.64 to 0.90 p=0.001). In patients with IHD, ICD implantation (at a dedicated procedure), also reduced mortality by 24% (HR 0.76, 95% CI 0.60 to 0.96, p=0.02).ConclusionsUntil now, it has never been explicitly stated that the patients without IHD in COMPANION showed significant survival benefit from adding ICD therapy (to a background of CRT). Furthermore, even with only the trials before DANISH, meta-analysis shows reduced mortality. DANISH is consistent with these data.With a significant 24% mortality reduction in both aetiologies, it may no longer be necessaryto distinguish between them when deciding on primary prevention ICD implantation.

Journal article

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