Adeel Shahzad

Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial

BACKGROUND Bivalirudin, with selective use of glycoprotein (GP) IIb/IIIa inhibitor agents, is an accepted standard of care in primary percutaneous coronary intervention (PPCI). We aimed to compare antithrombotic therapy with bivalirudin or unfractionated heparin during this procedure. METHODS In our open-label, randomised controlled trial, we enrolled consecutive adults scheduled for angiography in the context of a PPCI presentation at Liverpool Heart and Chest Hospital (Liverpool, UK) with a strategy of delayed consent. Before angiography, we randomly allocated patients (1:1; stratified by age [<75 years vs ≥75 years] and presence of cardiogenic shock [yes vs no]) to heparin (70 U/kg) or bivalirudin (bolus 0·75 mg/kg; infusion 1·75 mg/kg per h). Patients were followed up for 28 days. The primary efficacy outcome was a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation. The primary safety outcome was incidence of major bleeding (type 3-5 as per Bleeding Academic Research Consortium definitions). This study is registered with ClinicalTrials.gov, number NCT01519518. FINDINGS Between Feb 7, 2012, and Nov 20, 2013, 1829 of 1917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8·7%) of 905 patients in the bivalirudin group and 52 (5·7%) of 907 patients in the heparin group (absolute risk difference 3·0%; relative risk [RR] 1·52, 95% CI 1·09-2·13, p=0·01). The primary safety outcome occurred in 32 (3·5%) of 905 patients in the bivalirudin group and 28 (3·1%) of 907 patients in the heparin group (0·4%; 1·15, 0·70-1·89, p=0·59). INTERPRETATION Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially. FUNDING Liverpool Heart and Chest Hospital, UK National Institute of Health Research, The Medicines Company, AstraZeneca, The Bentley Drivers Club (UK).

Radiofrequency ablation of the interventricular septum to treat outflow tract gradients in hypertrophic obstructive cardiomyopathy: a novel use of CARTOSound® technology to guide ablation.

AIMS Septal reduction is needed for hypertrophic obstructive cardiomyopathy (HOCM) patients with severe left ventricular outflow tract (LVOT) gradients and symptoms despite medication. Myectomy cannot be performed in all. Alcohol septal ablation cannot be performed in 5-15% due to technical difficulties. A method of delivering percutaneous tissue damage to the septum that is not reliant on coronary anatomy is desirable. To directly ablate the interventricular septum at the mitral valve (MV) systolic anterior motion (SAM)-septal contact point using radiofrequency (RF) energy guided by CARTOSound. METHODS AND RESULTS Five patients underwent RF ablation (RFA); we describe follow-up at 6 months in four patients. Intracardiac echocardiography (ICE) images are merged with CARTO to create a shell of the cardiac chambers. The SAM-septal contact area is marked from ICE images and mapped on to the CARTO shell; this becomes the target for RF delivery. Conduction tissue is mapped and avoided where possible. Twenty-eight to 42 min of RF energy was delivered to the target area using retrograde aortic access and SmartTouch catheters. Resting LVOT gradient improved from 64.2 (±50.6) to 12.3 (±2.5) mmHg. Valsalva/exercise-induced gradient reduced from 93.5 (±30.9) to 23.3 (±8.3) mmHg. Three patients improved New York Heart Association status from III to II, one patient improved from class III to I. Exercise time on bicycle ergometer increased from 612 to 730 s. Cardiac magnetic resonance shows late gadolinium enhancement up to 8 mm depth at LV target myocardium. One patient died following a significant retroperitoneal haemorrhage. CONCLUSION Radiofrequency ablation using CARTOSound(®) guidance is accurate and effective in treating LVOT gradients in HOCM in this preliminary group of patients.

Computed tomography angiography planning identifies the target vessel for optimum infarct location and improves clinical outcome in alcohol septal ablation for hypertrophic obstructive cardiomyopathy

AIMS Alcohol septal ablation (ASA) is an established treatment option in hypertrophic obstructive cardiomyopathy (HOCM). ASA is ineffective in some: inaccurate infarct and inability to identify a vessel contribute. We aimed to improve accuracy of infarct using CT angiography guidance and provide a more predictable and satisfactory outcome. METHODS AND RESULTS Twenty-one successive patients with symptomatic LVOT obstruction refractory to medication underwent CT angiography planning to guide ASA. CT was performed using a dual-source CT system. Alcohol was delivered to the artery identified from CT: in 17/21 this was a sub-branch of a septal artery, in 2/21 the septal vessel was identified from the circumflex artery. Peak gradient improved from 98 (IQR 89.50-111.50) mmHg to 14 (IQR 8.50-22) mmHg (p=0.003). Systolic anterior motion (SAM) improved in 18/20 patients. NYHA class improved by ≥1 in 18/20. Peak VO2 improved from 79.19% of predicted value (±14.01) to 91.62% (±12.02) predicted (p<0.0001). Success at the first procedure is greater with CT guidance, 17/20 vs. 50/75 with traditional methods (pre-CT guidance) (p=0.02); 9/20 had six-month CMR with target septum infarct in all. ASA-related RBBB reduced from 62% to 13% (p=0.0004). CONCLUSIONS CT angiography planning improves localisation of infarct and procedural success at the first attempt in ASA when compared to traditional methods. Follow-up to six months suggests a symptomatic, functional and haemodynamic improvement.

Intra-cardiac echocardiography in alcohol septal ablation: a prospective comparative study against trans-thoracic echocardiography

Alcohol septal ablation (ASA) in hypertrophic obstructive cardiomyopathy reduces left ventricular outflow tract gradients. A third of patients do not respond; inaccurate localisation of the iatrogenic infarct can be responsible. Transthoracic echocardiography (TTE) using myocardial contrast can be difficult in the laboratory environment. Intra-cardiac echocardiography (ICE) provides high-quality images. We aimed to assess ICE against TTE in ASA. The ability of ICE and TTE to assess three key domains (mitral valve (MV) anatomy and systolic anterior motion, visualisation of target septum, adjacent structures) was evaluated in 20 consecutive patients undergoing ASA. Two independent experts scored paired TTE and ICE images off line for each domain in both groups. The ability to see myocardial contrast following septal arterial injection was also assessed by the cardiologist performing ASA. In patients undergoing ASA, ICE was superior in viewing MV anatomy (P=0.02). TTE was superior in assessing adjacent structures (P=0.002). There was no difference in assessing target septum. Myocardial contrast: ICE did not clearly identify the area of contrast in 17/19 patients due to dense acoustic shadowing (8/19) and inadequate opacification of the myocardium (6/19). ICE only clearly localised contrast in 2/19 cases. ICE does not visualise myocardial contrast well and therefore cannot be used to guide ASA. TTE was substantially better at viewing myocardial contrast. There was no significant difference between ICE and TTE in the overall ability to comment on cardiac anatomy relevant to ASA.

Intervention in HCM: patient selection, procedural approach and emerging techniques in alcohol septal ablation

Hypertrophic cardiomyopathy (HCM) is a highly heterogeneous disease with varied patterns of hypertrophy. Basal septal hypertrophy and systolic anterior motion (SAM) of the mitral valve (MV) are the key pathophysiological components to left ventricular outflow tract (LVOT) obstruction in HCM. LVOT is associated with higher morbidity and mortality in patients with HCM. Percutaneous septal reduction therapy with alcohol septal ablation (ASA) can lead to a significant improvement in left ventricle haemodynamics, patient symptoms and perhaps prognosis. ASA delivers pure alcohol to an area of myocardium via septal coronary arteries; this creates damage to tissue akin to a myocardial infarction. The basal septal myocardium involved in SAM–septal contact is the target for this iatrogenic infarct. Appropriate patient selection and accurate delivery of alcohol are critical to safe and effective ASA. Securing the correct diagnosis and ensuring suitable cardiac anatomy are essential before considering ASA. Pre-procedural planning and intra-procedural imaging guidance are important to delivering precise damage to the desired area. The procedure is performed worldwide and is generally safe; the need for a pacemaker is the most prominent complication. It is successful in the majority of patients but room for improvement exists. New techniques have been proposed to perform percutaneous septal reduction. We present a review of the relevant pathophysiology, current methods and a summary of available evidence for ASA. We also provide a glimpse into emerging techniques to deliver percutaneous septal reduction therapy.

Comparison of the antiplatelet and antithrombotic effects of bivalirudin versus unfractionated heparin: A platelet substudy of the HEAT PPCI trial

In randomised trials, bivalirudin has been associated with higher rates of acute stent thrombosis (AST) compared to unfractionated heparin (UFH), without mechanistic explanation. Furthermore, data are discrepant regards the antiplatelet effects of bivalirudin. This prespecified study, part of a larger HEAT-PPCI Platelet Substudy, aimed to compare the antiplatelet and antithrombotic effects of bivalirudin and UFH using short thrombelastography (s-TEG), an ex vivo whole blood platelet function assay. In HEAT-PPCI, patients were randomised to receive UFH or bivalirudin before angiography. Assay with s-TEG was performed in 184 patients (10.2%) at end of procedure (EOP) and repeated at 24 h. In addition to adenosine diphosphate- (ADP) and arachidonic acid- (AA) mediated platelet aggregation, thrombin-mediated clotting (TMC) was assessed using kaolin with and without heparinase. There were no significant differences between UFH and bivalirudin in ADP- and AA-mediated platelet aggregation at EOP or 24 h. Whilst UFH obliterated TMC at EOP, bivalirudin prolonged R time (19.7 min [15.9-25.4] vs. 8.4 min [7.5-10]; P < 0.0001), K time (2.4 min [1.9-3.4] vs. 2.2 min [1.8-2.7]; P = 0.007) and significantly increased maximum clot strength (MA 62.7 mm [58.7-67.4] vs. 58.6 [55-63]; P = 0.0005), compared to control. In conclusion, there were no significant differences in the antiplatelet effects of UFH and bivalirudin. However, whilst UFH obliterated TMC, bivalirudin prolonged clot initiation but potentiated maximum clot strength. As AST is likely multifactorial in aetiology, in patients treated with bivalirudin, increased clot strength may contribute to this hazard in some individuals and this observation warrants further investigation.

17 Radial vs. femoral access in heat-PPCI: MACE and bleeding outcomes - exploring the limitations of observational research

Background Primary Percutaneous Coronary Intervention (PPCI) through the radial artery is considered to be safer in the hands of operators, experienced in that approach. We examined the impact of radial and femoral access in the HEAT-PPCI trial. Methods We compared the primary safety and efficacy outcomes* at 28 days, by final access site used (radial or femoral) and by default operator type. We then specifically assessed outcomes in femoral cases performed by both, default radial and femoral operators. Findings 1804 cases were included in the final analysis. In a simple analysis, radial access was associated with significantly fewer MACE and bleeding events.* When analysed by default operator type, the incidence of MACE and bleeding events were similar.* In the femoral cases done by radial or femoral operators, MACE and bleeding events were significantly worse for the radial operators, potentially explained by less favourable baseline characteristics.* Interpretation In this unselected, real-world population treated with PPCI, default femoral operators, when compared to high volume radial operators, achieved comparable MACE outcomes but at the expense of increased bleeding - mainly minor bleeding. The less favourable outcomes observed for femoral access in the whole population is probably due to its use by radial operators in high risk cases. *See Table Abstract 17 Table 1 Baseline characteristics, Primary efficacy and Safety outcomes (as defined in the HEAT—PPCI trial). SBP: Systolic Blood Pressure, eGFR:estimated Glomerular Filtration Rate, Ml: Myocardial Infarction, CABG: Coronary Artery Bypass Grafting, PCI: Percutaneous Coronary Intervention, GPI: Glycoprotein IIb/IIIa inhibitor, MACE: Major Adverse Cardiovascular Events

RADIOFREQUENCY ABLATION OF THE INTERVENTRICULAR SEPTUM TO TREAT OUTFLOW TRACT GRADIENTS IN HOCM: NOVEL USE OF CARTOSOUND TECHNOLOGY TO GUIDE ABLATION

Septal reduction is used for HOCM patients severe LVOT gradients and symptoms refractory to medication. Surgical myectomy may not be preferable due to patient choice or operative risk. Alcohol septal ablation is not possible due to anatomical restrictions in upto 15%. A percutaneous method of septal

91 Intra-Cardiac Echocardiography (ICE) to Guide Alcohol Septal Ablation (ASA) in Hypertrophic Obstructive Cardiomyopathy (HOCM): A Prospective Comparison Study against Trans-Thoracic Echocardiography (TTE)

Introduction Successful alcohol septal ablation (ASA) in hypertrophic obstructive cardiomyopathy (HOCM) reduces LVOT gradients. A third of patients do not respond; inaccurate location of the iatrogenic infarct can be responsible. Myocardial contrast studies following injection into a septal coronary artery guide ASA. Transthoracic echocardiography (TTE) is the current gold standard. TTE can be difficult in the lab environment. The ideal echocardiographic modality will see crucial anatomy relevant to ASA and delineate myocardial contrast well. We assessed ICE against TTE in ASA. Methods The ability of ICE and TTE to see relevant anatomy was assessed in two phases. Phase one recruited 25 successive patients undergoing PFO closure under ICE guidance. This was predominantly a feasibility study. Phase 2 recruited 20 successive HOCM patients undergoing ASA. The ability to assess myocardial contrast was assessed in phase 2. A scoring system to assess three key domains was used (see Table 1). Two independent experts scored paired, off-line TTE and ICE images, a score was allocated to each modality in each domain. Results Phase 1: ICE catheter manipulation to visualise the relevant anatomy was quick and safe. TTE was superior in viewing MV anatomy and SAM (score 1.4 vs. 0.4, p < 0.0001) but ICE visualised the target septum better (1.66 vs 1.08; p < 0.0001). There was no difference in ability to see adjacent structures. Phase 2: ICE was superior in viewing MV anatomy (1.88 vs 1.6; p = 0.02), superior catheter manipulation caused better scores in ICE. There was no difference in assessing target septum. TTE was superior in assessing adjacent structures (1.03 vs 0.63, p = 0.002). Myocardial Contrast injection was performed in 19/20 patients: ICE was able to visualise contrast satisfactorily in just 2/19. This was due to dense acoustic shadowing with inability to comment on surrounding myocardium (8/19), and inadequate opacification of the myocardium (6/19). Contrast localised to myocardium outside the field in 3/19 (RV cavity). This was not seen on ICE due to a narrower field of echo. TTE saw myocardial contrast location in all. Conclusions ICE cannot be used to guide ASA due to the inability to describe myocardial contrast distribution. ICE was better at seeing the motion of the MV, but TTE saw adjacent structures better. The ability of ICE to see SAM of the MV may lend itself to non-surgical septal reduction therapies that are not reliant on myocardial contrast. Abstract 91 Table 1 Scoring system used to analyse ICE/TTE. It is imperative to be able to see SAM of the mitral valve to know the location of target myocardium. Being able to see this myocardium and other adjacent structures that may be closely linked in vascular supply allows the operator to comment on suitability for alcohol Domain 1: Mitral valve and systolic anterior motion Score Observation 2 Able to determine SAM – septal contact point with precision such that images could allow determination of the length of AMVL in contact with septum at maximum excursion (or if no contact – ability to measure with precision the distance from AMVL tip to septum (Analogous to parasternal long axis m-mode measurement of E-point septal separation [EPSS] distance)) 1 Able to localise approximate SAM – septal contact point (or, if there is no contact with the septum, able to localise approximate anterior leaflet tip position at point of maximum excursion) 0 Unable to determine tip position of the anterior leaflet in relation to the interventricular septum Domain 2: Target septum Score Observation 2 Able to define endocardial border of basal ventricular septum in both RV and LV with visualisation of central intra-septal ‘fusion line’ between RV and LV. On-axis images 1 Able to define endocardial border of proximal ventricular septum in both RV and LV but no visualisation of central intra-septal ‘fusion line’ between RV and LV 0 Unable to clearly define endocardial border of one or both sides of the ventricular septum. Domain 3: Adjacent structures; Mid septum, Right ventricular cavity, anterior papillary muscle Score Observation 2 3 key structures 1 2 key structures 0 0 or 1 key structure

89 Radiofrequency Ablation of the Interventricular Septum to Treat Left Ventricular Outflow Tract Gradients in HOCM: Novel Use of Cartosound Technology to Guide Ablation

Introduction Septal reduction is required for HOCM patients with severe LVOT gradients and symptoms refractory to medications. Myectomy cannot be performed in all due to operative risk and patient choice. Alcohol ablation cannot be performed in 5–15% due to technical difficulties and reliance on septal coronary anatomy. A method of delivering percutaneous damage to the basal septum that is not reliant on coronary anatomy is desirable. Methods 5 patients underwent RF ablation; we describe follow up at 6 months in 4. CARTOsound technology (Intracardiac echocardiography (ICE) merged with the electroanatomic mapping system, CARTO) was used to create a virtual shell of the LV and aorta (Figure 1 (F1), panel A). The precise SAM-septal contact area is ascertained from realtime ICE images and is superimposed onto the CARTO LV shell (pink area, F1, B). This pink area becomes the target for RF energy delivery. Left bundle branch conduction tissue is mapped and superimposed (F1, C). Intravenous heparin is given to keep activated clotting time >250 s. A mean of 31.7 (28–36) minutes of RF energy (50W, 60º) was delivered to the target area using retrograde aortic access and an irrigated 4 mm SmartTouch D-curve ablation catheter (F1, D) Abstract 89 Figure 1 Results Peak resting gradient improved from 64.25 (±50.60) to 12.25 (±2.50) mmHg. Valsalva/exercise gradient improved from 93.50 (±30.88) to 23.25 (±8.30) mmHg. SAM improved in all patients. IVSd reduced from 18.25 (±1.89)mm to 16.75 (±2.5)mm. All patients improved NYHA class from 3 to 2. CPEX data was available in 3. Pre-procedural peak VO2 measured 15.48 (±2.27) mL/min/Kg, this improved to 16.53 (±5.16). Total exercise time increased from 558 (±129) to 730 (±63)secs. EQ5D-5L quality of life index value increased from 0.57 (±0.17) to 0.65 (±0.18). Health score improved from 44 (±18.93) to 70 (±3.54). Two patients had CMR post ASA. Scar can be seen upto 8 mm depth at the endocardial surface of the LV target myocardium (Figure 2). Scar measured 6.3 and 2.2 g respectively, representing 2.4 and 1.1% of total LV mass. LV mass prior to ablation measured 259 and 198 g. This reduced to 236 and 160 g, representing a 9 and 19% reduction. Patient 4 died following femoral artery access point bleeding complications. Hypotension was poorly tolerated leading to cardiac arrest. The artery was repaired surgically but deterioration over the subsequent 48 h lead to multi-organ failure. Patient 5 had a paradoxical increase in LVOT gradients post procedure requiring unplanned ITU care. Abstract 89 Figure 2 Conclusions Radiofrequency ablation to treat LVOT gradients in HOCM using CARTOsound shows significant promise. The unprecedented accuracy of damage reduces SAM and results in improvements in LVOT gradients, symptoms and quality of life in this preliminary group. A small amount of damage at the correct location can lead to significant LV mass regression. This indicates part of the hypertrophy in HCM is afterload dependent