Thomas R. Keeble

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

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 events, including two in the PCI group and three in the placebo group. INTERPRETATION In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Plasma Antioxidants: Evidence for a Protective Role against Reactive Oxygen Species following Cardiac Surgery

Total plasma antioxidant status (TPAS), lipid peroxide concentration (LPX) and cardiac troponin T (cTnT) were measured in 24 patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Samples were obtained preoperatively and at 1.5 h, 6 h, 24 h and 72 h after CPB. The absolute TPAS values were significantly lower at 1.5 h, 6 h, 24 h and 72 h after CPB than were preoperative values (P < 0.05). The LPX concentration was significantly elevated at 1.5 h after CPB (P < 0.05). Cardiac troponin T concentrations were significantly elevated at all time points postoperatively (P < 0.05). Preoperative TPAS values were significantly correlated with the magnitude of fall in TPAS at 1.5 h (P < 0.05). The greater the fall in TPAS between 0 and 1.5 h, the less LPX was formed between 0 and 1.5 h. The LPX at 1.5 h displayed a significant correlation with cTnT release from myocardial myocytes (P < 0.05). These data provide evidence for the first time that the consumption of antioxidants during CABG surgery with CPB protects against the production of reactive oxygen species and subsequent myocyte necrosis. Furthermore, the availability of protective antioxidants is dependent upon preoperative TPAS.

Percutaneous balloon aortic valvuloplasty in the era of transcatheter aortic valve implantation: a narrative review

The role of percutaneous balloon aortic valvuloplasty (BAV) in the management of severe symptomatic aortic stenosis has come under the spotlight following the development of the transcatheter aortic valve implantation (TAVI) technique. Previous indications for BAV were limited to symptom palliation and as a bridge to definitive therapy for patients undergoing conventional surgical aortic valve replacement (AVR). In the TAVI era, BAV may also be undertaken to assess the ‘therapeutic response’ of a reduction in aortic gradient in borderline patients often with multiple comorbidities, to assess symptomatic improvement prior to consideration of definitive TAVI intervention. This narrative review aims to update the reader on the current indications and practical techniques involved in undertaking a BAV procedure. In addition, a summary of the haemodynamic and clinical outcomes, as well as the frequently encountered procedural complications is presented for BAV procedures conducted during both the pre-TAVI and post-TAVI era.

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

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 decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.

Early targeted brain COOLing in the cardiac CATHeterisation laboratory following cardiac arrest (COOLCATH).

INTRODUCTION Trials demonstrate significant clinical benefit in patients receiving therapeutic hypothermia (TH) after cardiac arrest. However, incidence of mortality and morbidity remains high in this patient group. Rapid targeted brain hypothermia induction, together with prompt correction of the underlying cause may improve outcomes in these patients. This study investigates the efficacy of Rhinochill, an intranasal cooling device over Blanketrol, a surface cooling device in inducing TH in cardiac arrest patients within the cardiac catheter laboratory. METHODS 70 patients were randomized to TH induction with either Rhinochill or Blanketrol. Primary outcome measures were time to reach tympanic ≤34 °C from randomisation as a surrogate for brain temperature and oesophageal ≤34 °C from randomisation as a measurement of core body temperature. Secondary outcomes included first hour temperature drop, length of stay in intensive care unit, hospital stay, neurological recovery and all-cause mortality at hospital discharge. RESULTS There was no difference in time to reach ≤34 °C between Rhinochill and Blanketrol (Tympanic ≤34 °C, 75 vs. 107 mins; p=0.101; Oesophageal ≤34 °C, 85 vs. 115 mins; p=0.151). Tympanic temperature dropped significantly with Rhinochill in the first hour (1.75 vs. 0.94 °C; p<0.001). No difference was detected in any other secondary outcome measures. Catheter laboratory-based TH induction resulted in a survival to hospital discharge of 67.1%. CONCLUSION In this study, Rhinochill was not found to be more efficient than Blanketrol for TH induction, although there was a non-significant trend in favour of Rhinochill that potentially warrants further investigation with a larger trial.

Current Advances in the Use of Therapeutic Hypothermia

Temperature management and therapeutic hypothermia is being investigated in stroke, subarachnoid hemorrhage, myocardial infarction, and neonatal encephalopathy. Previous clinical studies have provided support for the use of hypothermia in these clinical conditions, and new studies are currently underway to establish safety and efficacy of this therapeutic intervention. Thus, this particular session brought together experts in the field of therapeutic hypothermia to discuss its use in several important patient populations. Dr. Neeraj Badjatia from the University of Maryland School of Medicine discussed antishivering strategies targeting stroke and subarachnoid hemorrhage. This lecture emphasized thermoregulatory systems and systematic approaches toward shiver control during cooling in patients with acute stroke. Various pharmacological strategies are currently used for shiver control, including drug combinations and counterwarming approaches. Dr. Christopher J. White of the Ochsner Medical Center emphasized the use of hypothermia in myocardial infarction. Myocardial infarction is an extremely important clinical problem, and the use of hypothermia to reduce ischemic injury and reperfusion-injury is currently being assessed in both preclinical and clinical studies. Previous clinical studies including a prospective randomized trial reported that postreperfusion cooling provided no significant improvement. However, recent investigations are concentrating on hypothermia treatment initiated before reperfusion, and these have been very promising. Dr. Abbot Laptook, Brown University, updated the attendees on therapeutic cooling and neonatal hypoxic ischemic encephalopathy. Results from published multicenter trials have emphasized the benefits of therapeutic hypothermia in newborn hypoxic ischemic encephalopathy patients, and issues regarding implementation of hypothermia on transport to hospitals are being evaluated along with combination approaches. Dr. Markus Foedisch from Bonn, Germany, discussed the use of brain damage markers to determine how best to utilize hypothermia after cardiac arrest. Dr. Foedisch updated the attendees regarding the cool brain register as well as the effects of cooling on available biomarkers, including neuron-specific enolase and S100B. This session had an extensive question-and-answer exchange and provided new information regarding the advances being made in the use of hypothermia in these clinical conditions.

Setting Up an Efficient Therapeutic Hypothermia Team in Conscious ST Elevation Myocardial Infarction Patients: A UK Heart Attack Center Experience

Patients presenting with ST elevation myocardial infarction (STEMI) are routinely treated with percutaneous coronary intervention to restore blood flow in the occluded artery to reduce infarct size (IS). However, there is evidence to suggest that the restoration of blood flow can cause further damage to the myocardium through reperfusion injury (RI). Recent research in this area has focused on minimizing damage to the myocardium caused by RI. Therapeutic hypothermia (TH) has been shown to be beneficial in animal models of coronary artery occlusion in reducing IS caused by RI if instituted early in an ischemic myocardium. Data in humans are less convincing to date, although exploratory analyses suggest that there is significant clinical benefit in reducing IS if TH can be administered at the earliest recognition of ischemia in anterior myocardial infarction. The Essex Cardiothoracic Centre is the first UK center to have participated in administering TH in conscious patients presenting with STEMI as part of the COOL-AMI case series study. In this article, we outline our experience of efficiently integrating conscious TH into our primary percutaneous intervention program to achieve 18 minutes of cooling duration before reperfusion, with no significant increase in door-to-balloon times, in the setting of the clinical trial.

The impact of coronary chronic total occlusion percutaneous coronary intervention upon donor vessel fractional flow reserve and instantaneous wave-free ratio: Implications for physiology-guided PCI in patients with CTO

To investigate the immediate and short term impact of right coronary artery (RCA) chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) upon collateral donor vessel fractional flow reserve (FFR) and instantaneous wave‐free ratio (iFR).

INSTANTANEOUS WAVE-FREE RATIO SCOUT PULLBACK (IFR SCOUT) PRE-ANGIOPLASTY PREDICTS HEMODYNAMIC OUTCOME IN HUMANS WITH CORONARY ARTERY DISEASE: PRIMARY RESULTS OF INTERNATIONAL MULTICENTRE IFR GRADIENT REGISTRY

Background: In tandem and diffuse disease, offline analysis of continuous instantaneous wave-free ratio (iFR) pullback measurement has been demonstrated to accurately predict the physiological outcome of revascularization. However, the accuracy of the real-time online analysis approach (iFR Scout)

Peri-procedural ST segment resolution during Primary Percutaneous Coronary Intervention (PPCI) for acute myocardial infarction: predictors and clinical consequences

OBJECTIVE ECG ST segment resolution (STR) has been used to assess myocardial perfusion in STEMI patients undergoing PPCI. However, in most of the studies ECGs recorded at different time points after the actual procedure have been used, limiting the options of therapeutic interventions while the patient is still in the catheterisation laboratory. The aim of this study was to investigate the presence and clinical consequences of intra-procedural STR during PPCI. METHODS We analysed 12 lead ECGs recorded at the onset and the end of the PPCI procedure, measuring STR in the lead with maximum ST elevation on the initial recording. STR was defined as good when > 50% compared to baseline. RESULTS Pre and immediately post PPCI ECGs were recorded in 467 STEMI cases whilst the patient was on the catheter lab table. Mean patient age was 63 (+/- 12) years old and 75% were men. Mean duration of symptoms to admission was 3.8 (+/- 3.4) hours and 51% of infarcts were anterior. Good ST resolution at the end of the procedure was seen in 46.5% of patients and was observed more commonly in inferior compared to anterior infarcts (60.1% vs. 32.6%, p<0.001), and in current smokers (53.2% vs. 42.4%, p=0.031). In patients presenting with symptoms for < 4 hours, good STR was more common (74% vs. 66%, p=0.019). Thrombus aspiration was used more frequently in patients who had good STR (88.5% vs 79.8% p=0.011). Patients with good ST resolution had a shorter mean hospital length of stay (3.8 vs. 4.5 days, p=0.009) and a higher left ventricular ejection fraction (49.9% vs. 44.2%, p<0.001) measured by transthoracic echocardiography prior to discharge. CONCLUSION Good peri-procedural ST resolution was seen in less than half of STEMI patients undergoing PPCI. There were important clinical consequences of good ST resolution. Identification of suboptimal peri-procedural ST resolution could help identify patients who may benefit from new treatments aimed at protecting the microcirculation, whilst the patients are still in the angiography laboratory.