Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Real-world bleeding in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and prescribed different combinations of dual antiplatelet therapy (DAPT) in England: a population-based cohort study emulating a 'target trial'.

OBJECTIVE: To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England. DESIGN: A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT). DATA SOURCES: Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). SETTING: Primary and secondary care. PARTICIPANTS: Patients ≥18 years old with ACS undergoing emergency PCI. INTERVENTIONS: Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI). MAIN OUTCOME MEASURES: Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only). CONCLUSIONS: In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel. TRIAL REGISTRATION NUMBER: ISRCTN76607611.

Confounders and co-interventions identified in non-randomized studies of interventions.

OBJECTIVES: To identify potential confounders and co-interventions systematically to optimise control of confounding for three non-randomized studies of interventions (NRSI) designed to quantify bleeding in populations exposed to different dual antiplatelet therapy (DAPT). STUDY DESIGN AND SETTING: Systematic review, interviews, and surveys with clinicians. We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify randomized-controlled trials and cohort studies of DAPT interventions. Two researchers independently screened citations, identified eligible studies and extracted data. We conducted individual semi-structured interviews with six cardiologists and six cardiac surgeons to elicit factors clinicians consider when they prescribe DAPT. We administered two online surveys for members of professional cardiology and cardiac surgery organisations. RESULTS: We screened 2,544 records, identified 322 eligible studies, and extracted data from 47. We identified 10 co-interventions and 70 potential confounders: review 31 (91%); interviews 19 (56%); surveys 31 (91%). 16/34 (47%) were identified by all three methods while, 3/34 (9%) were picked up by one method only. CONCLUSION: The review identified the majority of factors, but the interviews identified hard-to-measure factors such as perceived patient adherence and local prescribing culture. The methods could, in principle, be widely applied when designing or reviewing non-randomized studies of interventions (NRSI).

Impact of paramedic education on door-to-balloon times and appropriate use of the primary PCI pathway in ST-elevation myocardial infarction.

OBJECTIVE: Evidence supports improved outcomes and reduced mortality with rapid reperfusion through primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). UK national audit data (Myocardial Ischaemia National Audit Project [MINAP]) demonstrates minor improvements in door-to-balloon times (DTB) of <90 min but increasing call-to-balloon times (CTB). We evaluate the effect of a regional Cardiologist delivered paramedic education programme (PEP) on DTB times and appropriate use of the PPCI pathway. METHODS: This was a prospective single-centre study of patients with STEMI brought directly to hospital via ambulance services. Data sources included ambulance charts, in-patient notes, British Cardiovascular Interventional Society (BCIS) database and local MINAP data. All DTB breaches were investigated. A local PEP was implemented with focus on ECG interpretation, STEMI diagnosis and appropriate use of the PPCI pathway. Non-parametric Wilcoxon rank test was used for comparisons of DTB and CTB times between direct versus ED-associated cath lab transfer. RESULTS: A total of 728 patients with STEMI were admitted directly to our centre via ambulance, 66% (n=484) directly to the Catheterisation Laboratory (Cath Lab) and 34% (n=244) via the Emergency Department (ED). There was a significant increase in median DTB, 83 vs 37 min (p<0.001) and median CTB 144 vs 97.5 min (p<0.001) when transfer to the Cath Lab occurred via the ED versus direct transfer. The PEP increased direct cath lab transfers (52%-85%) and generated annual reductions in median DTB times, with sustained improvement seen throughout the 7-year study period. CONCLUSIONS: Paramedic education increases direct transfer of STEMI patients to the Cath Lab, and reduces DTB times. This is an effective and reproducible intervention to facilitate timely reperfusion in STEMI.

Intravascular lithotripsy for treatment of calcific coronary lesions in ST elevation myocardial infarction.

AIMS: To describe the utility and safety of intravascular lithotripsy (IVL) in the setting of primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: We performed a retrospective analysis, across six UK sites of all patients in whom IVL was used for coronary calcium modification of the culprit lesion during primary PCI for STEMI. The 72 patients were included. IVL was used in de-novo culprit lesions in 57 (79%) of cases and culprit in-stent restenoses in 11 (15%) of cases. In four cases (6%) it was used in a newly deployed stent when this was under-expanded due to inadequate calcium modification. Of the 30 cases in which intracoronary imaging was available for stent analysis, the average stent expansion was 104%. Intra-procedural stent thrombosis occurred in one case (1%), and no-reflow in three cases (4%). The 30 day MACE rates were 18%. CONCLUSION: IVL appears to be feasible and safe for use in the treatment of calcific coronary artery disease in the setting of STEMI.

Factors Influencing Stent Failure in Chronic Total Occlusion Coronary Intervention.

Stent failure remains one of the greatest challenges for interventional cardiologists. Despite the evolution to superior second- and third-generation drug-eluting stent designs, increasing use of intracoronary imaging and the adoption of more potent antiplatelet regimens, registries continue to demonstrate a prevalence of stent failure or target lesion revascularisation of 15-20%. Predisposition to stent failure is consistent across both chronic total occlusion (CTO) and non-CTO populations and includes patient-, lesion- and procedure-related factors. However, histological and pathophysiological properties specific to CTOs, alongside complex strategies to treat these lesions, may potentially render percutaneous coronary interventions in this cohort more vulnerable to failure. Prevention requires recognition and mitigation of the precipitants of stent failure, optimisation of interventional techniques, including image-guided precision percutaneous coronary intervention, and aggressive modification of a patient's cardiovascular risk factors. Management of stent failure in the CTO population is technically challenging and itself begets recurrence. We aim to provide a comprehensive review of factors influencing stent failure in the CTO population and strategies to attenuate these.

The Impact of Calcium on Chronic Total Occlusion Management.

Coronary artery calcification is prevalent in chronic total occlusions (CTO), particularly in those of longer duration and post-coronary artery bypass. The presence of calcium predicts lower procedural success rates and a higher risk of complications of CTO percutaneous coronary intervention. Adjunctive imaging, including pre-procedural computed tomography and intracoronary imaging, are useful to understand the distribution and morphology of the calcium. Specialised guidewires and microcatheters, as well as penetration, subintimal entry and luminal re-entry techniques, are required to cross calcific CTOs. The use of both atherectomy devices and balloon-based calcium modification tools has been reported during CTO percutaneous coronary intervention, although they are limited by concerns regarding safety and efficacy in the subintimal space.

Distractions in the cardiac catheterisation laboratory: impact for cardiologists and patient safety.

OBJECTIVE: To understand human factors (HF) contributing to disturbances during invasive cardiac procedures, including frequency and nature of distractions, and assessment of operator workload. METHODS: Single centre prospective observational evaluation of 194 cardiac procedures in three adult cardiac catheterisation laboratories over 6 weeks. A proforma including frequency, nature, magnitude and level of procedural risk at the time of each distraction/interruption was completed for each case. The primary operator completed a National Aeronautical and Space Administration (NASA) task load questionnaire rating mental/physical effort, level of frustration, time-urgency, and overall effort and performance. RESULTS: 264 distractions occurred in 106 (55%) out of 194 procedures observed; 80% were not relevant to the case being undertaken; 14% were urgent including discussions of potential ST-elevation myocardial infarction requiring emergency angioplasty. In procedures where distractions were observed, frequency per case ranged from 1 to 16 (mean 2.5, SD ±2.2); 43 were documented during high-risk stages of the procedure. Operator rating of NASA task load parameters demonstrated higher levels of mental and physical workload and effort during cases in which distractions occurred. CONCLUSIONS: In this first description of HF in adult cardiac catheter laboratories, we found that fewer than half of all procedures were completed without interruption/distraction. The majority were unnecessary and without relation to the case or list. We propose the introduction of a 'sterile cockpit' environment within catheter laboratories, as adapted from aviation and used in surgical operating theatres, to minimise non-emergent interruptions and disturbances, to improve operator conditions and overall patient safety.

Novel Techniques to Crossing a Severely Stenotic Aortic Valve.

This report presents 2 cases with the use of different techniques to facilitate aortic valve crossing during transcatheter aortic valve replacement with a balloon-expandable system. Case 1 involves a balloon cushion technique with an Edwards Sapien 3 valve (Edwards Lifesciences), and case 2 describes successful crossing and implantation using a buddy balloon technique with an Edwards Sapien Ultra valve. (Level of Difficulty: Advanced.).

Case-Based Review of the Current Global Evidence Supporting Impella-Facilitated Complex and Complete Revascularization.

A 74-year-old male patient who was admitted with non-ST-segment elevation myocardial infarction, severe left ventricular impairment, severe mitral regurgitation, and full viability who was turned down for surgery underwent high-risk and indicated multivessel stenting with Impella (Abiomed) support. At 6-month follow-up he was angina free, with complete resolution of the mitral regurgitation. (Level of Difficulty: Intermediate.).

Renal artery sympathetic denervation: observations from the UK experience.

BACKGROUND: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response-particularly in those prescribed aldosterone antagonists at the time of RDN. METHODS: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. RESULTS: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2). CONCLUSION: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response.

Cardiorenal medicine in the changing health system.

The phenomenon of Cardiorenal Syndrome is complex, well recognised and poses challenges to all levels of global healthcare. Ongoing research in this area continually manifests new ideas and theories with respect to the pathophysiology and clinical management of this condition. The 6th Cardiorenal Forum held in London on 7th October 2011 discussed some of the latest ideas and advances in this field of medicine.