Interactions between glaciers and rivers in the Pleistocene Mediterranean

-

Novel approaches to the diagnostic and prognostic assessment of coronary heart disease

BACKGROUND Cardiovascular disease, principally manifest as myocardial infarction or stroke, is the dominant cause of death worldwide and despite therapeutic advances, the global burden of these conditions continues to increase. In order to address this ongoing disease burden, there is a clear need to more effectively target the use of existing and novel diagnostic investigations and medical therapies. Emerging cardiovascular biomarkers include the biochemical, such as high-sensitivity cardiac troponin, and the radiological, such as computed tomography coronary angiography (CTCA) and 18Ffluoride positron emission tomography (PET). Cardiac troponins can now be reliably quantified in clinically stable or asymptomatic populations and provide information about myocardial pathophysiology, whilst CTCA can non-invasively quantify atherosclerotic burden and 18F-fluoride PET imaging offers insight into plaque vulnerability. Improved targeting of diagnostic investigations requires more reliable estimation of pre-test probability of coronary disease whilst optimizing the use of pharmacological or interventional treatments requires more accurate prognostic stratification. Achieving both objectives in an equitable manner across all population groups will depend upon updated clinical guidelines containing improved risk models and enhanced management pathways. The objective of this thesis was to investigate the potential clinical benefit of novel approaches to the diagnostic and prognostic assessment of coronary heart disease. EVALUATION OF THE 2016 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE) GUIDANCE ON THE ASSESSMENT OF SUSPECTED STABLE ANGINA. A post-hoc analysis was undertaken of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial of 4,146 participants with suspected angina randomised to assessment with computed tomography coronary angiography or standard care. Patients were dichotomised according to guideline definitions into groups representing possible angina and non-anginal presentations. The primary (diagnostic) endpoint was diagnostic certainty of angina at 6 weeks and the prognostic endpoint comprised fatal and non-fatal myocardial infarction. In 3,770 eligible participants, CTCA increased diagnostic certainty more in those with possible angina (relative risk [RR] 2.22 (95% CI 1.91-2.60), p<0.001) than those with non-anginal symptoms (RR 1.30 (1.11-1.53), p=0.002; pinteraction<0.001). In the possible angina cohort, CTCA did not change rates of invasive angiography (p=0.481) but markedly reduced rates of normal coronary angiography (hazard ratio [HR] 0.32 (0.19-0.52), p<0.001). In the non-anginal cohort, rates of invasive angiography increased (HR 1.82 (1.13-2.92), p=0.014) without reducing rates of normal coronary angiography (HR 0.78 (0.30-2.05), p=0.622). At 3.2 years of follow-up, fatal or nonfatal MI was reduced in patients with possible angina (3.2% to 1.9%; HR 0.58 (0.34- 0.99), p=0.045) but not in those with non-anginal symptoms (HR 0.65 (0.25-1.69), p=0.379). Overall the updated NICE guidance on patient assessment maximises the benefits of CTCA with respect to diagnostic certainty, the use of invasive coronary angiography, and reductions in fatal and non-fatal myocardial infarction. Patients with non-anginal chest pain derive minimal benefit from CTCA, which instead increases rates of invasive investigation. EXTERNAL VALIDATION OF THE PROSPECTIVE MULTICENTER IMAGING STUDY FOR EVALUATION OF CHEST PAIN (PROMISE) TOOL FOR DETERMINING MINIMAL-RISK OF CORONARY ARTERY DISEASE. The PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) minimal-risk tool was recently developed to identify patients with suspected stable angina at very low risk of coronary artery disease and clinical events. The external validity of this tool was investigated within the context of the Scottish Computed Tomography of the HEART multicenter randomised controlled trial of patients with suspected stable angina due to coronary artery disease. Model discrimination and calibration was determined amongst 1,764 patients in whom complete CCTA data were available and compared with the European Society of Cardiology guideline-endorsed Coronary Artery Disease Consortium (CADC) risk score. The PROMISE minimal-risk tool improved discrimination compared with the CADC model (c-statistic 0.785 vs 0.730, p<0.001) and was improved further following re-estimation of covariate coefficients (c-statistic 0.805, p<0.001). Model calibration was initially poor (c2 197.6, Hosmer-Lemeshow [HL] p<0.001), with significant overestimation of probability of minimal risk, but improved significantly following revision of the PROMISE minimal-risk intercept and covariate coefficients (c2 5.6, HL p=0.692). HIGH-SENSITIVITY CARDIAC TROPONIN I IN THE DIAGNOSIS OF STABLE CORONARY ARTERY DISEASE In a pre-specified sub-study of the Scottish COmputed Tomography of the Heart trial, plasma cardiac troponin was measured using a high-sensitivity single molecule counting assay in 943 adults with suspected stable angina who had undergone coronary computed tomography angiography. Rates of obstructive coronary artery disease were compared with the pre-test probability determined by the European Society of Cardiology Coronary Artery Disease Consortium risk model with and without cardiac troponin concentrations. External validation was undertaken in an independent study population from Denmark comprising 487 patients with suspected stable angina. Higher cardiac troponin concentrations were associated with obstructive coronary artery disease with a 5-fold increase across quintiles (9 to 48%, p<0.001) independent of known cardiovascular risk factors (odds ratio [OR] 1.35 [95% confidence interval (CI) 1.25-1.46] per doubling of troponin). Cardiac troponin concentrations improved the discrimination of the ESC model for identifying obstructive coronary artery disease (c-statistic 0.785 to 0.800, p=0.003) and improved classification into ESCrecommended categories of clinical risk (net reclassification improvement 0.143 [95% CI, 0.093-0.193]). The revised model achieved similar improvements in discrimination and net reclassification when applied in the external validation cohort. HIGH-SENSITIVITY CARDIAC TROPONIN I IN CARDIOVASCULAR RISK STRATIFICATION OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND HEIGHTENED CARDIOVASCULAR RISK. The association between plasma high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with chronic obstructive pulmonary disease and heightened cardiovascular risk was examined within the context of a double-blind randomised controlled trial of inhaled corticosteroids and bronchodilators (1 placebo arm and 3 different treatment arms). Plasma cardiac troponin I concentrations were measured with a high-sensitivity assay in a subgroup of 1,599 patients. The cardiovascular endpoint was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina and transient ischaemic attack during follow-up of 1.5 years. Baseline plasma cardiac troponin I concentrations were above the lower limit of detection (1.0 ng/L) in 1,559 (97.5%) patients and were unaffected by inhaled therapies at 3 months (p>0.05 for all). Compared with the lowest tertile (cardiac troponin I ≤3.0 ng/L), patients in the highest tertile (≥ 5.5 ng/L) were at greater risk of cardiovascular events (hazard ratio 3.0, 95% confidence interval 1.5 to 6.2, p=0.002) and cardiovascular death (hazard ratio 9.6, 95% confidence interval 2.6 to 35.6, p<0.001) after adjustment for cardiovascular risk factors. There were no differences in COPD exacerbations between tertiles even after adjustment (p>0.05). REPRODUCIBILITY OF CORONARY 18F-FLUORIDE PET-CT IMAGING The inter-observer and scan-rescan reproducibility of coronary 18F-fluoride PET-CT imaging was investigated in 20 patients with clinically stable but high risk multi-vessel coronary artery disease who underwent repeated 18F-fluoride PET-CT scans 11.5±4.5 days apart. Scan analysis using the currently accepted approach of normalisation to a referent coronary segment (TBRREFERENT) identified 10 (50%) patients with evidence of focal coronary 18F-fluoride uptake and demonstrated moderate agreement across observers on a per-patient level (k = 0.56). This was similar to the level of agreement achieved with visual assessment alone (k = 0.64). Reproducibility was improved by semi-quantitative reporting combining visual assessment with a threshold uptake value for determining the presence of tracer uptake (k = 0.84). Using the optimised approach achieved excellent agreement on overall segmental uptake counts (intra-class correlation = 0.97). CONCLUSION Cardiovascular diagnostic and prognostic assessments represent a complex endeavour and established tools for risk prediction can demonstrate suboptimal predictive accuracy when evaluated in patient cohorts that are independent of the population used for model derivation. The process of risk stratification has important potential for improvement through the integration of existing approaches with novel biochemical and non-invasive diagnostic imaging technologies that provide unique insights into structural and pathophysiological processes. The promise such developments hold requires rigorous assessment in well-designed trials involving patients who closely reflect the population most likely to receive treatment. Such trials are difficult and costly to conduct with traditional methods and careful consideration should be given to more pragmatic clinical trial designs

Determining prescriptions in electronic healthcare record data: methods for development of standardized, reproducible drug codelists

OBJECTIVE: To develop a standardizable, reproducible method for creating drug codelists that incorporates clinical expertise and is adaptable to other studies and databases. MATERIALS AND METHODS: We developed methods to generate drug codelists and tested this using the Clinical Practice Research Datalink (CPRD) Aurum database, accounting for missing data in the database. We generated codelists for: (1) cardiovascular disease and (2) inhaled Chronic Obstructive Pulmonary Disease (COPD) therapies, applying them to a sample cohort of 335 931 COPD patients. We compared searching all drug dictionary variables (A) against searching only (B) chemical or (C) ontological variables. RESULTS: In Search A, we identified 165 150 patients prescribed cardiovascular drugs (49.2% of cohort), and 317 963 prescribed COPD inhalers (94.7% of cohort). Evaluating output per search strategy, Search C missed numerous prescriptions, including vasodilator anti-hypertensives (A and B:19 696 prescriptions; C:1145) and SAMA inhalers (A and B:35 310; C:564). DISCUSSION: We recommend the full search (A) for comprehensiveness. There are special considerations when generating adaptable and generalizable drug codelists, including fluctuating status, cohort-specific drug indications, underlying hierarchical ontology, and statistical analyses. CONCLUSIONS: Methods must have end-to-end clinical input, and be standardizable, reproducible, and understandable to all researchers across data contexts

Positron emission tomography imaging of coronary atherosclerosis

Inflammation has a central role in the progression of coronary atherosclerosis. Recent developments in cardiovascular imaging with the advent of hybrid positron emission tomography have provided a window into the molecular pathophysiology underlying coronary plaque inflammation. Using novel radiotracers targeted at specific cellular pathways, the potential exists to observe inflammation, apoptosis, cellular hypoxia, microcalcification and angiogenesis in vivo. Several clinical studies are now underway assessing the ability of this hybrid imaging modality to inform about atherosclerotic disease activity and the prediction of future cardiovascular risk. A better understanding of the molecular mechanisms governing coronary atherosclerosis may be the first step toward offering patients a more stratified, personalized approach to treatment

Non-invasive imaging of high-risk coronary plaque: the role of computed tomography and positron emission tomography

Despite recent advances, cardiovascular disease remains the leading cause of death globally. As such, there is a need to optimise our current diagnostic and risk stratification pathways in order to better deliver individualised preventative therapies. Non-invasive imaging of coronary artery plaque can interrogate multiple aspects of coronary atherosclerotic disease, including plaque morphology, anatomy and flow. More recently, disease activity is being assessed to provide mechanistic insights into in vivo atherosclerosis biology. Molecular imaging using positron emission tomography is unique in this field, with the potential to identify specific biological processes using either bespoke or re-purposed radiotracers. This review provides an overview of non-invasive vulnerable plaque detection and molecular imaging of coronary atherosclerosis