Personalisation of heart failure care using clinical trial data

Heart failure is a common, debilitating and life limiting disease, resulting in a large burden for both the individual patient and healthcare provision. Therefore, optimisation of treatments for these patients is of prime importance. Heart failure with reduced ejection fraction has a large evidence base for effective treatments, and more recently effective treatments have started to be identified for those with preserved ejection fraction. The effectiveness of these treatments is calculated at a population level, and there is a great deal of interest to try and identify if different patients may benefit more from certain treatments. In addition, we wish to understand more about different phenotypes in heart failure, to help understand what the patient might expect for the trajectory of their illness and potentially develop targeted treatments. To explore these issues further, this thesis presents several approaches using heart failure clinical trial data to try and further understand the patient journey and explore how treatment may be delivered in a more personalised fashion. The first analyses look at the patterns of heart failure hospitalisations, including the timing of admissions, and the relationship with different modes of death. This was examined in both heart failure with preserved and reduced ejection fraction. The accepted trajectory of recurrent admissions falling closer together over time was confirmed, and admissions closer together were linked to a higher risk of cardiovascular death, particularly due to progressive pump failure. Sudden death did appear to be truly sudden and not strongly linked to hospitalisations. The next approach was to perform latent class analysis to try and identify clusters of patients, or phenotypes, within heart failure with preserved and reduced ejection fraction separately using a data driven method. Phenotypes were identified with consistency across different data and using different approaches. These phenotypes were clinically recognisable. Identifying phenotypes in this way may be a route to looking for differential responses to treatments. Lastly, supervised machine learning methods were used to predict outcomes in patients with heart failure and reduced ejection fraction. These techniques provide more analytical flexibility, but did not show performance benefit compared with prognostic models based on survival analysis methods. Overall, the predictive abilities were modest. In conclusion, several avenues were explored to help understand the patient journey in heart failure, aiming to give more detail about the expected patient trajectory and exploring methods to examine for differential treatment responses in phenotypes of patients in heart failure

Post-operative myocardial infarction following aortic root surgery with coronary reimplantation: a case series treated with percutaneous coronary intervention

Background: Coronary ostial stenosis is an uncommon but potentially lethal complication following aortic root replacement with or without aortic valve replacement (including Bentall and David procedures). This manifests clinically as acute myocardial ischaemia in the early or late post-operative period. Traditionally, this might be managed with redo open-heart surgery. Case summary:  This case series describes two presentations where urgent percutaneous coronary intervention was used to manage myocardial infarction complicating aortic root surgery with coronary reimplantation. Discussion: This series highlights the risk of acute myocardial infarction after cardiac surgery involving coronary reimplantation. Emergency percutaneous coronary intervention is feasible and illustrates the importance of shared post-operative care involving the cardiac surgeons and the cardiology team

Joint modelling of longitudinal processes and time-to-event outcomes in heart failure: systematic review and exemplar examining the relationship between serum digoxin levels and mortality

Background: Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research. Methods: A systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial. Results: Overall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34–2.33) times when adjusting for clinically relevant covariates. Conclusion: Recently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error

Common carotid intima media thickness and ankle-brachial pressure index correlate with local but not global atheroma burden:a cross sectional study using whole body magnetic resonance angiography

Common carotid intima media thickness (CIMT) and ankle brachial pressure index (ABPI) are used as surrogate marker of atherosclerosis, and have been shown to correlate with arterial stiffness, however their correlation with global atherosclerotic burden has not been previously assessed. We compare CIMT and ABPI with atheroma burden as measured by whole body magnetic resonance angiography (WB-MRA).50 patients with symptomatic peripheral arterial disease were recruited. CIMT was measured using ultrasound while rest and exercise ABPI were performed. WB-MRA was performed in a 1.5T MRI scanner using 4 volume acquisitions with a divided dose of intravenous gadolinium gadoterate meglumine (Dotarem, Guerbet, FR). The WB-MRA data was divided into 31 anatomical arterial segments with each scored according to degree of luminal narrowing: 0 = normal, 1 = <50%, 2 = 50-70%, 3 = 70-99%, 4 = vessel occlusion. The segment scores were summed and from this a standardized atheroma score was calculated.The atherosclerotic burden was high with a standardised atheroma score of 39.5±11. Common CIMT showed a positive correlation with the whole body atheroma score (β 0.32, p = 0.045), however this was due to its strong correlation with the neck and thoracic segments (β 0.42 p = 0.01) with no correlation with the rest of the body. ABPI correlated with the whole body atheroma score (β -0.39, p = 0.012), which was due to a strong correlation with the ilio-femoral vessels with no correlation with the thoracic or neck vessels. On multiple linear regression, no correlation between CIMT and global atheroma burden was present (β 0.13 p = 0.45), while the correlation between ABPI and atheroma burden persisted (β -0.45 p = 0.005).ABPI but not CIMT correlates with global atheroma burden as measured by whole body contrast enhanced magnetic resonance angiography in a population with symptomatic peripheral arterial disease. However this is primarily due to a strong correlation with ilio-femoral atheroma burden

Regional trends in soil acidification and exchangeable metal concentrations in relation to acid deposition rates

The deposition of high levels of reactive nitrogen (N) and sulphur (S), or the legacy of that deposition, remain among the world's most important environmental problems. Although regional impacts of acid deposition in aquatic ecosystems have been well documented, quantitative evidence of wide-scale impacts on terrestrial ecosystems is not common. In this study we analysed surface and subsoil chemistry of 68 acid grassland sites across the UK along a gradient of acid deposition, and statistically related the concentrations of exchangeable soil metals (1 M KCl extraction) to a range of potential drivers. The deposition of N, S or acid deposition was the primary correlate for 8 of 13 exchangeable metals measured in the topsoil and 5 of 14 exchangeable metals in the subsoil. In particular, exchangeable aluminium and lead both show increased levels above a soil pH threshold of about 4.5, strongly related to the deposition flux of acid compound

Coronary artery perforations: Glasgow Natural History Study of Covered Stent Coronary Interventions (GNOCCI) Study

Background: The objective of the GNOCCI (Glasgow Natural History Study of Covered Stent Coronary Interventions) Study was to report the incidence and outcomes of coronary artery perforations over an 18‐year period at a single, high‐volume percutaneous coronary intervention center. We considered both the temporal trends and long‐term outcomes of covered stent deployment. Methods and Results: We evaluated procedural and long‐term clinical outcomes following coronary perforation in a cohort of 43,343 consecutive percutaneous coronary intervention procedures. Procedural major adverse cardiac events were defined as a composite of death, myocardial infarction, stroke, target vessel revascularization, or cardiac surgery within 24 hours. A total of 161 (0.37%) procedures were complicated by coronary perforation of which 57 (35%) were Ellis grade III. Incidence increased with time over the study period (r=0.73; P&lt;0.001). Perforation severity was linearly associated with procedural mortality (median 2.9‐year follow‐up): Ellis I (0%), Ellis II (1.7%), Ellis III/IIIB (21%), P&lt;0.001. Procedural major adverse cardiac events occurred in 47% of patients with Ellis III/IIIB versus 13.5% of those with Ellis I/II perforations (odds ratio, 5.8; 95% CI, 2.7–12.5; P&lt;0.001). Covered stents were associated with an increased risk of stent thrombosis at 2.9‐year follow‐up (Academic Research Consortium definite or probable; 9.1% versus 0.9%; risk ratio, 10.5; 95% CI, 1.1–97; P=0.04). Conclusions: The incidence of coronary perforation increased between 2001 and 2019. Severe perforation was associated with higher procedural major adverse cardiac events and was an independent predictor of long‐term mortality. Although covered stents are a potentially lifesaving treatment, the generation of devices used during the study period was limited by their efficacy and high risk of stent thrombosis. Registration Information: Clinicaltrials.gov. Identifier: NCT03862352

Prevalent and incident anemia in PARADIGM-HF and the effect of sacubitril/valsartan

Background: Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia. Objectives: The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure). Methods: Anemia was defined as hemoglobin &lt;120 g/L in women and &lt;130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia. Results: Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P &lt; 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (odds ratio [OR]: 0.70 [95% CI: 0.60-0.81]; P &lt; 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan. Conclusions: Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (This study will evaluate the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255)

Coronary perforation incidence, outcomes and temporal trends (COPIT): a systematic review and meta-analysis

Coronary perforation is a potentially life-threatening complication of percutaneous coronary intervention (PCI). We studied incidence, outcomes and temporal trends following PCI-related coronary artery perforation (CAP). Methods: Prospective systematic review and meta-analysis including meta-regression using MEDLINE and EMBASE to November 2020. We included ‘all-comer’ PCI cohorts including large PCI registries and randomised controlled trials and excluding registries or trials limited to PCI in high-risk populations such as chronic total occlusion PCI or cohorts treated only with atheroablative devices. Regression analysis and corresponding correlation coefficients were performed comparing perforation incidence, mortality rate, tamponade rate and the rate of Ellis III perforations against the midpoint (year) of data collection to determine if a significant temporal relationship was present. Results: 3997 studies were screened for inclusion. 67 studies met eligibility criteria with a total of 5 568 191 PCIs included over a 38-year period (1982–2020). The overall pooled incidence of perforation was 0.39% (95% CI 0.34% to 0.45%) and remained similar throughout the study period. Around 1 in 5 coronary perforations led to tamponade (21.1%). Ellis III perforations are increasing in frequency and account for 43% of all perforations. Perforation mortality has trended lower over the years (7.5%; 95% CI 6.7% to 8.4%). Perforation risk factors derived using meta-regression were female sex, hypertension, chronic kidney disease and previous coronary bypass grafting. Coronary perforation was most frequently caused by distal wire exit (37%) followed by balloon dilation catheters (28%). Covered stents were used to treat 25% of perforations, with emergency cardiac surgery needed in 17%. Conclusion: Coronary perforation complicates approximately 1 in 250 PCIs. Ellis III perforations are increasing in incidence although it is unclear whether this is due to reporting bias. Despite this, the overall perforation mortality rate (7.5%) has trended lower in recent years. Limitations of our findings include bias that may be introduced through analysis of multidesign studies and registries without pre-specified standardised perforation reporting CMore research into coronary perforation management including the optimal use of covered stents seems warranted

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index

Background: In heart failure with reduced ejection fraction (HFrEF), there is an “obesity paradox”, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a SGLT2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods and Results: BMI was examined using standard categories i.e. underweight (&lt;18.5 kg/m2); normal weight (18.5-24.9 Kg/m2); overweight (25.0-29.9 Kg/m2); obesity class I (30.0-34.9 Kg/m2); class II (35.0-39.9 Kg/m2) and class III (≥40 Kg/m2). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% CI) for the primary outcome with obesity category 1, the lowest risk group, as reference was: under-/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI e.g., HR for primary outcome: under-/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00); P for interaction=0.79. The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) Kg (p&lt;0.001). Conclusion: We confirmed an “obesity survival paradox” in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied. Clinical Trial Registration: ClinicalTrials.gov number NCT03036124 (https://clinicaltrials.gov/ct2/show/NCT03036124