Natalie K Fitzpatrick

The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model

OBJECTIVE To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG). DATA SOURCES MEDLINE and EMBASE were searched from 1966 until 30 November 2008. REVIEW METHODS We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model. RESULTS We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario). CONCLUSIONS Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.

Evaluating the quality of research into a single prognostic biomarker: a systematic review and meta-analysis of 83 studies of C-reactive protein in stable coronary artery disease.

In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.

Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study in prioritising patients waiting for coronary artery surgery

Objective To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. Design Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. Data sources Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. Results The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10 000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of £20 000-£30 000 (€22 000-€33 000;

Ethnic differences in long-term improvement of angina following revascularization or medical management: a comparison between south Asians and white Europeans

32 000-

Use of electronic health records to ascertain, validate and phenotype acute myocardial infarction: A systematic review and recommendations

48 000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was <£410 compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100 000 patients at an additional cost of £245 000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. Conclusion Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.

Translational phases of evidence in a prognostic biomarker: a systematic review and meta-analysis of natriuretic peptides and the prognosis of stable coronary disease

BACKGROUND It is not known whether there are disparities in morbidity outcomes between south Asians and whites with established coronary disease. METHODS Six-year prospective cohort study to determine whether improvement of angina symptoms differs between 196 south Asians and 1508 whites following revascularization or medical management. RESULTS 43.9% of south Asians reported improvement in angina at 6 years compared with 60.3% of whites (age-adjusted OR 0.56, 95% CI 0.41-0.76, adjusted for diabetes, hypertension, smoking, number of diseased vessels, left ventricular function and social class OR 0.59, 95% CI 0.41-0.85). Similar proportions of whites and south Asians underwent percutaneous coronary intervention (PCI) (19.6% versus 19.9%) and coronary artery bypass surgery (CABG) (32.8% versus 30.1%). South Asians were less likely to report improved angina after PCI (OR 0.19, 95% CI 0.06-0.56) or CABG (OR 0.36, 95% CI 0.17-0.74). There was less evidence of ethnic differences in angina improvement when treatment was medical (OR 0.87, 95% CI 0.48-1.57). CONCLUSION South Asians were less likely to experience long-term improvements in angina than whites after receipt of revascularization. Further research is needed to identify why these ethnic groups differ in symptomatic prognosis following revascularization for coronary disease and how these differences may be mitigated.

The determinants and effect of shared care on patient outcomes and psychiatric admissions - an inner city primary care cohort study.

Electronic health records (EHRs) offer the opportunity to ascertain clinical outcomes at large scale and low cost, thus facilitating cohort studies, quality of care research and clinical trials. For acute myocardial infarction (AMI) the extent to which different EHR sources are accessible and accurate remains uncertain. Using MEDLINE and EMBASE we identified thirty three studies, reporting a total of 128658 patients, published between January 2000 and July 2014 that permitted assessment of the validity of AMI diagnosis drawn from EHR sources against a reference such as manual chart review. In contrast to clinical practice, only one study used EHR-derived markers of myocardial necrosis to identify possible AMI cases, none used electrocardiogram findings and one used symptoms in the form of free text combined with coded diagnosis. The remaining studies relied mostly on coded diagnosis. Thirty one studies reported positive predictive value (PPV)≥ 70% between AMI diagnosis from both secondary care and primary care EHRs and the reference. Among fifteen studies reporting EHR-derived AMI phenotypes, three cross-referenced ST-segment elevation AMI diagnosis (PPV range 71-100%), two non-ST-segment elevation AMI (PPV 91.0, 92.1%), three non-fatal AMI (PPV range 82-92.2%) and six fatal AMI (PPV range 64-91.7%). Clinical coding of EHR-derived AMI diagnosis in primary care and secondary care was found to be accurate in different clinical settings and for different phenotypes. However, markers of myocardial necrosis, ECG and symptoms, the cornerstones of a clinical diagnosis, are underutilised and remain a challenge to retrieve from EHRs.

Methods for Enhancing the Reproducibility of Observational Research Using Electronic Health Records: Preliminary Findings from the CALIBER Resource

Context Translational phases of study are important in evaluating whether a prognostic biomarker is likely to have impact on clinical practice but systematic evaluations of such evidence are lacking. Objective To systematically evaluate the clinical usefulness of the published literature on the association of natriuretic peptides (NP) and prognosis in stable coronary disease. Data sources MEDLINE and EMBASE until the end of July 2009, without restrictions. Study selection Prospective studies measuring NP in people with stable coronary disease who were followed-up for all cause mortality, coronary or cardiovascular events. Data extraction Two independent reviewers categorised studies according to the American Heart Association phase of study, and extracted data according to the study reporting guidelines from the American Heart Association and REMARK. Results Systematic review of 19 studies found 17 which were phase 2, reporting an association between NP and events, two phase 3 studies, statistically examining the incremental prognostic value of NP, but no studies assessing whether NP predicted risk sufficiently to change management (phase 4), improve clinical outcomes (phase 5) or cost effectiveness (phase 6). No study referred to a statistical analytic protocol. Meta-analysis of 14 studies, reporting 18 841 patients and 1655 outcome events, found an RR for events of 3.28 (95% CI 2.45 to 4.38) comparing top versus bottom third of NP. This effect was 26% lower among the five studies which adjusted for a priori confounders (age, sex, renal function and left ventricular function) and 38% lower when adjusting for publication bias (Eggers p=0.001). Conclusion The unbiased strength of association of NP with prognosis in stable coronary disease is unclear, and there is a lack of reports of clinically useful measures of prediction and discrimination or studies relating NP levels to clinical decision making. The available literature is confined to early phases and is of limited clinical usefulness.

Serotonin reuptake inhibitors and mortality in epilepsy: A linked primary-care cohort study

The aim of this study was to determine the factors associated with receipt of different levels of shared care, and the effect of shared care on patient outcomes. A total of 349 patients with severe mental illness were selected from general practice lists. Patient functioning was assessed using standardised questionnaires, and GPs completed a questionnaire about patients’ shared care arrangements at baseline (response-rate 79 %). Patients were followed up at 12 months. Receipt of high shared care was associated with greater patient satisfaction with services and social functioning at baseline (p < 0.005). Patients receiving high shared care showed greater improvements in SF-12 mental health scores at follow-up compared to low shared care groups (p = 0.02). This effect was abolished after adjustment for age, sex and psychiatric diagnosis. Receipt of high shared care was not associated with demographic or clinical characteristics. High shared care had limited value for patients in terms of improved clinical, social or general health functioning over one year.

Prospective validity of measuring angina severity with Canadian Cardiovascular Society class: The ACRE study

The ability of external investigators to reproduce published scientific findings is critical for the evaluation and validation of health research by the wider community. However, a substantial proportion of health research using electronic health records, data collected and generated during routine clinical care, potentially cannot reproduced. With the complexity, volume and variety of electronic health records made available for research steadily increasing, it is critical to ensure that findings from such data are reproducible and replicable by researchers. In this paper, we present some preliminary findings on how a series of methods and tools utilized in adjunct scientific disciplines can be used to enhance the reproducibility of research using electronic health records.