Cornelia Junghans

Recruiting patients to medical research: double blind randomised trial of "opt-in" versus "opt-out" strategies

Abstract ObjectiveTo evaluate the effect of opt-in compared with opt-out recruitment strategies on response rate and selection bias. DesignDouble blind randomised controlled trial. SettingTwo general practices in England. Participants510 patients with angina. InterventionPatients were randomly allocated to an opt-in (asked to actively signal willingness to participate in research) or opt-out (contacted repeatedly unless they signalled unwillingness to participate) approach for recruitment to an observational prognostic study of patients with angina. Main outcome measuresRecruitment rate and clinical characteristics of patients. Results The recruitment rate, defined by clinic attendance, was 38% (96/252) in the opt-in arm and 50% (128/258) in the opt-out arm (P = 0.014). Once an appointment had been made, non-attendance at the clinic was similar (20% opt-in arm v 17% opt-out arm; P = 0.86). Patients in the opt-in arm had fewer risk factors (44% v 60%; P = 0.053), less treatment for angina (69% v 82%; P = 0.010), and less functional impairment (9% v 20%; P = 0.023) than patients in the opt-out arm. Conclusions The opt-in approach to participant recruitment, increasingly required by ethics committees, resulted in lower response rates and a biased sample. We propose that the opt-out approach should be the default recruitment strategy for studies with low risk to participants.

Inequity of access to investigation and effect on clinical outcomes: prognostic study of coronary angiography for suspected stable angina pectoris

Objectives To determine whether coronary angiography for suspected stable angina pectoris is underused in older patients, women, south Asian patients, and those from socioeconomically deprived areas, and, if it is, whether this is associated with higher coronary event rates. Design Multicentre cohort with five year follow-up. Setting Six ambulatory care clinics in England. Participants 1375 consecutive patients in whom coronary angiography was individually rated as appropriate with the Rand consensus method. Main outcome measures Receipt of angiography (420 procedures); coronary mortality and acute coronary syndrome events. Results In a multivariable analysis, angiography was less likely to be performed in patients aged over 64 compared with those aged under 50 (hazard ratio 0.60, 95% confidence interval 0.38 to 0.96), women compared with men (0.42, 0.35 to 0.50), south Asians compared with white people (0.48, 0.34 to 0.67), and patients in the most deprived fifth compared with the other four fifths (0.66, 0.40 to 1.08). Not undergoing angiography when it was deemed appropriate was associated with higher rates of coronary event. Conclusions At an early stage after presentation with suspected angina, coronary angiography is underused in older people, women, south Asians, and people from deprived areas. Not receiving appropriate angiography was associated with a higher risk of coronary events in all groups. Interventions based on clinical guidance that supports individualised management decisions might improve access and outcomes.

Incremental prognostic value of the exercise electrocardiogram in the initial assessment of patients with suspected angina: cohort study

Objective To determine whether resting and exercise electrocardiograms (ECGs) provide prognostic value that is incremental to that obtained from the clinical history in ambulatory patients with suspected angina attending chest pain clinics. Design Multicentre cohort study. Setting Rapid access chest pain clinics of six hospitals in England. Participants 8176 consecutive patients with suspected angina and no previous diagnosis of coronary artery disease, all of whom had a resting ECG recorded. 4848 patients with a summary exercise ECG result recorded (positive, negative, equivocal for ischaemia) comprised the summary ECG subset of whom 1422 with more detailed exercise ECG data recorded comprised the detailed ECG subset. Main outcome measure Composite of death due to coronary heart disease or non-fatal acute coronary syndrome during median follow-up of 2.46 years. Results Receiver operating characteristics curves for the basic clinical assessment model alone and with the results of resting ECGs were superimposed with little difference in the C statistic. With the exercise ECGs the C statistic in the summary ECG subset increased from 0.70 (95% confidence interval 0.68 to 0.73) to 0.74 (0.71 to 0.76) and in the detailed ECG subset from 0.74 (0.70 to 0.79) to 0.78 (0.74 to 0.82). However, risk stratified cumulative probabilities of the primary end point at one year and six years for all three prognostic indices (clinical assessment only; clinical assessment plus resting ECG; clinical assessment plus resting ECG plus exercise ECG) showed only small differences at all time points and at all levels of risk. Conclusion In ambulatory patients with suspected angina, basic clinical assessment encompasses nearly all the prognostic value of resting ECGs and most of the prognostic value of exercise ECGs. The limited incremental value of these widely applied tests emphasises the need for more effective methods of risk stratification in this group of patients.

Appropriateness Criteria for Coronary Angiography in Angina: Reliability and Validity

Context Can patient-specific appropriateness criteria developed by experts validly determine which patients with suspected angina should undergo coronary angiography? Contribution In this study, expert panels scored hundreds of patient-specific scenarios for coronary angiography as inappropriate, uncertain, or appropriate. Using a computer algorithm, researchers matched the devised appropriateness indications to 9356 clinic patients with recent-onset chest pain. They found that many patients judged as appropriate candidates did not undergo angiography and that this group had more subsequent coronary events than did patients who appropriately did have angiography. Implication Patient-specific appropriateness criteria are a promising tool for improving care of patients with suspected angina. The Editors The decision to perform diagnostic and prognostic investigations in clinical medicine is uncommonly supported by evidence from randomized trials, yet it has major consequences in terms of cost and clinical outcomes when treatments are contingent on investigation results. Deciding which patients with suspected chronic stable angina pectoris should undergo coronary angiography is an important example of this general phenomenon. Although broad conventional clinical guideline recommendations (1, 2) and patient-specific appropriateness criteria (3) have been developed, 3 key questions about their clinical value remain unanswered. First, are the recommendations for investigation reliable, in the sense of being reproducible by independent groups? Good levels of agreement are essential for clinical credibility and accurate measurement of the frequency of underuse. Second, are the recommendations graded? Although the decision to perform angiography is binary (it either is or is not done), many decisions in clinical medicine are made in the gray zone, where understanding thresholds of benefit is crucial (4). For revascularization, prognostically important underuse was found not only among patients rated as appropriate candidates for revascularization but also among patients with scores denoting uncertainty about the appropriateness of this procedure (5). Third, and most important, are the recommendations valid in terms of prognosis? If so, then coronary event rates should be higher among patients not undergoing the recommended procedure (reflecting underuse). This might occur if medical or invasive management were optimized (6) in patients with the more definitive diagnosis that angiography offers. Although some studies have reported that angiography for suspected angina is underused (79), they have not reported whether such underuse has prognostic consequences. In the setting of acute myocardial infarction, patients not undergoing angiography that was considered necessary had worse outcomes (4, 10), but studies among ambulatory patients with chest pain at the point of diagnosis are lacking. We sought to address these 3 questions in the ARIA (Appropriateness of Referral and Investigation of Angina) study, in which 2 independent panels rated the appropriateness of patient-specific clinical indications by using the RAND appropriateness method. These appropriateness ratings were then matched to a large consecutive ambulatory cohort of patients with first-presentation chest pain who were followed for coronary events. Methods Design The study involved 3 stages: development of new appropriateness ratings (on which full details are published elsewhere [11]), matching these ratings to a patient cohort, and following the cohort for clinical outcomes (Figure 1). Figure 1. Study flow diagram. ACS= acute coronary syndrome; CHD= coronary heart disease. Panel Members We convened 2 independent panels with different moderators, who at each stage were unaware of the others ratings. Twenty-two physicians from 9 centers in England, Ireland, and Scotland took part in these panels, rating the appropriateness of angiography by using the RAND appropriateness method (12). Only 1 of the 9 centers was also involved in the 6 centers for patient recruitment. We sought nominations within centers to reflect a balance of experience (years since qualification); sex; and, among specialists, invasive and noninvasive practice. Sixteen of the clinicians had published research on the management of coronary disease. Each panel consisted of 5 cardiologists, 5 family physicians, and 1 cardiothoracic surgeon. Indications for Angiography Panelists judged appropriateness of angiography on a 9-point scale, on which scores of 1 to 3 denoted inappropriate use (no benefit of angiography, possible harms), 4 to 6 denoted uncertainty about use (when harms and benefits were judged as approximately equal, or when the best available evidence did not support a judgment either way), and 7 to 9 denoted appropriate use (benefits were judged to outweigh harms). Combinations of routinely assessed clinical factors were used to define specific clinical indications (scenarios) spanning the range of pretest probability of coronary disease from very low (<5%) to very high (>95%). Eight clinical descriptors were identified that influence the decision to perform angiography in people with suspected angina (but in the absence of previous definite coronary disease); Table 1 shows how these descriptors were combined into clinical indications. The descriptors are age (<40, 40 to 49, 50 to 59, 60 to 74, or 75 to 84 years), sex, typicality of symptoms, severity of symptoms (Canadian Cardiovascular Society class), medication for symptoms (submaximal or maximal), coronary risk factors (low, medium, or high), resting electrocardiography (ECG) findings (normal or abnormal), and exercise ECG findings (none, normal, abnormal, or very abnormal). Indications were grouped in 3 broad clinical presentations: typical angina symptoms (900 indications), atypical angina symptoms (900 indications), and nonspecific chest pain (600 indications). Table 1. Most Frequent Indications for Angiography and Guideline Recommendations, by Angiography Appropriateness Rating and Symptom Typicality Appropriateness Scores We developed software for the panel members to enter and review their own scores for each patient indication and access definitions of terms. Panelists were invited to base their ratings on peer-reviewed research evidence and were given a literature review with evidence tables, narrative synopses, and graded strength of evidence (11). We identified key articles on the role of angiography in the diagnosis of coronary artery disease from existing guidelines, systematic reviews, and MEDLINE, and then performed forward citation tracking in the Science Citation Index until March 2003. Panel members did the first round of rating independently. Panels then met over 2 days in July 2003, during which they followed an identical protocol. Each panelist was given a personalized report containing their own first-round ratings; the medians of their whole panel; and the range, with areas of disagreement highlighted. Panel members had the opportunity to change their ratings in light of the panel discussion, but in accordance with the RAND appropriateness method (12); no attempt was made to force the panel to consensus. Table 1 shows the most frequently occurring indications according to symptom typicality and gives the appropriateness category and the nearest match recommendation from conventional broad guidelines. Patients Using a computer algorithm, we matched the ARIA indications and their associated ratings to 9356 consecutive patients attending rapid-access chest pain clinics in 6 urban centers in the United Kingdom (Oldchurch, Newham, Kingston, Manchester, Blackburn, and Burnley) between 1996 and 2002. The sample size was determined by the availability of baseline data in these clinics that were systematically collected by using the same electronic record system. Physicians made decisions about investigation on these patients independent of the ARIA appropriateness ratings. These ambulatory care clinics are run by cardiology teams and accept same-day referrals from family physicians of patients with recent-onset chest pain in whom stable angina pectoris is suspected. Patients who had previously undergone angiography or received a diagnosis of coronary disease and those in whom acute or unstable coronary syndromes were suspected were not eligible for referral to these clinics. Using a common database, each center recorded patient age, sex, and ethnicity (South Asian, white, black, or other); whether chest pain was typical, atypical, or nonspecific; smoking, hypertension, hypercholesterolemia, and diabetes status; whether the resting ECG was abnormal; the exercise ECG result; and medical therapy at discharge. Angina symptom severity was not recorded; we assumed that angina was mild when matching patients to indications and performed sensitivity analyses on this assumption. Ethical approval was obtained from a multicenter research ethics committee. Follow-up and Clinical Outcomes More than 99% of patients were successfully matched at the Office for National Statistics and the National Health Service (NHS)wide clearing system. The Office for National Statistics informed us of the date and cause of death or date of hospital discharge. Causes of death and hospitalization were coded according to the International Classification of Diseases, 10th revision. Median follow-up for the cohort was 3 years, until the end of 2003. Use of coronary angiography was obtained from the NHS-wide clearing system. Our a priori primary end point, used in all reports from this data set (1315), was death from coronary heart disease (codes I20 to I25) and hospitalizations due to acute myocardial infarction (codes I21 to I23) and unstable angina (codes I20.0 to I20.9, I24.0, I24.8, and I24.9). The primary discharge diagnosis after hospital admission was used to define nonfatal events in these analyses. To define a group of patients without majo

Presentation of stable angina pectoris among women and South Asian people

Background: There is speculation that women and South Asian people are more likely than men and white people to report atypical angina and that they are less likely to undergo invasive management of angina. We sought to determine whether atypical symptoms of angina pectoris in women and South Asians impacted clinically important outcomes and clinical management. Methods: We prospectively identified 2189 South Asian people and 5605 white people with recent-onset chest pain at 6 chest-pain clinics in the United Kingdom. We documented hospital admissions for acute coronary syndromes, coronary deaths as well as coronary angiography and revascularization procedures. Results: Atypical chest pain was reported by more women than men (56.5% vs 54.5%, p < 0.054) and by more South Asian patients than white patients (59.9% vs 52.5%, p < 0.001). Typical symptoms were associated with coronary death or acute coronary syndromes among women (hazard ratio [HR] 2.30, 95% CI 1.70–3.11, p < 0.001) but not among men (HR 1.23, 95% CI 0.96–1.57, p = 0.10). Typical symptoms were associated with coronary outcomes in both South Asian and white patients. Among those with typical symptoms, women (HR 0.76, 95% CI 0.63–0.92, p = 0.004) and South Asian patients (HR 0.52, 95% CI 0.41–0.67, p < 0.001) were less likely than men and white patients to receive angiography. Interpretation: Compared to those with atypical chest pain, women and South Asian patients with typical pain had worse clinical outcomes. However, sex and ethnic background did not explain differences in the use of invasive procedures.

Case fatality rates for South Asian and Caucasian patients show no difference 2.5 years after percutaneous coronary intervention

Objective To compare short and medium-term prognosis in South Asian and Caucasian patients undergoing percutaneous coronary intervention (PCI) to determine if there are ethnic differences in case death rates. Design Retrospective cohort study. Setting A cardiology referral centre in east London. Patients 9771 patients who underwent PCI from October 2003 to December 2007 of whom 7966 (81.5%) were Caucasian and 1805 (18.5%) were South Asian. Main outcome measures In-hospital major adverse cardiac events (MACE; death, myocardial infarction, stroke and target vessel revascularisation), subsequent revascularisation rates (PCI and coronary artery bypass grafting; CABG) and all-cause mortality during a median follow-up of 2.5 years (range 1.5–3.6 years). Results South Asian patients were younger than Caucasian patients (59.69±0.27 vs 64.69±0.13 years, p<0.0001), and more burdened by cardiovascular risk factors, particularly type II diabetes mellitus (45.9%±1.2% vs 15.7%±0.4%, p<0.0001). The in-hospital rates of MACE were similar for South Asians and Caucasians (3.5% vs 2.8%, p=0.40). South Asians had higher rates of clinically driven PCI for restenosis and subsequent CABG, although Kaplan–Meier estimates of all-cause mortality showed no significant differences; this was regardless of whether PCI was performed post-acute coronary syndrome or as an elective procedure. The adjusted hazard of death for South Asians compared with Caucasians was 1.00 (95% CI 0.81 to 1.23). Conclusion In this large PCI cohort, the in-hospital and longer-term mortality of South Asians appeared no worse than that of Caucasians. South Asians had higher rates of restenosis and CABG during follow-up. Data suggest that the excess coronary mortality for South Asians compared with Caucasians is not explained by differences in case-fatality rates.

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

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.

Is access to specialist assessment of chest pain equitable by age, gender, ethnicity and socioeconomic status? An enhanced ecological analysis

Objectives To determine whether access to rapid access chest pain clinics of people with recent onset symptoms is equitable by age, socioeconomic status, ethnicity and gender, according to need. Design Retrospective cohort study with ecological analysis. Setting Patients referred from primary care to five rapid access chest pain clinics in secondary care, across England. Participants Of 8647 patients aged ≥35 years referred to chest pain clinics with new-onset stable chest pain but no known cardiac history, 7570 with documented census ward codes, age, gender and ethnicity comprised the study group. Patients excluded were those with missing date of birth, gender or ethnicity (n=782) and those with missing census ward codes (n=295). Outcome measures Effects of age, gender, ethnicity and socioeconomic status on clinic attendance were calculated as attendance rate ratios, with number of attendances as the outcome and resident population-years as the exposure in each stratum, using Poisson regression. Attendance rate ratios were then compared with coronary heart disease (CHD) mortality ratios to determine whether attendance was equitable according to need. Results Adjusted attendance rate ratios for patients aged >65 years were similar to younger patients (1.1, 95% CI 1.05 to 1.16), despite population CHD mortality rate ratios nearly 15 times higher in the older age group. Women had lower attendance rate ratios (0.81, 95% CI 0.77 to 0.84) and also lower population CHD mortality rate ratios compared with men. South Asians had higher attendance rates (1.67, 95% CI 1.57 to 1.77) compared with whites and had a higher standardised CHD mortality ratio of 1.46 (95% CI 1.41 to 1.51). Although univariable analysis showed that the most deprived patients (quintile 5) had an attendance rate twice that of less deprived quintiles, the adjusted analysis showed their attendance to be 13% lower (0.87, 95% CI 0.81 to 0.94) despite a higher population CHD mortality rate. Conclusion There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status. More robust and patient focused administrative pathways need to be developed to detect inequity, correction of which has the potential to substantially reduce coronary mortality.

Inpatient Coronary Angiography and Revascularisation following Non-ST-Elevation Acute Coronary Syndrome in Patients with Renal Impairment: A Cohort Study Using the Myocardial Ischaemia National Audit Project

Background International guidelines support an early invasive management strategy (including early coronary angiography and revascularisation) for non-ST-elevation acute coronary syndrome (NSTE-ACS) in patients with renal impairment. However, evidence from outside the UK suggests that this approach is underutilised. We aimed to describe practice within the NHS, and to determine whether the severity of renal dysfunction influenced the provision of angiography and modified the association between early revascularisation and survival. Methods We performed a cohort study, using multivariable logistic regression and propensity score analyses, of data from the Myocardial Ischaemia National Audit Project for patients presenting with NSTE-ACS to English or Welsh hospitals between 2008 and 2010. Findings Of 35 881 patients diagnosed with NSTE-ACS, eGFR of <60 ml/minute/1.73 m2 was present in 15 680 (43.7%). There was a stepwise decline in the odds of undergoing inpatient angiography with worsening renal dysfunction. Compared with an eGFR>90 ml/minute/1.73 m2, patients with an eGFR between 45–59 ml/minute/1.73 m2 were 33% less likely to undergo angiography (adjusted OR 0.67, 95% CI 0.55–0.81); those with an eGFR<30/minute/1.73 m2 had a 64% reduction in odds of undergoing angiography (adjusted OR 0.36, 95%CI 0.29–0.43). Of 16 646 patients who had inpatient coronary angiography, 58.5% underwent inpatient revascularisation. After adjusting for co-variables, inpatient revascularisation was associated with approximately a 30% reduction in death within 1 year compared with those managed medically after coronary angiography (adjusted OR 0.66, 95%CI 0.57–0.77), with no evidence of modification by renal function (p interaction = 0.744). Interpretation Early revascularisation may offer a similar survival benefit in patients with and without renal dysfunction, yet renal impairment is an important determinant of the provision of coronary angiography following NSTE-ACS. A randomised controlled trial is needed to evaluate the efficacy of an early invasive approach in patients with severe renal dysfunction to ensure that all patients who may benefit are offered this treatment option.

Risk assessment after acute coronary syndrome.

Lots of potential but will it end up being yet another risk score?