Inadequate control of heart rate in patients with stable angina: results from the European heart survey.

AIMS: To examine resting heart rate (HR) in a population presenting with stable angina in relation to prior and subsequent pharmacological treatment, comorbid conditions and clinical outcome. METHODS AND RESULTS: The European Heart Survey was a prospective, observational, cohort study of 3779 patients with stable angina newly presenting to cardiology services. Mean baseline resting HR was 73 beats/min (bpm) and 52.3% of patients had a baseline HR > 70 bpm. Over half of patients were on no chronotropic medication at baseline. Patients with chronic respiratory disease or diabetes had higher resting HRs (75-76 bpm), and were more likely to have been receiving calcium channel blockers at baseline assessment. Overall, beta-blockers were the most common treatment administered following cardiologist assessment, but were used less frequently in patients with chronic respiratory disease and diabetes, and the dosages used were less than that found to be effective in clinical trials. Mean daily doses of metoprolol, bisoprolol, carvedilol, and atenolol were 75 mg, 6 mg, 19 mg and 55 mg, respectively. Higher HR at baseline was associated with higher rates of cardiovascular mortality and hospitalisation for heart failure. CONCLUSION: Control of ischaemic symptoms through heart rate modification in patients with angina is currently inadequate, both by primary referring physicians and cardiologists. Given the adverse outcome associated with higher resting heart rates in this as in other studies, and the availability of specific HR reducing strategies, attention should be given to achieving optimal HR control.

Gender differences in the management and clinical outcome of stable angina.

BACKGROUND: We sought to examine the impact of gender on the investigation and subsequent management of stable angina and to assess gender differences in clinical outcome at 1 year. METHODS AND RESULTS: The Euro Heart Survey of Stable Angina enrolled patients with a clinical diagnosis of stable angina on initial assessment by a cardiologist. Baseline clinical details and cardiac investigations planned or performed within a 4-week period of the assessment were recorded, and follow-up data were collected at 1 year. A total of 3779 patients were included in the survey; 42% were female. Women were less likely to undergo an exercise ECG (odds ratio, 0.81; 95% CI, 0.69 to 0.95) and less likely to be referred for coronary angiography (odds ratio, 0.59; 95% CI, 0.48 to 0.72). Antiplatelet and statin therapies were used significantly less in women than in men, both at initial assessment and at 1 year, even in those in whom coronary disease had been confirmed. Women with confirmed coronary disease were less likely to be revascularized than their male counterparts and were twice as likely to suffer death or nonfatal myocardial infarction during the 1-year follow-up period (hazard ratio, 2.09; 95% CI, 1.13 to 3.85), even after multivariable adjustment for age, abnormal ventricular function, severity of coronary disease, and diabetes. CONCLUSIONS: Significant gender bias has been identified in the use of investigations and evidence-based medical therapy in stable angina. Women were also less likely to be revascularized. The observed bias is of particular concern in light of the adverse prognosis observed among women with stable angina and confirmed coronary disease.

Achievements and Limitations of Evidence-Based Medicine.

Evidence-based medicine (EBM) has a long history, but was revived in the early 1990s by a campaign mounted by a movement that took its name. The EBM movement focused attention on the need for greater objectivity in medical decision-making and led to the Cochrane Collaboration, which provides reviews of evidence on the basis of comparative research. Important limitations of EBM's effect on medicine have also emerged. Failure to acknowledge the limitations of clinical trials and systematic reviews has limited their applicability to individual patients' circumstances. An almost exclusive focus on drugs and devices has left vast areas of health care in an evidence vacuum. An overdependence on commissions for its research may have limited its independence in selecting what it investigates. EBM needs to widen its scope beyond drugs and devices to address many areas that often lack evidence at present, notably, health policy, management, and reforms.

Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy.

OBJECTIVES: This study was designed to compare the long-term consequences of percutaneous transluminal coronary angioplasty (PTCA) and continued medical treatment. BACKGROUND: The long-term effects of percutaneous coronary intervention need evaluating, especially in comparison with an alternative policy of continued medical treatment. METHODS: The Second Randomized Intervention Treatment of Angina (RITA-2) is a randomized trial of PTCA versus conservative (medical) care in 1,018 patients considered suitable for either treatment option. Information on clinical events, interventions, and symptoms is available for a median seven years follow-up. RESULTS: Death or myocardial infarction (MI) occurred in 73 (14.5%) PTCA patients and 63 (12.3%) medical patients (difference +2.2%, 95% confidence interval -2.0% to +6.4%, p = 0.21). There were 43 deaths in both groups, of which 41% were cardiac-related. Among patients assigned PTCA 12.7% subsequently had coronary artery bypass grafts, and 14.5% required additional non-randomized PTCA. Most of these re-interventions occurred within a year of randomization, and after two years the re-intervention rate was 2.3% per annum. In the medical group, 35.4% required myocardial revascularization: 15.0% in the first year and an annual rate of 3.6% after two years. An initial policy of PTCA was associated with improved anginal symptoms and exercise times. These treatment differences narrowed over time, mainly because of coronary interventions in medical patients with severe symptoms. CONCLUSIONS: In RITA-2 an initial strategy of PTCA did not influence the risk of death or MI, but it improved angina and exercise tolerance. Patients considered suitable for PTCA or medical therapy can be safely managed with continued medical therapy, but percutaneous intervention is appropriate if symptoms are not controlled.

Long-Term Use of Cardiovascular Drugs: Challenges for Research and for Patient Care.

Little is known about the benefits and risks of the long-term use of cardiovascular drugs. Evidence from randomized clinical trials (RCTs) rarely goes beyond a few years of follow-up, but patients are often given continuous treatment with multiple drugs well into old age. We focus on 4 commonly used cardiovascular drug classes: aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors given to patients after myocardial infarction. However, the issues raised apply more broadly to all long-term medications across cardiovascular diseases and the whole of medicine. The evidence and limitations of RCTs are addressed, as well as current practice in pre-licensing trials, the increasing problems of polypharmacy (especially in the elderly), the lack of trial evidence for withdrawal of drugs, the role of regulatory authorities and other stakeholders in this challenging situation, and the potential educational solutions for the medical profession. We conclude with a set of recommendations on how to improve the situation of long-term drug use.

Debate: A subversive view of subsets - a dissident clinician's opinion.

Clinical trialists and statisticians are very wary of subgroup analysis, for good reasons. Clinicians have to deal with situations in which subgroups of patients differ widely from one another in their prognosis and response to treatment. Few trials are large enough to demonstrate convincingly these differences in outcome, but often provide suggestive evidence. Should we ignore this and treat all patients as the same, or should we allow dubious statistical evidence to buttress biological plausibility in making clinical decisions?

Experience collecting interim data on mortality: an example from the RALES study.

INTRODUCTION: The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps.

The impact of guideline compliant medical therapy on clinical outcome in patients with stable angina: findings from the Euro Heart Survey of stable angina.

AIMS: The European Society of Cardiology published guidelines for the management of stable angina in 1997, with the objective of promoting an evidence-based approach to the condition. This study focuses on the impact of guideline compliant medical treatment on clinical outcome in patients with stable angina. METHODS AND RESULTS: The Euro Heart Survey of Stable Angina is a multicentre prospective observational study conducted between 2002 and 2003. Patients with a clinical diagnosis of stable angina by a cardiologist were enrolled and follow-up was conducted at 1 year. The primary outcome of interest was death or myocardial infarction (MI). The increasing intensity of guideline compliant medical therapy was quantified by means of a simple treatment score based on the use of guideline advocated therapies: antiplatelets, statins, and beta-blockers. A total of 3779 patients were included in the initial survey. Increasing intensity of guideline compliant therapy at initial assessment was associated with a reduction in death and MI during follow-up in patients with angina and confirmed coronary disease (HR 0.68; 95% CI 0.49-0.95 per unit increase in treatment score). All cardiovascular events were also significantly reduced in this subgroup (HR 0.82; 95% CI 0.69-0.97). The benefits of guideline compliant therapy were only observed in patients with objective evidence of coronary disease. CONCLUSION: Guideline compliant medical therapy improves clinical outcome in patients with stable angina and objective evidence of coronary disease.

Predicting prognosis in stable angina--results from the Euro heart survey of stable angina: prospective observational study.

OBJECTIVES: To investigate the prognosis associated with stable angina in a contemporary population as seen in clinical practice, to identify the key prognostic features, and from this to construct a simple score to assist risk prediction. DESIGN: Prospective observational cohort study. SETTING: Pan-European survey in 156 outpatient cardiology clinics. PARTICIPANTS: 3031 patients were included on the basis of a new clinical diagnosis by a cardiologist of stable angina with follow-up at one year. MAIN OUTCOME MEASURE: Death or non-fatal myocardial infarction. RESULTS: The rate of death and non-fatal myocardial infarction in the first year was 2.3 per 100 patient years; the rate was 3.9 per 100 patient years in the subgroup (n = 994) with angiographic confirmation of coronary disease. The clinical and investigative factors most predictive of adverse outcome were comorbidity, diabetes, shorter duration of symptoms, increasing severity of symptoms, abnormal ventricular function, resting electrocardiogaphic changes, or not having any stress test done. Results of non-invasive stress tests did not significantly predict outcome in the population who had tests done. A score was constructed using the parameters predictive of outcome to estimate the probability of death or myocardial infarction within one year of presentation with stable angina. CONCLUSIONS: A score based on the presence of simple, objective clinical and investigative variables makes it possible to discriminate effectively between very low risk and very high risk patients and to estimate the probability of death or non-fatal myocardial infarction over one year.

The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina.

AIMS: The Euro Heart Survey of Stable Angina set out to prospectively study the presentation and management of patients with stable angina as first seen by a cardiologist in Europe, with particular reference to adherence to existing guidelines and regional variability in patient presentation and initial assessment. METHODS AND RESULTS: Consecutive outpatients with a clinical diagnosis by a cardiologist of stable angina were enrolled in the study and 3779 patients were included in the analysis. The average age was 61 years and 58% were male. The majority of patients (88%) had mild to moderate angina, CCS class I or II. Despite a high prevalence of recognized risk factors, 27% did not have cholesterol and 33% did not have glucose measured within 4 weeks of assessment. The resting ECG was abnormal in 41% of patients. An exercise ECG was performed or planned as part of initial investigation in 76% of patients and 18% had a stress imaging test such as perfusion scanning or stress echo. A coronary angiogram was performed or planned in 41%, and 64% had an echo. The time from assessment to investigation varied widely, particularly for angiography. One in 10 patients had neither any form of stress test nor angiography, with marked regional variation. Availability of invasive facilities increased the likelihood of both non-invasive and invasive investigations. Those with more severe symptoms or longer duration of symptoms or a positive non-invasive test were more likely to have angiography. In multivariable analysis, a positive stress test was the strongest predictor of the use of angiography, associated with a six-fold increase in the likelihood of invasive investigation. However, gender and availability of facilities were also predictive. CONCLUSION: Considerable variation in features at presentation and use of investigations has been identified in the stable angina population in Europe. The evaluation of biochemical cardiovascular risk factors was suboptimal. Overall rates of non-invasive investigation for angina and the clinical appropriateness of factors predictive of the use of invasive investigation were broadly in line with guidelines. However, the influence of access to facilities, and marked international variation in rates and timing of investigation suggest that factors unrelated to clinical need are also influential in the management of patients with stable angina.

The initial management of stable angina in Europe, from the Euro Heart Survey: a description of pharmacological management and revascularization strategies initiated within the first month of presentation to a cardiologist in the Euro Heart Survey of Stable Angina.

AIMS: In order to assess adherence to guidelines and international variability in management, the Euro Heart Survey of Newly Presenting Angina prospectively studied medical therapy, percutaneous coronary intervention (PCI), and surgery in patients with new-onset stable angina in Europe. METHODS AND RESULTS: Consecutive patients, 3779 in total, with a clinical diagnosis of stable angina by a cardiologist were enrolled. After initial assessment by a cardiologist, 78% were treated with aspirin, 48% with a statin, and 67% with a beta-blocker. ACE-inhibitors were prescribed by the cardiologist in 37% overall. Revascularization rates were low, with only 501 (13%) patients having PCI or coronary bypass surgery performed or planned. However, when restricted to patients with coronary disease documented within 4 weeks of assessment, over 50% had revascularization performed or planned. Among other factors, the national rate of angiography and availability of invasive facilities significantly predicted the likelihood of revascularization, OR 2.4 and 2.0, respectively. CONCLUSION: This survey shows a shortfall between guidelines and practice with regard to the use of evidence-based drug therapy and evidence that revascularization rates are strongly influenced by non-clinical, in addition to clinical, factors.

What is right and what is wrong about evidence-based medicine?

Practice should, as much as possible, be based on good science. Randomized clinical trials can provide the best evidence, but they have serious limitations. First, many clinical situations, such as cardiac arrest and pain relief, do not lend themselves to randomization. Second, trials seldom can study the effects seen in different subgroups, nor can the results always be extrapolated from the restricted groups of patients recruited into trials. Finally, there is publication bias: the failure to report "negative" trials and the biased presentation of results by investigators and sponsors.

Issues in regulatory guidelines for data monitoring committees.

As clinical trials have emerged as the major research method for evaluating new interventions, the process for monitoring intervention safety and benefit has also evolved. The Data Monitoring Committee (DMC) has become the standard approach to implement this responsibility for many Phase III trials. Recent draft guidelines on the operation of DMCs by the Food and Drug Administration (FDA) have raised issues that need further clarification or discussion, especially for industry sponsored trials. These include, the time when DMCs are needed, the role of the independent statistician to support the DMC, and sponsor participation at DMC meetings. This paper provides an overview of these issues, based on the discussions at the January, 2003 workshop sponsored by Duke Clinical Research Institute.