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Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease: Comparative Effectiveness Research of Existing Technologies

Periodic Report Summary 1 - DISCHARGE (Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease: Comparative Effectiveness Research of Existing Technologies)

Project Context and Objectives:
Coronary artery disease (CAD) is the leading cause of death in high-income countries. Invasive coronary angiography (ICA) is the reference standard for the diagnosis of CAD and allows immediate therapy. However, only 40% of patients undergoing ICA actually have obstructive CAD and ICA has relatively rare but considerable risks. Coronary computed tomography (CT) is the most accurate diagnostic test for CAD currently available, excellent for the exclusion of disease with high certainty. CT may become the most effective strategy to reduce the ca. 2 million annual negative ICAs in Europe by enabling early and safe discharge of the majority of patients with an intermediate risk of CAD.
To evaluate this, the DISCHARGE project with a 5-year duration was implemented by a multinational European consortium. The core of the project is the DISCHARGE trial, a pragmatic randomised controlled trial (PRCT). The primary hypothesis is that CT is superior to ICA for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke) after a maximum follow-up of 4 years in a selected broad population of stable chest pain patients with intermediate pretest probability (10-60%) of CAD. This will be assessed using a pragmatic randomised controlled design in order to generate practical and usable outcomes for clinical decision-making according to comparative effectiveness research methodology. The trial includes 23 clinical sites from 18 European countries which will recruit more than 3500 patients ensuring broad geographical representation. Further areas of interest to which own work packages are dedicated to in the trial are radiation exposure, cost-effectiveness, quality of life, systematic review of evidence and health technology assessment, and gender differences. All work packages are supported by the lead statistician and his staff and are led by experts in the field.

Project Results:
During the kick-off meeting in 2014 and annual meeting in 2015 the work package leaders introduced their topics and all investigators and other staff members were trained for the pilot study and the PRCT. Ethical approval was obtained at all clinical sites, except for the UK due to the lengthy process. Final approval in the UK is expected by fall 2015. The PRCT was registered at https://clinicaltrials.gov/NCT02400229 with the primary outcome MACE and over 100 secondary and other outcomes. A Dissemination Committee (DC) with 13 members and Dissemination Policies were established to ensure efficient and maximum output of the project and a fair distribution of authorships.
To ensure consistency and quality in cardiac CT reading, all clinical sites participated in a workshop at Charité for one week in March 2014. This workshop was especially valuable for junior physicians with less experience to enable their participation in the PRCT. Readers with SCCT level II or equivalents also participated.
So far, over 900 patients have been included in the DISCHARGE pilot study to collect micro-costing data for cost-effectiveness and to choose and evaluate quality of life instruments. A general 10-steps guide for cardiac CT acquisition and reconstruction was developed and complemented by scanner-specific protocols for the scanners in the trial. For image quality, test images had to be sent for evaluation to the corelab at Charité and their quality improved through this measure.
The PRCT will start after this reporting period and all investigators are well prepared. Clinical monitoring is being set up in all participating countries to ensure adherence to Good Clinical Practice. A GCP-compliant study-specific database was developed with SecuTrial® for continuous efficient data management. Serious Adverse Events (SAEs) will be reported in the database and faxed to Charité to ensure safety. A Data Safety Monitoring Board (DSMB) will review the safety data regularly and a Clinical Events Committee (CEC) will assess MACE. The Steering Committee was confirmed during the kick-off meeting to give advice and provide decisions when issues arise that cannot be solved by the responsible party. For independent expert advice, an External Advisory Board (EAB) has been formed.
To inform DISCHARGE partners and stakeholders, a homepage was set up under www.dischargetrial.eu with an external area for the public and an internal one for the DISCHARGE partners.

Potential Impact:
Although diagnostic accuracy of computed tomography angiography (CTA) has been confirmed in several studies in the near past, there is little evidence of the effectiveness in the large population of patients with an intermediate pretest probability. We expect our results to support the hypothesis that CTA is also effective in this important patient population.
From the economic point of view, our hypothesis is that CTA is cost-effective compared to invasive coronary angiography (ICA). The reason is that patients with a low to intermediate pretest probability are likely to have negative results, gained by the cheaper CTA, making a more expensive ICA obsolete. On the other hand, we take into account, that CTA is obsolete in patients with CAD, requiring treatment by ICA. We assume that the potential savings by avoiding ICA in patients without CAD exceed additional costs, caused by diseased patients, requiring ICA after CTA for treatment. This leads to potential savings on a macroeconomic level. Currently, there are 2 million ICA examinations with negative results in the EU. By using CTA as a non-invasive and cheaper diagnostic alternative, a reasonable amount of possible savings becomes evident.
Although ICA is a well-known and widely spread diagnostic test, being conducted by experienced physicians, it remains an invasive test with a low but evident chance of adverse events (AEs). Our research hypothesis is that replacing a certain amount of ICA examinations by CTA, being a non-invasive test, leads to reduced AE rates. Adverse events can be subdivided into non-serious and serious adverse events (SAE). Major adverse cardiovascular events (MACE) are an important subcategory of SAE because of their severity and therefore the need of fast and intensive treatment. Therefore, the occurrence of MACE is the primary endpoint. We expect that the rate of MACE is lower in patients, receiving CTA in comparison with patients, being diagnosed by using ICA.
Because of these two explanations, we expect our results to support the hypothesis that the supplement of ICA by CTA will lead to relevant savings for health care systems and with that, for national economies.

List of Websites:
www.dischargetrial.eu