The theory and practice of imaging outcomes research
Authors: Pamela S Douglas
Journal: The Lancet (2015)

About a decade ago, triggered by unexplained growth and variability in cardiovascular testing,1Iglehart JK Health insurers and medical-imaging policy—a work in progress.N Engl J Med. 2009; 360: 1030-1037Crossref PubMed Scopus (268) Google Scholar efforts to redefine imaging quality led to an appreciation of the importance of selecting the right test for the right patient (ie, giving rise to appropriate use criteria) and measuring the effect of testing on outcomes, in addition to measures such as image acquisition and interpretation.2Douglas PS Taylor A Bild D et al.Outcomes research in cardiovascular imaging: report of a workshop sponsored by the National Heart, Lung, and Blood Institute.JACC Cardiovasc Imaging. 2009; 2: 897-907Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Although appropriate use criteria are now an established part of evidence-based cardiovascular care, imaging outcomes have not been defined in a more meaningful way, partly because of the many steps needed to translate test data into knowledge (ie, diagnostic thinking), action (ie, treatments), and ultimately outcomes.Nevertheless, there have been strong calls to explore the downstream consequences of imaging as a necessary step in more fully understanding its risks and benefits, which would then help to establish scenarios in which imaging does, and does not, add value.3Douglas PS Iskandrian AE Krumholz HM et al.Achieving quality in cardiovascular imaging: proceedings from the American College of Cardiology–Duke University Medical Center think tank on quality in cardiovascular imaging.J Am Coll Cardiol. 2006; 48: 2141-2151Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar This task has been made more difficult in the era following the COURAGE4Boden WE O'Rourke RA Teo KK et al.for the COURAGE Trial Research GroupOptimal medical therapy with or without PCI for stable coronary disease.N Engl J Med. 2007; 356: 1503-1516Crossref PubMed Scopus (3618) Google Scholar and FAME5Tonino PA De Bruyne B Pijls NH et al.for the FAME Study InvestigatorsFractional flow reserve versus angiography for guiding percutaneous coronary intervention.N Engl J Med. 2009; 360: 213-224Crossref PubMed Scopus (2959) Google Scholar trials, in which the diagnosis of anatomical coronary artery disease has been uncoupled from a need for revascularisation, and in the post-CONFIRM era,6Min JK Dunning A Lin FY et al.Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23 854 patients without known coronary artery disease.J Am Coll Cardiol. 2011; 58: 849-860Summary Full Text Full Text PDF PubMed Scopus (570) Google Scholar in which non-obstructive coronary artery disease is recognised to be a powerful predictor of future events.A few trials have been done to rise to this challenge in the primary prevention area and in the triage of acute chest pain, variously using risk factor burden, clinical events, and efficiency as endpoints. Randomised trial data assessing the effect of testing in the very large stable chest pain population have been scarce, but are now present in the form of two new large studies—the Computed Tomography Coronary Angiography in Patients with Suspected Angina due to Coronary Heart Disease: the Scottish Computed Tomography of the HEART (SCOT-HEART) trial7The SCOT-HEART investigatorsCT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel group multicentre trial.Lancet. 2015; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(15)60291-4Google Scholar reported by David Newby and colleagues in The Lancet, and the PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.8Douglas PS, Hoffmann U, Patel MR, et al, for the PROMISE study investigators. Outcomes of anatomic versus functional testing for coronary artery disease. N Engl J Med (in press).Google ScholarIn SCOT-HEART, 4146 patients completing an assessment for stable chest pain were randomly assigned to CT coronary angiography (CTCA) in addition to usual care or to usual care alone, which generally included an exercise treadmill test. The trial's primary endpoint, certainty of the attribution of symptoms to angina due to presence of coronary artery disease, showed an increase in the CTCA group (relative risk 1·79, 95% CI 1·62–1·96), as did the closely related secondary endpoint of certainty of diagnosis of coronary artery disease (2·56, 2·33–2·79). Additional secondary endpoints included diagnostic reclassification and changes in diagnostic and therapeutic approaches, which all happened more frequently in the CTCA group. Although investigators recorded no differences in the frequency or stability of angina, rates of revascularisation, or admittance to hospital, there was a non-significant reduction in the rate of death or myocardial infarction in the CTCA group. This latter finding is intriguing but should be treated with caution: it was one of 22 prespecified secondary endpoints, and the absolute difference between the two groups was only 16 events.Because randomised trials of cardiovascular imaging are fairly new, much can be learned from the well-done SCOT-HEART study to guide clinical care and future research. Many crucial questions are raised: first, in the absence of a feasible placebo strategy, how can imaging studies prevent or control bias in favour of the intervention? In SCOT-HEART, CTCA created greater diagnostic certainty in CT readers than in non-reader clinicians. Second, should imaging findings be prospectively linked to mandated care algorithms? Because a test can only affect outcomes by changing care, the failure to follow best practices, or the ineffectiveness of treatments, can be falsely attributed to the test. Indeed in the PARR-2 trial,9Beanlands RSB Nichol G Huszti E et al.for the PARR-2 InvestigatorsF-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).J Am Coll Cardiol. 2007; 50: 2002-2012Summary Full Text Full Text PDF PubMed Scopus (339) Google Scholar although performance of a cardiac PET viability scan did not change outcomes in patients with heart failure overall, patients who received PET-guided care (and not just a scan) had fewer events. SCOT-HEART bypassed this issue by using the upstream outcome of diagnostic certainty, but clinical events remain the preferred evidentiary standard.Third, if intermediate outcomes are used, what outcomes are most important to both patients and clinicians in guiding test selection? Diagnostic thinking is important, and might change processes of care, as shown in SCOT-HEART, but other unexamined parameters such as efficiency, safety, and avoidance of unnecessary invasive procedures might be equally, if not more, salient. Finally, although the very low rate of clinical events in SCOT-HEART (ie, cardiovascular death or myocardial infarction were reported in just 68 [1·6%] participants in 1·7 years of follow-up) is encouraging in documenting an excellent prognosis for patients with new-onset stable chest pain receiving contemporary care, to show a difference in patient outcomes with different testing strategies in view of this excellent prognosis would need a large incremental test effect driving differences in downstream care, an extremely large study sample, prolonged follow-up, or a combination of these factors.SCOT-HEART7The SCOT-HEART investigatorsCT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel group multicentre trial.Lancet. 2015; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(15)60291-4Google Scholar provides important data regarding the effect of the addition of a new technology to usual care, and explores new methods for the theory and practice of imaging outcomes research. However, more work is needed in this new specialty before the value of cardiovascular imaging can be fully understood.PSD is the principal investigator of the PROMISE trial, and has received research funding to her institution from HeartFlow. About a decade ago, triggered by unexplained growth and variability in cardiovascular testing,1Iglehart JK Health insurers and medical-imaging policy—a work in progress.N Engl J Med. 2009; 360: 1030-1037Crossref PubMed Scopus (268) Google Scholar efforts to redefine imaging quality led to an appreciation of the importance of selecting the right test for the right patient (ie, giving rise to appropriate use criteria) and measuring the effect of testing on outcomes, in addition to measures such as image acquisition and interpretation.2Douglas PS Taylor A Bild D et al.Outcomes research in cardiovascular imaging: report of a workshop sponsored by the National Heart, Lung, and Blood Institute.JACC Cardiovasc Imaging. 2009; 2: 897-907Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Although appropriate use criteria are now an established part of evidence-based cardiovascular care, imaging outcomes have not been defined in a more meaningful way, partly because of the many steps needed to translate test data into knowledge (ie, diagnostic thinking), action (ie, treatments), and ultimately outcomes. Nevertheless, there have been strong calls to explore the downstream consequences of imaging as a necessary step in more fully understanding its risks and benefits, which would then help to establish scenarios in which imaging does, and does not, add value.3Douglas PS Iskandrian AE Krumholz HM et al.Achieving quality in cardiovascular imaging: proceedings from the American College of Cardiology–Duke University Medical Center think tank on quality in cardiovascular imaging.J Am Coll Cardiol. 2006; 48: 2141-2151Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar This task has been made more difficult in the era following the COURAGE4Boden WE O'Rourke RA Teo KK et al.for the COURAGE Trial Research GroupOptimal medical therapy with or without PCI for stable coronary disease.N Engl J Med. 2007; 356: 1503-1516Crossref PubMed Scopus (3618) Google Scholar and FAME5Tonino PA De Bruyne B Pijls NH et al.for the FAME Study InvestigatorsFractional flow reserve versus angiography for guiding percutaneous coronary intervention.N Engl J Med. 2009; 360: 213-224Crossref PubMed Scopus (2959) Google Scholar trials, in which the diagnosis of anatomical coronary artery disease has been uncoupled from a need for revascularisation, and in the post-CONFIRM era,6Min JK Dunning A Lin FY et al.Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23 854 patients without known coronary artery disease.J Am Coll Cardiol. 2011; 58: 849-860Summary Full Text Full Text PDF PubMed Scopus (570) Google Scholar in which non-obstructive coronary artery disease is recognised to be a powerful predictor of future events. A few trials have been done to rise to this challenge in the primary prevention area and in the triage of acute chest pain, variously using risk factor burden, clinical events, and efficiency as endpoints. Randomised trial data assessing the effect of testing in the very large stable chest pain population have been scarce, but are now present in the form of two new large studies—the Computed Tomography Coronary Angiography in Patients with Suspected Angina due to Coronary Heart Disease: the Scottish Computed Tomography of the HEART (SCOT-HEART) trial7The SCOT-HEART investigatorsCT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel group multicentre trial.Lancet. 2015; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(15)60291-4Google Scholar reported by David Newby and colleagues in The Lancet, and the PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial.8Douglas PS, Hoffmann U, Patel MR, et al, for the PROMISE study investigators. Outcomes of anatomic versus functional testing for coronary artery disease. N Engl J Med (in press).Google Scholar In SCOT-HEART, 4146 patients completing an assessment for stable chest pain were randomly assigned to CT coronary angiography (CTCA) in addition to usual care or to usual care alone, which generally included an exercise treadmill test. The trial's primary endpoint, certainty of the attribution of symptoms to angina due to presence of coronary artery disease, showed an increase in the CTCA group (relative risk 1·79, 95% CI 1·62–1·96), as did the closely related secondary endpoint of certainty of diagnosis of coronary artery disease (2·56, 2·33–2·79). Additional secondary endpoints included diagnostic reclassification and changes in diagnostic and therapeutic approaches, which all happened more frequently in the CTCA group. Although investigators recorded no differences in the frequency or stability of angina, rates of revascularisation, or admittance to hospital, there was a non-significant reduction in the rate of death or myocardial infarction in the CTCA group. This latter finding is intriguing but should be treated with caution: it was one of 22 prespecified secondary endpoints, and the absolute difference between the two groups was only 16 events. Because randomised trials of cardiovascular imaging are fairly new, much can be learned from the well-done SCOT-HEART study to guide clinical care and future research. Many crucial questions are raised: first, in the absence of a feasible placebo strategy, how can imaging studies prevent or control bias in favour of the intervention? In SCOT-HEART, CTCA created greater diagnostic certainty in CT readers than in non-reader clinicians. Second, should imaging findings be prospectively linked to mandated care algorithms? Because a test can only affect outcomes by changing care, the failure to follow best practices, or the ineffectiveness of treatments, can be falsely attributed to the test. Indeed in the PARR-2 trial,9Beanlands RSB Nichol G Huszti E et al.for the PARR-2 InvestigatorsF-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).J Am Coll Cardiol. 2007; 50: 2002-2012Summary Full Text Full Text PDF PubMed Scopus (339) Google Scholar although performance of a cardiac PET viability scan did not change outcomes in patients with heart failure overall, patients who received PET-guided care (and not just a scan) had fewer events. SCOT-HEART bypassed this issue by using the upstream outcome of diagnostic certainty, but clinical events remain the preferred evidentiary standard. Third, if intermediate outcomes are used, what outcomes are most important to both patients and clinicians in guiding test selection? Diagnostic thinking is important, and might change processes of care, as shown in SCOT-HEART, but other unexamined parameters such as efficiency, safety, and avoidance of unnecessary invasive procedures might be equally, if not more, salient. Finally, although the very low rate of clinical events in SCOT-HEART (ie, cardiovascular death or myocardial infarction were reported in just 68 [1·6%] participants in 1·7 years of follow-up) is encouraging in documenting an excellent prognosis for patients with new-onset stable chest pain receiving contemporary care, to show a difference in patient outcomes with different testing strategies in view of this excellent prognosis would need a large incremental test effect driving differences in downstream care, an extremely large study sample, prolonged follow-up, or a combination of these factors. SCOT-HEART7The SCOT-HEART investigatorsCT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel group multicentre trial.Lancet. 2015; (published online March 15.)http://dx.doi.org/10.1016/S0140-6736(15)60291-4Google Scholar provides important data regarding the effect of the addition of a new technology to usual care, and explores new methods for the theory and practice of imaging outcomes research. However, more work is needed in this new specialty before the value of cardiovascular imaging can be fully understood. PSD is the principal investigator of the PROMISE trial, and has received research funding to her institution from HeartFlow. CT coronary angiography in patients with suspected angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-group, multicentre trialIn patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. Full-Text PDF Open Access