Guiding Therapy by Coronary CT Angiography Improves Outcomes in Patients With Stable Chest Pain.

BACKGROUND
Within the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) trial of patients with stable chest pain, the use of coronary computed tomography angiography (CTA) reduced the rate of death from coronary heart disease or nonfatal myocardial infarction (primary endpoint).


OBJECTIVES
This study sought to assess the consistency and mechanisms of the 5-year reduction in this endpoint.


METHODS
In this open-label trial, 4,146 participants were randomized to standard care alone or standard care plus coronary CTA. This study explored the primary endpoint by symptoms, diagnosis, coronary revascularizations, and preventative therapies.


RESULTS
Event reductions were consistent across symptom and risk categories (p = NS for interactions). In patients who were not diagnosed with angina due to coronary heart disease, coronary CTA was associated with a lower primary endpoint incidence rate (0.23; 95% confidence interval [CI]: 0.13 to 0.35 vs. 0.59; 95% CI: 0.42 to 0.80 per 100 patient-years; p < 0.001). In those who had undergone coronary CTA, rates of coronary revascularization were higher in the first year (hazard ratio [HR]: 1.21; 95% CI: 1.01 to 1.46; p = 0.042) but lower beyond 1 year (HR: 0.59; 95% CI: 0.38 to 0.90; p = 0.015). Patients assigned to coronary CTA had higher rates of preventative therapies throughout follow-up (p < 0.001 for all), with rates highest in those with CT-defined coronary artery disease. Modeling studies demonstrated the plausibility of the observed effect size.


CONCLUSIONS
The beneficial effect of coronary CTA on outcomes is consistent across subgroups with plausible underlying mechanisms. Coronary CTA improves coronary heart disease outcomes by enabling better targeting of preventative treatments to those with coronary artery disease. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

C oronary computed tomography angiography (CTA) has high sensitivity and specificity for the detection of coronary artery disease (1,2). This has prompted the evaluation of coronary CTA as a diagnostic test for coronary artery disease in patients presenting with stable chest pain. The short-term benefits of coronary CTA in this population have included better diagnostic certainty, lower rates of normal coronary arteries at the time of invasive coronary angiography, and improved targeting of symptomatic and preventative therapies (3,4).
Large-scale clinical trials have also suggested that short-term coronary heart disease events are reduced (4,5). In the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial), we recently reported the effects of coronary CTA on the pre-specified 5- year clinical outcomes including investigations, treatments, and clinical events (6). We demonstrated that an initial strategy of coronary CTA was associated with a 41% relative risk reduction in coronary heart disease death or nonfatal myocardial infarction at 5 years. This major reduction in events has prompted questions about the mechanisms of benefit, the potential for bias, and the plausibility of the effect size.
We here present further analyses of the 5-year data from the SCOT-HEART trial to assess the robustness of the event reductions seen with coronary CTA with respect to the participant subgroups, the changes in diagnosis, and the alterations to procedural and pharmacological treatments. Drawing these disparate effects together, we wanted to determine the overall attribution of benefits in relation to the primary endpoint and the study intervention effect size.

METHODS
The study population and trial design were reported previously (4,5,7). In brief, adult patients age #75 years who attended the outpatient cardiology clinic with stable chest pain were invited to participate in the trial in    (11). This has been successfully applied in other settings (12,13) and for longer-term clinical trial followup (14). Under the observed difference between the trial arms in use of preventative therapies, this represents a best-case scenario.
Statistical significance was taken as a 2-sided p < 0.05. All analysis was undertaken using R version 3.5.0 (R Foundation, Vienna, Austria).

RESULTS
We randomized 4,146 patients with stable chest pain at 12 cardiology centers across Scotland to either standard of care alone (n ¼ 2,073) or standard of care Values are n (%) or mean AE SD.

Follow-Up (Years)
Abbreviations as in Figure 1.
Adamson et al.  Table 2). Following clinic consultation, 1 in 20 patients (5%) had their treatment altered at 6 weeks in the standard care arm compared with nearly 1 in 4 (23%) in the coronary CTA group ( Table 4) (4). In particular, there were differences in the pre- One of the main advantages of coronary CTA is its negative predictive value. As such, it moves beyond traditional symptom assessment and ischemia testing, providing confidence to clinicians and patients alike regarding the absence of disease. This was   Values are n (%). *Denominator excludes those receiving therapy at baseline. †Prognostically important CAD defined as any of the following: $50% stenosis of left main coronary artery; $70% stenosis of at least 3 main epicardial arteries; or $70% stenosis of at least 2 epicardial arteries including the proximal left anterior descending artery.
Abbreviations as in Tables 1 and 3.   Using treatment effect estimates from published randomized controlled trials, systematic reviews, and meta-analyses (14,16,(21)(22)(23)(24)(25)(26), we explored for the first time whether the effect of additional treatment with antiplatelet, statin, and revascularization interventions could account for the observed effect size. Whereas this modeling required a number of assumptions, they were nonetheless reasonable, and more reasonable than assuming that patients receiving additional treatment in the coronary CTA group shared the same cardiovascular event rate as the entire cohort. This modeling allowed us to demonstrate that at least some of the effect size we observed was plausible and could be accounted for by current evidence. In addition, we would also highlight that the effect size reported in the SCOT-HEART trial is consistent with rates of myocardial infarction reported in other trials of coronary CTA in patients with stable chest pain (5,27) and meta-analyses (28,29), as well as large-scale observation studies However, we think this is unlikely. First, the delayed separation of the event curves suggests that there was no early bias in event reporting because the CT result would be available after 2 weeks, whereas treatment changes took a further 4 to 6 weeks to implement.
Second, the finding that coronary CTA was associated with less normal invasive coronary angiography and higher early rates of revascularization suggests that the coronary CTA more accurately identified the disease process. Third, coronary CTA increased the rate outcomes as reported by that health care system. We believe clinical outcomes reported by routine health records data remain the most appropriate, independent, and accurate method of clinical endpoint ascertainment for the SCOT-HEART trial. Finally, we acknowledge our modeling approach does assume that the highest risk patients were those who had received additional preventative therapies as a result of the coronary CTA intervention, and this may have overestimated some of the benefits. This is particularly applicable to the assumption of treatment benefit derived from coronary revascularization.
Although we chose treatment effects applicable to an unstable angina population, we believe this is justifiable as the shape of the instantaneous hazard curves supports a high short-term risk that plateaus after 6 to 12 months in a pattern consistent with acute coronary syndrome populations.

CONCLUSIONS
We have presented a multifaceted analysis that consistently and robustly demonstrates the plausi- KEY WORDS angina pectoris, computed tomography, coronary heart disease APPENDIX For supplemental methods, a figure, and tables, please see the online version of this paper.