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November 30, 2021 Circulation. 2021;144:e368–e454. DOI: 10.1161/CIR.0000000000001029 e418

CLINICAL STATEMENTS AND GUIDELINES of flow within the epicardial coronary arteries and microvasculature and independently predicts risk of major CAD events.5-7,17 PET measurement of MBFR improves risk stratification, including for patients with nonobstructive CAD, especially women, for whom coronary microvascular dysfunction is suspected.18

3.	 CMR has been used to evaluate MBFR. When validated against invasive coronary physiology measures, pixel-wise quantitative myocardial perfusion mapping by CMR was able to identify coronary microvascular dysfunction in a small study that included 23 patients with nonobstructive CAD.19 The addition of coronary flow reserve improves prognostication.12-14 Stress CMR studies of MBFR have shown reasonable agreement with PET (n=21).20 4.	 Stress echocardiography assessing coronary flow velocity reserve in the left anterior descending artery with Doppler can currently be combined with wall motion analysis during vasodilator stress echocardiography. Limited data have shown that abnormal coronary flow velocity reserve (≤2) adds incremental value to the prognostic stratification achieved with clinical and angiographic data for events such as death and nonfatal MI in patients with angiographically normal or near-normal coronary arteries and preserved at-rest regional and global left ventricular function at baseline and during stress.21

5.3 Cost-Value Considerations in Diagnostic

Testing A general concept regarding cost is that layered testing (ie, when a test is followed by more tests) leads to higher costs. To minimize the potential needs for downstream testing, clinicians should select the test that is most likely to answer a particular question.

5.3.1. CCTA and CAC Scanning Cost-Value Considerations In the outpatient setting, long-term costs were generally similar between CCTA and stress testing strategies.1 Higher invasive angiography rates after CCTA are matched by a greater use of downstream stress testing after initial stress testing, resulting in minimal differences in cost at 2 to 3 years of follow-up.1,2 From the CONSERVE (Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization) trial, 823 patients were randomized to a selective versus direct referral strategy to ICA. Enrollment was limited to patients with nonemergent indications for ICA.3 The selective re- ferral arm included CCTA-guided use of ICA. Cumulative diagnostic costs were $1183 for the selective arm and $2755 for the direct referral arm of the CONSERVE trial (57% lower costs). In the CCTA-guided arm, follow-up stress testing was applied and contributed to reduced referrals to ICA.

A recent tiered testing strategy was evaluated in both the CRESCENT I and II trials.2,4 From the CRESCENT I trial, CAC was used as the index test, with follow-up CCTA used only in patients with detectable CAC or for those with a high pretest risk.2 In this trial, nearly 40% of patients did not undergo CCTA, which reduced diagnostic evaluation costs; no events were reported in this subgroup. By comparison, nearly half of those randomized to the exercise ECG had additional confirmatory diagnostic testing. Overall, 1-year costs were significantly lower in the CAC tiered testing protocol (16% cost savings; P<0.0001).2 Moreover, 1-year MACE-free survival was higher in the CAC-guided testing arm (97%) compared with exercise ECG (90%; HR: 0.32; P=0.011). 5.3.2. Exercise Electrocardiographic Cost-Value Considerations The economic evidence for the exercise ECG supports that tiered testing may offset its reduced diagnostic accuracy.1,2 In a decision model, tiered testing of exercise ECG followed by selective stress echocardiography resulted in improved diagnostic accuracy and favorable cost-effective ratios when compared with other testing strategies.2 In a Medicare cohort, observed 180-day costs were lowest for the exercise ECG when compared with stress echocardiography, MPI, or CCTA.3 Randomized trial data on cost are available and from the PROMISE trial initial test costs were $174 for exercise ECG, >50% lower than that of other imaging procedures.4 At 3-years of follow-up, the mean cost difference was $1731 higher for CCTA (n=4818) when compared with the exercise ECG (n=858); however, the 95% CIs for cost differences was wide ($2 to $3519), and there was no overall difference by randomization.4 Overall, results from the PROMISE trial showed that stress testing was associated with similar costs and CAD outcomes over ∼3 years of follow-up.4,5 In a randomized trial of 824 symptomatic women, cumulative procedural costs were nearly 50% lower for exercise ECG versus MPI SPECT (P<0.0001), with no difference in 2-year event-free survival (P=0.59).6 5.3.3. Stress Echocardiographic Cost-Value Considerations Several cost-effectiveness models have reported an increased incremental cost-effectiveness ratio for stress echocardiography, compared with exercise ECG and

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