Quality of Life Outcomes With a Risk-Based Precision Testing Strategy Versus Usual Testing in Stable Patients With Suspected Coronary Disease: Results From the PRECISE Randomized Trial.
Feb 3, 2025DOI: 10.1161/circoutcomes.124.011414Journal ArticleAHA
Written by: Daniel B MarkYanhong LiMichael G NannaMichelle D KelseyMelanie R DanielsCampbell RogersManesh R PatelKhaula N BalochBenjamin J W ChowKevin J AnstromSreekanth VemulapalliJonathan R Weir-McCallGregg W StoneDerek S ChewPamela S DouglasPRECISE Investigators
Find these authors on Roon
DM
Dr. Daniel Mark
Cardiac Critical Care · Duke
MP
Dr. Manesh Patel
Interventional Cardiology · Duke University
Methods
There are no plans to make a deidentified data set publicly available at present.The rationale and design of the PRECISE trial (https://www.clinicaltrials.gov; Unique identifier: NCT03702244) have been published.6 Patients randomized to the Precision Strategy underwent a risk assessment using the PROMISE Minimal Risk Tool,7 and those in the lowest-risk decile based on PROMISE criteria were assigned to deferred testing and guideline-recommended care. The remaining patients randomized to the Precision Strategy were assigned to undergo diagnostic testing using cCTA with selective use of FFRCT (for site read stenosis between 30% and 90%). Patients randomized to the Usual Testing arm underwent functional testing or went directly to invasive catheterization. The choice of which approach to use if randomized to Usual Testing (ie, initial invasive or initial noninvasive) was prespecified by the investigators before randomization. The trial’s primary composite end point was invasive catheterization without obstructive CAD, death, or nonfatal myocardial infarction.Between December 3, 2018 and May 18, 2021, the PRECISE trial randomized 1057 patients to the Precision Strategy and 1046 to Usual Testing at 65 sites in North America and Europe.8 Median follow-up was 11.8 months. The primary end point occurred in 4.2% of the Precision Strategy group and 11.3% in the Usual Testing group (hazard ratio, 0.35 [95% CI, 0.25–0.50]).All patients provided written informed consent and study protocol approval was obtained from each site or a central Institutional Review Board. The trial work was funded by an investigator-initiated research grant from HeartFlow Inc to the Duke Clinical Research Institute.We collected both a disease-specific and a generic QOL survey to evaluate different dimensions of the patient experience. The Seattle Angina Questionnaire (SAQ) is a 19-item CAD-specific health status instrument that assesses patients’ function, symptoms, and QOL over the past 4 weeks.9 We assessed 3 SAQ domains: physical limitations, angina frequency, and QOL. Scores were calculated for each domain as well as a summary score that averaged the physical limitations, angina frequency, and QOL scores. All scores were scaled from 0 to 100, with 0 representing the worst possible health status and 100 the best. For SAQ scales, ≥5 points represent a benchmark for a clinically significant change for an individual patient.9
To assess generic health status, we used the EQ-5D-5L, which consists of 2 components.10 The first component is an index comprising 5 items that assess specific dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The version used in PRECISE (EQ-5D-5L)11 includes 5 response options for each item. Combinations of responses to these items define different possible health states, which are then mapped to country-specific preference weights, thus reflecting societal valuations (utility weights) of the health states. The second component is a visual analog scale that assesses the patient’s own valuation of their health, ranging from best imaginable health state (100) to worst imaginable health state (0).
Patient satisfaction with the initial diagnostic testing and associated care received was assessed at the day 45 visit using an ad hoc survey (Table S1). The survey consisted of 4 questions asking about the patient’s satisfaction with their heart care over the past 6 weeks, with 5 response levels ranging from not satisfied at all (scored as 0) to highly satisfied (scored as 4). The 4 components were then summed to generate a summary satisfaction score with 0 indicating the lowest patient satisfaction with their heart care and 16 representing the highest level of satisfaction.
All primary analyses were performed with treatment groups defined by the principle of intention to treat (as randomized). Descriptive statistics include percentages for discrete variables and medians with 25th and 75th percentiles and means with standard deviations for continuous variables. The prespecified primary comparison was the SAQ Summary Score 6-month outcomes.
The SAQ and EQ-5D end points were analyzed using repeated measures mixed model with the baseline score, day 45, month 6, and month 12 responses included as outcome variables, and time, treatment, and time by treatment interaction terms included as fixed effects. Restricted maximum likelihood estimation with an unstructured covariance matrix and Kenward-Roger df approximation were used to model all available data from each patient. At each time point, the estimated effect size on the QOL measure was estimated along with the 95% CI. This modeling approach assumes missing data are missing at random. No formal imputation procedures for missing scores were used in our analyses because the mixed effects model does not require complete data or the same length of follow-up for each patient.
Point estimates for each treatment strategy arm and strategy arm mean differences (precision testing strategy minus usual care) with 95% CIs were generated for each time point. The intervention effect size was also averaged across all 3 follow-up time points. The estimated intervention difference and 95% CIs for the models were implemented using the ESTIMATE statement in SAS PROC MIXED.
Where P values are provided as interpretive aids, significance, understood as a heuristic of unexpectedness about the consistency of the data with the null hypothesis, was defined using the convention of P<0.05.12
The primary subgroups examined were those prespecified as part of the PRECISE Statistical Analysis Plan. In addition, we examined post hoc subgroups defined according to baseline values of the SAQ Summary score and Angina Frequency score to determine if baseline QOL had an effect on the QOL outcome differences of the 2 diagnostic strategy arms. A response magnitude analysis examined whether the proportion of patients with small, moderate, and large QOL improvement (follow-up minus baseline) varied by randomized diagnostic strategy and baseline QOL.
Subgroup analyses used the mixed effects regression model approach to account for repeated measures from each patient, with strategy group, time point, subgroup, an interaction between treatment group and time point, an interaction between subgroup and time point, an interaction between subgroup and treatment group, and an interaction between subgroup, time point, and treatment group included in the model.
To examine post hoc whether the presence of significant CAD altered the patterns of QOL outcomes in PRECISE, we subgrouped patients in the Precision Strategy arm who were not assigned to deferred testing (ie, 80% of patients with more than minimal risk) according to the presence or absence of significant CAD on their initial cCTA test. Significant CAD was defined in 2 different ways for this analysis: (1) an anatomic definition: ≥50% and (2) a blended anatomic/functional definition using cCTA lesion 50% to 89% and lesion-specific FFRCT <0.80 or cCTA lesion ≥90%. Patients with a baseline cCTA who did not meet the relevant criteria for significant CAD were classified as No significant CAD. Between-group adjusted differences in QOL scores were estimated as described above.
Results
The PRECISE trial included 2103 patients with 1057 randomized to the investigational Precision Strategy and 1046 to the Usual Testing strategy. Baseline characteristics (Table 1) were well balanced, with a mean age 58.4 years, 49.8% women, and 16% non-White or Hispanic as self-reported by participants. The median follow-up was 11.8 months. QOL data collection was 99% complete at baseline, with 86.5% of participants providing QOL data at 6 months and 83.8% at 1 year.
Baseline Clinical Characteristics
At baseline, mean SAQ Summary scores were 70.9 in the Precision Strategy group and 70.4 in the Usual Testing group, with a mean adjusted difference of 0.4 (95% CI, −0.8 to 1.7; Table 2). By 6 months, mean SAQ Summary scores had improved: 89.9 in the Precision Strategy group, and 89.2 in the Usual Testing group, with a mean adjusted difference of 0.8 (95% CI, −0.3 to 2.0). Baseline SAQ Angina Frequency scores were 76.2 and 75.6 in the Precision Strategy and Usual Testing arms, respectively (mean adjusted difference, 0.5 [95% CI, −0.9 to 2.0]; Table 2). At 6 months, the mean Angina Frequency scores were 93.3 and 92.4, respectively (mean adjusted difference, 1.0 [95% CI, −0.1 to 2.1]). Mean adjusted differences at 6 months for the SAQ Physical Limitations score (0.5 [95% CI, −0.6 to 1.7]) and the SAQ Quality of Life score (0.7 [95% CI, −1.1 to 2.4]) were consistent with the overall SAQ Summary score results (Table 2). None of the SAQ scales showed statistically significant or clinically meaningful differences between the 2 groups at the 45-day assessment or at any subsequent follow-up time point.
Prespecified Quality of Life (QOL) Outcomes by Intention to Treat
At baseline, 12% of patients reported no angina (Angina Frequency score=100). At 6 months, 67% of the Precision Strategy and 66% of the Usual Testing strategy reported no angina. At 12 months, the corresponding rates were 73% and 70%, respectively.
Mean EQ-5D visual analog scale scores at baseline were 72.2 in the Precision Strategy group and 72.9 in participants randomized to Usual Testing, with a mean adjusted difference of −0.6 (95% CI, −2.1 to 0.8; Table 2). Both groups showed improvement at 6 months, with the Precision Strategy group improving to a mean score of 76.6 and the Usual Testing group 78.0. The adjusted mean difference between the groups was not statistically significant or clinically meaningful at −1.4 (95% CI, −2.9 to 0.0).
Satisfaction scores at 45 days were high in both arms (Table 3) with mean scores of 13.8 for the Precision Strategy and 13.5 for Usual Testing on a 0 (lowest) to 16 (highest) scale (adjusted mean difference, 0.3 [95% CI, 0.0–0.6]).
Patient Satisfaction Scores
At baseline, 30% of the trial cohort was taking an antiplatelet agent, 41% were on lipid-lowering therapy, 23% were on a β-blocker, and 11% were on other antianginal drug therapy. By the 45-day follow-up, 30% of Precision Strategy patients with a positive test had initiated aspirin therapy, 30% had initiated a statin, and 24% had initiated a β-blocker (Table S2). For the Usual Testing patients with a positive test, the comparable initiation rates were 23% for aspirin, 17% for statins, and 19% for β-blockers. Medication discontinuation rates after a negative test were comparably low in both arms. Patients who had no test at baseline also largely (90% or greater) had no changes in their baseline medical therapy regardless of randomized testing assignment.
QOL scores showed no difference throughout the study by intention to treat comparisons in prespecified subgroups of minimal or elevated risk, age <65 or ≥65 years, sex, race, region, or initial invasive diagnostic test versus initial noninvasive diagnostic test (Figures 1 through 5; Tables S3 through S14).
Adjusted mean differences with 95% CIs in Seattle Angina Questionnaire summary score by subgroups. The choice of which approach to use if randomized to Usual Testing (ie, invasive or initial noninvasive) was prespecified by the investigators before randomization.
Adjusted mean differences with 95% CIs in Seattle Angina Questionnaire Angina Frequency by subgroups. The choice of which approach to use if randomized to Usual Testing (ie, invasive or initial noninvasive) was prespecified by the investigators before randomization.
Adjusted mean differences with 95% CIs in Seattle Angina Questionnaire quality of life by subgroups. The choice of which approach to use if randomized to Usual Testing (ie, invasive or initial noninvasive) was prespecified by the investigators before randomization.
Adjusted mean differences with 95% CIs in Seattle Angina Questionnaire physical limitations by subgroups. The choice of which approach to use if randomized to Usual Testing (ie, invasive or initial noninvasive) was prespecified by the investigators before randomization.
Adjusted mean differences with 95% CIs in EQ-5D Visual Analog Scale by subgroups. The choice of which approach to use if randomized to Usual Testing (ie, invasive or initial noninvasive) was prespecified by the investigators before randomization.
Between baseline and 6-month assessments, 84% of Precision Strategy and 82% of Usual Testing strategy patients had a ≥5-point improvement in their SAQ Summary score (Table S15). A ≥10-point improvement was seen in 73% and 69% respectively, while a ≥20-point improvement occurred in 47% and 45%, respectively. When comparisons were performed according to baseline SAQ Summary score values (≤50, 51–74, ≥75), response magnitude over 6 months remained comparable in the 2 arms (Table S15).
Response magnitude analysis for SAQ Angina Frequency scores over 6 months showed 77% of Precision Strategy and 73% of Usual Testing strategy patients improved by 10 points or more, while 52% and 47%, respectively, improved by 20 points or more (Table S16). When further analyzed according to baseline SAQ Angina Frequency score (≤60, 61–99), the percentage of patients in each arm improving by at least 10 points or at least 20 points remained comparable (Table S16).
When significant CAD was defined on cCTA using standard anatomic criteria, baseline demographics showed that the significant CAD subgroup was older (mean age 64 years versus 59 years for patients with no significant CAD) and more often male (68% versus 52% for patients with no significant CAD; Table S17). Baseline SAQ Angina Frequency scores were 73.8 for the significant CAD subgroup and 76.8 for the no significant CAD subgroup (Table S18). At 6 months, the corresponding values were 91.9 and 93.7, respectively. Baseline SAQ Physical Limitations scores were 81.4 and 83.8 for the CAD and no CAD subgroups with corresponding 6-month values of 94.1 and 94.3, respectively. Baseline SAQ Quality of Life scores were 53.1 and 54.3 with 6-month scores of 81.6 and 83.2, respectively.
Results were essentially unchanged when significant CAD was defined using a blended anatomic/functional definition (Tables S19 and S20).
Discussion
Three findings from this analysis of the PRECISE randomized trial QOL outcome data deserve special emphasis. First, patients with nonacute chest pain and without known CAD who present for diagnostic evaluation improve their QOL substantially over the 6 months following the initial evaluation. Over 80% of patients in each arm improved their SAQ Summary score by at least 5 points and about 2-thirds became chest pain-free. The score improvement was a function of the baseline SAQ scores (lower scores associated with larger absolute improvement). Second, the assignment to a Precision Strategy versus Usual Testing had no clinically detectable effect on the rate, extent, or magnitude of QOL improvements out to 12 months. We found no evidence that any prespecified subgroup had a differential effect according to the assigned diagnostic strategy on QOL outcomes. Finally, in the Precision Strategy arm patients who were not assigned to deferred testing due to minimal risk, post hoc analysis showed that QOL scores at baseline and over follow-up were comparable between subgroups defined according to the presence or absence of significant CAD. These results did not depend on whether significant CAD was based on anatomic criteria or on blended anatomic/functional criteria.
An important underlying premise of PRECISE, as well as of the PROMISE and SCOT-HEART trials, was that, compared with usual testing practices, a cCTA-based partitioning of nonacute chest pain patients into significant obstructive disease versus no significant obstructive disease would allow for more accurate and effectively targeted angina/chest pain management for both groups. PROMISE and SCOT-HEART patients managed with an anatomic diagnostic strategy had a small absolute increase in the use of revascularization compared with a functional testing strategy. PRECISE results were consistent: 9.2% of the Precision Strategy received revascularization compared with 5.2% of the Usual Testing strategy.8 In the present report, this 77% relative increased use of revascularization associated with direct anatomic visualization and selective functional assessment with FFRCT was not associated with incremental improvement in angina-related QOL out to 12 months.
Two reasons likely explain why the use of a Precision Strategy increased revascularization rates but did not significantly improve angina-related QOL relative to the Usual Testing strategy. First, a substantial imbalance exists in this population between treatment signal and noise. Multiple studies including PRECISE have now shown that the majority of stable chest pain patients who seek clinical evaluation will turn out to not have significant obstructive CAD. In the cCTA arm of PRECISE, <20% of patients had significant obstructive CAD by cCTA.8 In the SCOT-HEART trial, 25% of the cCTA arm had significant CAD in their cCTA study.3 These data suggest that in comparable populations of stable chest discomfort patients, 75% or more of the subjects will have short- and intermediate-term QOL outcomes that are unlikely to be improved by the increased use of CAD-specific therapies. This further suggests that any difference in diagnostic strategies that does create a clinically meaningful gap in the use of symptomatically effective CAD therapies after testing will be more difficult to detect in terms of potential QOL improvements since only 25% or less of the cohort will contribute treatment difference signal while the majority of outcome variations will constitute only noise in this context.
A second possible reason why increased rates of revascularization in PRECISE did not translate into better QOL for the Precision Strategy arm relates to the surprisingly variable effectiveness of percutaneous coronary intervention (PCI) in relieving what is presumed clinically to be anginal chest pain. A common assumption among cardiologists is that if a patient has chest pain symptoms and also has significant anatomic obstructive disease, then the relationship between these 2 findings is causal, and revascularization should be a effective remedy. However, in the ORBITA (Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina) trial, routine PCI added to guideline-directed antianginal medical therapy produced full symptom relief in only 50% of 103 patients with mostly Canadian Class II or III angina.13 In the control sham PCI arm, 32% of patients were angina free at 12 weeks. In ORBITA-2, when PCI was used without any antianginal medical therapy, 40% were angina-free at 12 weeks compared with 15% of patients randomized to sham PCI.14 Taken together, these ORBITA results suggest that about 15% of patients with predominantly 1-vessel CAD and chest pain became spontaneously chest pain free by 12 weeks, an additional 15% had resolution of symptoms with antianginal therapy, and an additional 20% to 25% became symptom-free after PCI. Both trials demonstrated that PCI substantially improved or eliminated inducible ischemia on stress testing, so the PCI therapy was clearly effective at a physiological level. However the CAD/ischemia was apparently not the cause of the chest discomfort symptoms in roughly half of the CAD patients with severe stenoses enrolled in these trials. The CLARIFY (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease) reported concordant findings in 32 073 stable outpatients with CAD and 5-year follow-up.15 Among the 22% of patients with angina at baseline, 40% had resolution of their symptoms without revascularization over the first year of follow-up. By 5 years, only 34% still had anginal symptoms while 8% had died, 5% had had a myocardial infarction or undergone urgent revascularization, 7% had undergone elective revascularization, and 46% were angina-free and event-free. Angina control was attributed to coronary revascularization in 5%, to changes in antianginal medications in 11%, and regressed without specific medical intervention in 84%.
Thus, the causal associations of anatomic obstructive CAD, functional evidence of myocardial ischemia/impaired coronary blood flow, and chest discomfort symptoms are not as straightforward as often assumed in clinical decision-making. In the context of PRECISE, if only about 20% of patients had significant obstructive disease and only about half of those patients could expect to have resolution of their chest pain with PCI, then any difference in QOL outcomes with more versus less use of revascularization would have to come from differences in how the ≈10% of patients with PCI-responsive obstructive CAD are managed in each arm.
Given that over 75% of patients enrolled in PRECISE and similar trials have been found (in cCTA arms) not to have significant obstructive CAD it is useful to consider what can be learned from their QOL data. Such negative information can provide a signal to clinicians that it is now time to intensify the search for an alternate explanation for the symptoms, as well as to initiate or intensify medical therapies for presumed angina with no obstructive coronary disease. No significant CAD can also provide clinicians with information needed to reassure the patient about their negligible short-term risk of a cardiac event. However, recent work showing chest pain patients without significant obstructive CAD represent a heterogeneous mixture of several distinct endotypes of coronary vasomotor dysfunction as well as true noncardiac chest pain may leave clinicians uncertain what to do with the no-significant-disease findings.16 In the West of Scotland study of 250 angina patients without obstructive CAD (≤70%) who agreed to invasive endotyping, baseline SAQ Summary scores averaged around 55 with 12-month follow-up mean scores only modestly improved (64–66).17 The closest analog in PRECISE are the Precision Strategy patients who had a baseline cCTA and were found to have at least 1 coronary stenosis <50% but with FFRCT≤0.80. In those 58 patients, baseline SAQ Summary scores averaged 68 and by 6 months had increased to 90. It is unclear whether the blunted improvement in SAQ scores over time seen in the West of Scotland study is characteristic of patients with angina with no obstructive coronary disease due to definite vasomotor coronary dysfunction in general or represents something unusual about the particular sample selected for the study.
The practical utility of information about the results of endovascular subtyping in patients with nonobstructive CAD ultimately depends on whether it can help direct more effective management. In the West of Scotland study, the extent of improvement in SAQ scores was not affected by whether the invasive endotyping results were provided to the managing cardiologist or not. Providing the endotype information was associated with reduced use of β-blockers and increased use of calcium blockers and nitrates. The lack of a measurable effect of coronary vascular endotype information and resulting management changes on QOL outcomes may reflect insufficient use of or dosing of effective therapies, or limited effectiveness of available therapies for the clinical disorder. At present, therefore, the finding of no significant CAD in chest pain patients tested with a Precision Strategy does not support an initial invasive coronary endotyping, particularly since in the PRECISE experience most of these patients will have substantial improvement in their symptoms without such additional evaluation.
Several caveats should be considered in the interpretation of our results. First, PRECISE was not a masked trial and awareness of the diagnostic strategy assignment by clinicians or patients or both might have affected responses on the QOL instruments used in this trial. Second, since PRECISE did not require a blinded baseline cCTA in the Usual Testing arm, we cannot compare QOL outcomes in major anatomic subgroups by intention to treat. Third, PRECISE compared 2 specific initial testing strategies, including a hybrid Precision Strategy that represented an attempt to improve some inefficient aspects of the routine cCTA strategy previously studied in PROMISE. However, PROMISE and PRECISE do not reflect the full range of possible diagnostic strategies that could be offered to nonacute chest pain patients, and our QOL outcome results may have unclear relevance if strategies are used that are substantially different from what was tested in PRECISE. Finally, part of the PRECISE enrollment and follow-up took place during the COVID-19 pandemic and its immediate aftermath, and it is unclear whether pandemic-related factors might have affected the patient-reported outcomes described in this report, although both study arms would have been similarly affected.
In stable patients with nonacute symptoms suggesting CAD, angina-related QOL improved substantially over the initial 6 months and by the same magnitude for the predominantly cCTA-based anatomic testing strategy and the predominantly functional-based testing strategy.
ARTICLE INFORMATION
The authors are particularly indebted to the coordinators at the Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization (PRECISE) sites that collected data and to the patients who agreed to provide their quality of life data for the trial.
This study was funded by HeartFlow Inc.
PRECISE is an investigator-initiated trial funded by HeartFlow Inc. HeartFlow personnel participated in trial design and oversaw operations during trial conduct. The trial protocol, statistical analysis plans, and results interpretation were performed by the Steering Committee independently of HeartFlow. Outcome determination including data safety and monitoring board, clinical events committee, and Core Laboratories functioned independently of HeartFlow. All statistical analyses were performed and interpreted at Duke Clinical Research Institute independently of HeartFlow.
Dr Mark received grant support from HeartFlow Inc during the conduct of this study, Merck and Novo Nordisk outside the submitted work, grants or research support from National Institutes of Health/National Heart, Lung, and Blood Institute and American Heart Association, consulting fees from CeleCor, Novartis, and Boehringer Ingelheim outside the submitted work, and honoraria from Elsevier outside the submitted work. Dr Nanna received consulting fees from HeartFlow Inc, Novo Nordisk, and Merck, research support from the National Institute on Aging/National Institutes of Health (R03AG074067), the American College of Cardiology Foundation supported by the George F. and Ann Harris Bellows Foundation, the Patient-Centered Outcomes Research Institute, and the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342). Dr Kelsey is a member of the Advisory Board for Bayer and the Consultant/Speaker for Heartflow Inc. M.R. Daniels received honoraria from Elsevier outside the submitted work, and consulting fees from CeleCor outside the submitted work. Dr Rogers reported receiving salary and equity as an employee of HeartFlow Inc during the conduct of the study, in addition, Dr Rogers reported having a patent for HeartFlow Inc issued. Dr M.R. Patel received grants from HeartFlow during the conduct of the study and Bayer, Janssen, and Novartis outside the submitted work. Dr B.J.W. Chow receives research support from TD Bank and Artrya. He is a consultant for and has an equity interest in Artrya. Dr Anstrom received grants from Merck, Bayer, and the National Institutes of Health during the conduct of the study. Dr Vemulapalli received grants/contracts from the National Institutes of Health, Food and Drug Administration, American College of Cardiology, Cytokinetics, Edwards Lifesciences, Abbott Vascular, consulting/advisory: Astra Zeneca, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Medtronic, Total CME, Ikon, and Veralox Therapeutics. Dr Weir-McCall is supported by the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Center (BRC-1215-20014). Dr Stone reported receiving speaker fees from Medtronic, Pulnovo, Infraredx, Abiomed, Abbott, Amgen, and Boehringer Ingelheim, consultant fees from Daiichi Sankyo, Ablative Solutions, CorFlow, Apollo Therapeutics, Cardiomech, Gore, Robocath, Miracor, Vectorious, Abiomed, Valfix, TherOx, HeartFlow Inc, Neovasc, Ancora, Elucid Bio, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, and Oxitope, equity or stock options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, Xenter; and grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave outside the submitted work. Dr Stone’s daughter is an employee at IQVIA. Dr Chew received research support from the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research. Dr Douglas received grants from HeartFlow Inc during the conduct of the study.
