Abstract
Background
Patients evaluated for coronary artery disease (CAD) have a range of symptoms and underlying risk. The relationships between patient-described symptoms, clinician conclusions and subsequent clinical management and outcomes remain incompletely described.
Methods
In this secondary analysis, we examined the association between 4 types of presenting symptoms (substernal/left-sided chest pain, other chest/neck/arm pain, dyspnea, and other symptoms) and patient risk, non-invasive test results, clinical management and outcomes for stable outpatients randomized in the PROMISE trial. Multivariable regression models were used to evaluate differences in non-invasive test result, all-cause death/myocardial infarction (MI)/unstable angina (UA) hospitalization and cardiovascular death/MI by symptom type.
Results
Among 9,996 patients, most presented with chest pain (47.2% substernal, 29.2% other), followed by dyspnea (14.9%), and other symptoms (8.7%). Patients with dyspnea were older (median age 63 vs 60, p≤0.02) with higher baseline risk (78.2% with ASCVD>7.5% vs 67.6%, p≤0.02). Using patients with substernal chest pain as a reference, there was no difference in non-invasive test positivity across symptom groups (all p>0.05), but test-positive patients with dyspnea (adjusted OR 0.66, 95% CI 0.51–0.85) or other symptoms (adjusted OR 0.65, 95% CI 0.47–0.90) were less likely to be referred for cardiac catheterization. While symptom type alone was not associated with outcomes, symptom presentation with chest pain or dyspnea did modify the association between a positive non-invasive test and clinical outcome (interaction p=0.025 for both all-cause death/MI/UA hospitalization and cardiovascular death/MI).
Conclusions
Among low-risk outpatients evaluated for CAD, typicality of symptoms was not closely associated with higher baseline risk but was related to differences in processes of care and the prognostic value of a positive test. Adverse events were not associated with clinician risk estimates or symptoms alone. These unexpected findings highlight the limitation of relying solely on symptom presentation or clinician risk estimation to evaluate patients for suspected CAD.
Registration:
PROMISE Trial ClinicalTrials.gov Identifier: NCT01174550
Keywords: Coronary CTA, Imaging, Coronary artery disease, Risk Stratification
Background
Clinical symptoms remain a primary way in which patients identify and communicate to others the presence of a potentially important health problem. The language patients use to communicate that experience to clinicians has a major effect on the significance clinicians assign to that report and what subsequent management entails. The range of presenting symptoms of patients with suspected coronary artery disease (CAD) has been well described,1–3 including typical substernal chest pain, atypical pain, dyspnea, and assorted other symptoms. Clinicians integrate the patient’s description of the presenting symptoms with other clinical and demographic factors to formulate their assessment of the (pretest) likelihood of CAD, and on that basis select an initial testing sequence. There is a large literature base proposing normative management approaches to possible CAD symptoms based on Bayesian principles and other factors. However, the details of the ways in which these factors actually do interrelate in clinical practice, where such practices are infrequently applied, is not well described.
The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial randomized stable outpatients with symptoms suggestive of CAD to initial noninvasive evaluation with either anatomic (coronary computed tomographic angiography [CTA]) or functional (exercise or pharmacologic) testing.4 PROMISE results showed that over a median of 25 months of follow-up there was no significant difference in clinical or quality of life outcomes among patients randomized to an initial strategy of coronary CTA versus functional noninvasive testing (NIT). We used these data to examine the association between the type of symptoms at presentation and the resulting processes of care, test results and clinical outcomes.
Methods
Study Cohort and Design
The PROMISE trial was a pragmatic comparative effectiveness trial that examined clinical outcomes among patients presenting with symptoms concerning for CAD. Data are available in a public, open access repository. Study datasets are available at https://biolincc.nhlbi.nih.gov/studies/promise. There are no commercial use data restrictions, and no data restrictions based on area of research. Full details regarding the study rationale, design and results have been previously published.5 In brief, 10,003 stable outpatients were enrolled between June 2010 and September 2013 from 193 sites across North America and were randomized to undergo an initial strategy of anatomic or functional testing for further evaluation of their symptoms. For patients randomized to anatomic testing with coronary CTA, the decision to also perform coronary artery calcium scoring (CAC) was left to the discretion of the patient’s local clinician. Among patients randomized to functional testing, the choice of test modality (exercise ECG, stress echocardiography or stress nuclear) was similarly left to the discretion of the site. Randomization was stratified by site and by pre-specified functional test type. All tests that were completed following randomization were performed and interpreted by the site and subsequent care decisions were left to the discretion of the patient’s clinician. Patients were followed for a minimum of twelve months following enrollment.
At the time of enrollment, all symptoms leading to referral for testing were documented, and the clinician was asked to identify which was the primary symptom. All other symptoms were classified as secondary. We divided patients into four groups based on the evaluating clinician’s assessment of the primary symptoms recorded at the time of presentation: 1) Substernal or left-sided chest pain (chest pain/pressure substernal or left anterior); 2) Other chest pain or neck/arm pain (chest pain/pressure-other, arm or shoulder pain, neck or jaw pain); 3) Dyspnea (shortness of breath/dyspnea); and 4) Other (back pain, diaphoresis/sweating, dizziness/lightheaded, epigastric pain/abdominal pain, fatigue/weakness, nausea/vomiting, palpitations, syncope). For this analysis we excluded 7 patients from the 10,003 randomized for missing symptoms, leaving a final analysis population of 9,996 patients.
Coronary CTA results were classified according to severity of disease including normal (0% stenosis), non-obstructive disease (stenosis of 1% - 69% in epicardial coronary arteries or <50% in the left main) and obstructive CAD (stenosis ≥70% or ≥50% left main stenosis). A positive coronary CTA was defined as one with any obstructive CAD. A high-risk result was defined as left main obstruction ≥50%, proximal left anterior descending stenosis of ≥70%, or multivessel disease. Among patients who also underwent CAC scoring as a part of the coronary CTA, these were stratified as normal (0), mild (1–99), moderate (100–400) and severe (>400). For patients who underwent functional testing, an exercise ECG was defined as positive if there were ST-segment changes consistent with ischemia (ST-segment elevation, ≥1 mm horizontal ST-segment depression, or downsloping ST-segment depression) or if the test was terminated within 3 minutes due to reproduction of symptoms, arrhythmia, or hypotension. For functional testing with imaging, tests were considered positive if there was evidence of inducible ischemia in at least one coronary territory or if it similarly required early termination. A high-risk test was defined as a multivessel territory with inducible ischemia.
The primary clinical endpoints of interest included the primary endpoint from the PROMISE trial (composite of all-cause death, myocardial infarction (MI), and unstable angina (UA) hospitalization) and the composite of cardiovascular (CV) death or MI.
Statistical Analyses
Relationship of Presenting Symptoms with Clinical Characteristics and Pre-test Risk
We compared baseline characteristics for each group of patients based on initial presenting symptoms. We used well-accepted cardiovascular risk scores – Framingham, Diamond and Forrester and ASCVD risk scores6–9 - to evaluate the baseline cardiovascular risk for each group. We described continuous variables using median (25th, 75th percentiles) and categorical variables using frequency (percentages). For comparisons across the four groups, we used Wilcoxon rank sum tests for continuous variables and chi-square tests for categorical variables. We also compared the dyspnea group specifically to the three non-dyspnea groups with a Bonferroni-corrected chi-square test.
We compared test results for both CTA and functional NIT, including presence of a high-risk test, by the four symptom groups. For patients who were randomized to CTA and who also underwent CAC scoring, the proportion of patients with normal, mild, moderate or severe CAC was compared between the groups. Next, with substernal or left chest pain as a reference, we used multivariable logistic regression to evaluate the association between symptom presentation and positive test results for each of the groups. A similar multivariable logistic model was fit to determine whether the odds of a positive test differed by noninvasive test modality (CTA vs functional).
Relationship of Presenting Symptoms with Processes of Care
We evaluated processes of care based on presentation symptoms. We described the proportion of patients referred for cardiac catheterization within 90 days and the results of this test (obstructive, non-obstructive, normal) for each symptom presentation group. We used multivariable logistic regression to evaluate the association between noninvasive test modality (CTA vs functional), test positivity and referral to cardiac catheterization within 90 days. We used a three-way interaction test to evaluate the association of test modality and positive test results with referral to cardiac catheterization modified by presentation symptoms.
Relationship of Presenting Symptoms with Clinical Outcomes
Clinician assessment of presentation as “very low”, “low” and “intermediate” risk for obstructive CAD was categorized as low risk and clinician assessment as “high” or “very high” risk was categorized as high risk. Using these two categories, we used a multivariable Cox regression model to assess the prognostic value of clinician risk assessment based on symptom presentation. We tested the relationship between symptom presentation and the two clinical outcomes of interest, all-cause death/MI/UA hospitalization and CV death/MI. We also tested the interaction between symptom presentation and clinical outcome as modified by clinician risk estimate.
Finally, we evaluated the association between presentation symptoms and clinical outcomes. We used multivariable Cox regression models to assess the association between a positive test and the outcomes of interest: all-cause death/MI/UA hospitalization and CV death/MI. We used similar multivariable Cox regression models to evaluate time to each outcome based on test positivity stratified by symptom presentation. Using a multivariable Cox regression model, we assessed the prognostic value of a positive test based on symptom presentation and randomized test modality. We tested the interaction between test positivity and outcome as modified by symptom presentation.
Variables included for adjustment were consistent across analyses and included sex, race, body mass index (BMI), hypertension, diabetes, and site characterization of chest pain (typical, atypical or non-cardiac). Given the small number of events observed in some symptom presentation categories, we limited the number of covariates for adjustment. We chose the included covariates based on observed differences across symptom presentation categories and clinical judgement. For all analyses, rates of missingness for each variable were assessed. Complete case analyses were performed provided combined rate of missingness was low (missingness for all descriptive statistic variables was ≤1.0%) We considered a p-value of <.05 to be significant.
All statistical calculations were carried out using SAS version 9.4 (SAS Institute, Cary, North Carolina). For the PROMISE trial, institutional review boards approved of the study at each site and all patients provided informed consent.
Results
Baseline Characteristics
The 9996 participants had a median age of 60.0 (54.4, 65.9) years old, 52.7% were women and 15.6% were non-white (Table 1). Among these, 4715 (47.2%) presented with a primary symptom of substernal or left chest pain, 2923 (29.2%) presented with other chest pain, 1490 (14.9%) with dyspnea and 868 (8.7%) with other symptoms. Most patients presented with at least one additional, secondary, symptom (median total number of symptoms reported 2.0, (Q1 1.0, Q3 3.0)). Dyspnea was the most frequent secondary symptom, reported in 26.3% of patients (Table S1). Patients who presented with dyspnea as the primary symptom were older, more likely to have higher BMI, diabetes mellitus, or a smoking history, and were less likely to participate in physical activity (all p<0.02, Table 1). Gender did not differ by symptom group. In alignment with the higher baseline co-morbidity burden, patients who presented with dyspnea had the highest risk for cardiovascular disease of any group across the risk scores utilized (median Framingham 20.0, Diamond and Forrester 43.7, ASCVD 14.5). Over three-quarters (78.2%) of patients presenting with dyspnea had an ASCVD 10-year risk of greater than 7.5%. Similarly, clinician estimate of patient risk for obstructive CAD also varied based on symptom presentation; patients with dyspnea were slightly more frequently estimated as at high or very high risk for obstructive CAD (p=0.044, Table 1).
Table 1.
Baseline Patient Characteristics
| Symptom Presentation | ||||||
|---|---|---|---|---|---|---|
| Overall N=9996 |
Substernal or Left Chest Pain N=4715 (47.2%) |
Other Chest Pain N=2923 (29.2%) |
Dyspnea N=1490 (14.9%) |
Other N=868 (8.7%) |
P-Value* | |
| Demographics | ||||||
| Age Median (25th, 75th) |
60.0 (54.4, 65.9) |
59.2 (53.8, 65.3) |
59.5 (54.4, 65.3) |
63.0 (57.0, 69.1) |
60.5 (55.1, 67.7) |
<.001 |
| Female Sex | 5269 (52.7%) | 2516 (53.4%) | 1541 (52.7%) | 784 (52.6%) | 428 (49.3%) | 0.184 |
| Non-White Race | 1545 (15.6%) | 817 (18.6%) | 437 (15.0%) | 197 (13.3%) | 94 (10.9%) | <.001 |
| Cardiac Risk Factors | ||||||
| Body Mass Index Median (25th, 75th) |
29.7 (26.3, 33.9) |
29.6 (26.3, 33.9) |
29.5 (26.2, 33.6) |
30.4 (27.1, 34.8) |
29.3 (26.0, 33.5) |
<.001 |
| Hypertension | 6498 (65.0%) | 3018 (64.0%) | 1864 (63.8%) | 1027 (68.9%) | 589 (67.9%) | <.001 |
| Diabetes mellitus | 2144 (21.4%) | 1010 (21.4%) | 577 (19.7%) | 375 (25.2%) | 182 (21.0%) | <.001 |
| Dyslipidemia | 6761 (67.6%) | 3157 (67.0%) | 1961 (67.1%) | 1033 (69.3%) | 610 (70.3%) | 0.106 |
| Smoking (ever) | 5100 (51.0%) | 2422 (51.4%) | 1426 (48.8%) | 821 (55.1%) | 431 (49.7%) | <.001 |
| Family history of premature CAD | 3201 (32.1%) | 1524 (32.5%) | 915 (31.3%) | 431 (29.0%) | 331 (38.1%) | <.001 |
| History of depression | 2058 (20.6%) | 1031 (21.9%) | 540 (18.5%) | 313 (21.0%) | 174 (20.0%) | 0.005 |
| Participate in physical activity | 5111 (51.2%) | 2523 (53.6%) | 1413 (48.4%) | 711 (47.8%) | 464 (53.5%) | <.001 |
| Peripheral artery disease | 552 (5.5%) | 229 (4.9%) | 153 (5.2%) | 106 (7.1%) | 64 (7.4%) | <.001 |
| ECG Findings | ||||||
| Q Waves | 453 (4.6%) | 187 (4.0%) | 144 (5.0%) | 82 (5.6%) | 40 (4.7%) | 0.045 |
| ECG findings that could interfere with stress test interpretation | 586 (5.9%) | 260 (5.6%) | 170 (5.9%) | 108 (7.4%) | 48 (5.6%) | 0.082 |
| 10 Year Cardiovascular Risk | ||||||
| Framingham Median (25th, 75th) |
17.1 (10.6, 28.6) |
16.8 (10.4, 27.5) |
16.1 (10.1, 27.3) |
20.0 (12.1, 33.3) |
16.9 (10.9, 30.6) |
<.001 |
| Diamond and Forrester Median (25th, 75th) |
38.4 (27.7, 54.4) |
38.4 (24.8, 48.9) |
38.4 (24.8, 48.9) |
43.7 (27.7, 59.4) |
38.4 (24.8, 54.4) |
<.001 |
| ASCVD Median (25th, 75th) |
11.3 (6.1, 19.8) |
10.8 (6.0, 18.9) |
10.5 (5.8, 18.5) |
14.5 (8.2, 24.3) |
11.4 (5.8, 21.4) |
<.001 |
| ASCVD‡ >7.5% | 6694 (67.6%) | 3075 (66.1%) | 1901 (65.3%) | 1154 (78.2%) | 564 (65.7%) | <.001 |
| Clinician’s Estimate Likelihood of Obstructive CAD | <.001 | |||||
| Very low (<1 10%) | 633 (6.3%) | 296 (6.3%) | 245 (8.4%) | 44 (3.0%) | 48 (5.5%) | |
| Low (10 – 30%) | 3118 (31.2%) | 1541 (32.7%) | 975 (33.4%) | 376 (25.3%) | 226 (26.1%) | |
| Intermediate (31 – 70%) | 5748 (57.6%) | 2653 (56.4%) | 1573 (53.9%) | 975 (65.6%) | 547 (63.1%) | |
| High (71% – 90%) | 448 (4.5%) | 202 (4.3%) | 115 (3.9%) | 87 (5.9%) | 44 (5.1%) | |
| Very high (> 90%) | 33 (0.3%) | 16 (0.3%) | 11 (0.4%) | 4 (0.3%) | 2 (0.2%) | |
| Clinician’s Estimate of CAD by categories | 0.047 | |||||
| Very Low/Low/Intermediate (<70%) | 9499 (95.2%) | 4490 (95.4%) | 2793 (95.7%) | 1395 (93.9%) | 821 (94.7%) | |
| High/Very High (≥70%) | 481 (4.8%) | 218 (4.6%) | 126 (4.3%) | 91 (6.1%) | 46 (5.3%) | |
Chi-square test for four symptom presentation groups
CAD: Coronary artery disease; ASCVD: Atherosclerotic cardiovascular disease
Test Results and Processes of Care
Using substernal or left-sided chest pain as the reference group, there was no significant difference in test positivity among patients presenting with other chest pain (11.9% vs 12.5%, adj p=0.38), dyspnea (12.7% vs 12.5%, adj p=0.12), or other symptoms (11.5% vs 12.5%, adj p=0.16). When subset by type of test (functional vs anatomic), among the 4739 patients who underwent stress testing, 596 (12.6%) had a positive result. There was no significant difference in test positivity across the four symptom presentation groups (p=0.44, Table 2). Conversely, 537 (11.8%) of 4538 patients who underwent CTA had obstructive coronary disease, with 267 (49.7%) of these being high risk. There were significant differences in obstructive stenosis detected on CTA across the presentation groups (p<.001, Table 2). In addition, the dyspnea group had a higher CAD burden, as indicated by being the most likely to have either obstructive or nonobstructive CAD (73.1% vs 62.9–69.0% in other groups) or CAC (72.6% CAC≠0 vs 61.3–67.1% in other groups). There were also significant differences in medical management at the time of 60 day follow-up. While all groups were similarly likely to be prescribed aspirin, there were significant differences in the prescription of antihypertensives (p<0.001) and statin medications (p=0.015), among patients with an indication for treatment (Table 2). Patients with hypertension who presented with dyspnea were the most likely (81.1%) to be treated with an antihypertensive. Conversely, patients with dyslipidemia who presented with substernal chest pain were the least likely (67.0%) to be treated with a statin medication.
Table 2.
Test Results and Processes of Care
| Symptom Presentation | ||||||
|---|---|---|---|---|---|---|
| Overall (N=9996) |
Substernal or Left Chest Pain (N=4715) |
Other Chest Pain (N=2923) |
Dyspnea (N=1490) |
Other (N=868) |
P-Value | |
| Functional Test Group | ||||||
| Type of stress | <.001 | |||||
| Exercise | 2916 (67.2%) | 1425 (69.1%) | 798 (67.0%) | 429 (60.2%) | 264 (70.6%) | |
| Pharmacologic | 1423 (32.8%) | 636 (30.9%) | 393 (33.0%) | 284 (39.8%) | 110 (29.4%) | |
| Test Result* | 0.435 | |||||
| Positive | 596 (12.6%) | 284 (12.8%) | 157 (11.5%) | 104 (13.8%) | 51 (12.9%) | |
| High risk | 375 (62.9%) | 185 (65.1%) | 92 (58.6%) | 69 (66.3%) | 29 (56.9%) | |
| Negative | 4143 (87.4%) | 1938 (87.2%) | 1213 (88.5%) | 649 (86.2%) | 343 (87.1%) | |
| CTA Group | ||||||
| Test Result† | <.001 | |||||
| Normal | 1517 (33.4%) | 726 (33.6%) | 496 (37.0%) | 171 (26.9%) | 124 (31.0%) | |
| Non-obstructive | 2484 (54.7%) | 1176 (54.4%) | 680 (50.7%) | 392 (61.6%) | 236 (59.0%) | |
| Obstructive | 537 (11.8%) | 260 (12.0%) | 164 (12.2%) | 73 (11.5%) | 40 (10.0%) | |
| High risk | 267 (49.7%) | 125 (48.1%) | 82 (50.0%) | 41 (56.2%) | 19 (47.5%) | |
| Coronary Artery Calcium | <.001 | |||||
| Normal (0) |
1471 (35.4%) | 710 (36.2%) | 473 (38.7%) | 162 (27.4%) | 126 (32.9%) | |
| Mild (1–99) |
1274 (30.6%) | 617 (31.5%) | 370 (30.3%) | 171 (28.9%) | 116 (30.3%) | |
| Moderate (100–400) |
768 (18.5%) | 344 (17.5%) | 221 (18.1%) | 138 (23.3%) | 65 (17.0%) | |
| Severe (Over 400) |
645 (15.5%) | 290 (14.8%) | 158 (12.9%) | 121 (20.4%) | 76 (19.8%) | |
| Coronary Angiography within 90 days | 0.427 | |||||
| Obstructive | 641 (63.2%) | 343 (65.7%) | 167 (59.2%) | 85 (62.0%) | 46 (63.0%) | |
| High risk | 428 (66.8%) | 233 (67.9%) | 109 (65.3%) | 53 (62.4%) | 33 (71.7%) | |
| Non-obstructive | 246 (24.3%) | 113 (21.6%) | 76 (27.0%) | 39 (28.5%) | 18 (24.7%) | |
| Normal | 127 (12.5%) | 66 (12.6%) | 39 (13.8%) | 13 (9.5%) | 9 (12.3%) | |
| Medications at 60 days after baseline | ||||||
| Aspirin - all patients N=8611 |
4483 (52.1%) | 2113/4090 (51.7%) | 1272/2446 (52.0%) | 690/1326 (52.0%) | 408/749 (54.5%) | 0.571 |
| Antihypertensives‡ - Patients with hypertension N=6498 |
4967 (76.4%) | 2308/3018 (76.5%) | 1378/1864 (73.9%) | 833/1027 (81.1%) | 448/589 (76.1%) | <.001 |
| Statins – Patients with dyslipidemia N=5898 |
4064 (68.9%) | 1858/2773 (67.0%) | 1198/1674 (71.6%) | 639/922 (69.3%) | 369/529 (69.8%) | 0.015 |
p-value refers to the comparison of symptom presentation groups regarding a positive vs. negative test result
p-value refers to the comparison of symptom presentation groups regarding a normal vs non-obstructive vs obstructive test result
Antihypertensives: ACEi/ARB, beta-blockers or calcium channel blockers
Overall, 1442 (14.4%) of patients underwent coronary angiography within 90 days. This included 523 (11.1%) of patients with substernal or left-sided chest pain, 282 (9.7%) of patients with other chest pain, 138 (9.3%) of patients with dyspnea and 73 (8.4%) of patients with other symptoms. Using substernal or left-sided chest pain as a reference group, and controlling for noninvasive test results, there was no significant difference in referral to cardiac catheterization among patients with other chest pain (p=0.16). However, significantly fewer patients presenting with dyspnea (adj OR 0.66, 95% CI 0.51–0.85, p=0.001) or other symptoms (adj OR 0.65, 95% CI 0.47–0.90, p=0.01) were referred for invasive evaluation of coronary artery disease (Table 3). There was no significant interaction between test type, test positivity and symptom presentation with regards to referral to cardiac catheterization (interaction p=0.31). Obstructive disease was found in 641 (63.2%) of patients referred for cardiac catheterization within 90 days, with no significant difference in angiography results based on symptom presentation group (p=0.42).
Table 3:
Association between Symptom Presentation and Referral to Catheterization
| Frequency of Referral to Catheterization | Unadjusted | Adjusted* | ||||
|---|---|---|---|---|---|---|
| Comparison | Comparison group |
Substernal or Left Chest Pain | Odds Ratio (95% CI) |
P-value | Odds Ratio (95% CI) |
P-value |
| Other chest pain vs. substernal/left chest pain | 282 (9.65%) | 523 (11.09%) | 0.86 (0.73 – 1.00) | 0.046 | 0.87 (0.72 – 1.06) | 0.162 |
| Dyspnea vs. substernal/left chest pain |
138 (9.26%) | 523 (11.09%) | 0.82 (0.67 – 1.00) | 0.046 | 0.66 (0.51 – 0.85) | 0.001 |
| Other vs. substernal/left chest pain |
73 (8.41%) | 523 (11.09%) | 0.74 (0.57 – 0.95) | 0.019 | 0.65 (0.47 – 0.90) | 0.010 |
Adjusted logistic models control for age, sex, race, diabetes mellitus, body mass index, hypertension and test positivity.
Association between Symptom Presentation and Outcomes
Over a median of 24 months of follow up, 310 (3.1%) of patients had a clinical outcome of all-cause death, MI or UA hospitalization and 157 (1.6%) of patients had CV death or MI (Figure 1). After adjustment for clinical characteristics and using substernal or left-sided chest pain as a reference, there was no significant difference in clinical events across any of the presentation groups for all-cause death/MI/UA hospitalization (other chest pain p=0.90, dyspnea p=0.39, other symptoms p=0.24) or CV death/MI (other chest pain p=0.30, dyspnea p=0.71, other symptoms p=0.85).
Figure 1.
Time to Event based on Symptom Presentation
A) All-cause Death, Myocardial Infarction, Unstable Angina
Event rates during follow-up: Substernal or left chest pain: 146 (3.1%); other chest pain or neck/arm pain: 94 (3.2%); dyspnea: 48 (3.2%); other pain: 22 (2.5%)
B) Cardiovascular Death, Myocardial Infarction
Event rates during follow-up: Substernal or left chest pain: 65 (1.4%); other chest pain or neck/arm pain: 52 (1.8%); dyspnea: 28 (1.9%); other pain: 12 (1.4%)
MI: Myocardial Infarction; UAH: Unstable angina Hospitalization; CV: Cardiovascular
When patients were categorized into groups by high versus low probability for obstructive CAD based on clinician assessment, there were no significant interactions between clinician assessment of risk and symptom presentation group for both all-cause death/MI/UA hospitalization and CV death/MI (p>0.5 for both, Table S2).
Patients with a positive test result by either NIT modality were significantly more likely to have an event, as compared with those who had a negative result, for each of the outcomes (p<.001 for both). When stratified by symptom presentation, there were significant differences across the groups (Figure 2). For the outcome of all-cause death/MI/UA hospitalization, those patients who presented with substernal or left chest pain, other chest pain or dyspnea and had a positive test were significantly more likely to have a subsequent event than those with a negative test result (p<.001, <.001, and 0.007 respectively; Table 4). However, among patients with other symptoms, there was no significant difference in outcome frequency based on a positive vs negative test result (p=0.25). For the outcome of CV death/MI, patients who presented with substernal or left-sided chest pain or dyspnea and had a positive test result were significantly more likely to have an event compared with patients with a negative result (p<.001, p=.009 respectively, Table 4). However, there was no significant difference in outcomes based on test result for patients who presented with other chest pain or other symptoms (p=0.41 and 0.90, respectively). The association between a positive test result and clinical outcome was significantly modified based on symptom presentation (interaction p=0.025 for both all-cause death/MI/UA hospitalization and CV death/MI, Table 4).
Figure 2.
Association between Symptom Presentation and Clinical Outcomes
A) All-cause Death, Myocardial Infarction, Unstable Angina
B) Cardiovascular Death, Myocardial infarction
MI: Myocardial Infarction; UAH: Unstable angina Hospitalization; CV: Cardiovascular
Table 4:
Association between Positive Test Results and Clinical Outcomes
| Frequency of Outcome | Unadjusted | Adjusted* | ||||
|---|---|---|---|---|---|---|
| Comparison of Positive vs Negative Test Result | Positive Test Result |
Negative Test Result | Hazard Ratio (95% CI) |
P-value | Hazard Ratio (95% CI) |
P-value |
| All-cause death/MI/UAH | ||||||
| Interaction between Test Result and Symptom Presentation | 0.071 | 0.025 | ||||
| Substernal or left chest pain | 58 (10.56%) | 77 (2.00%) | 5.72 (4.07 – 8.05) | <0.001 | 5.17 (3.66 – 7.31) | <0.001 |
| Other chest pain or neck/arm pain | 29 (9.01%) | 60 (2.50%) | 4.50 (2.94 – 6.90) | <0.001 | 3.52 (2.26 – 5.50) | <0.001 |
| Dyspnea | 11 (6.21%) | 31 (2.55%) | 3.17 (1.69 – 5.96) | <0.001 | 2.44 (1.28 – 4.65) | 0.007 |
| Other pain | 4 (4.40%) | 15 (2.13%) | 2.38 (0.87 – 6.49) | 0.091 | 1.82 (0.66 – 5.01) | 0.246 |
| CV death/MI | ||||||
| Interaction between Test Result and Symptom Presentation | 0.053 | 0.025 | ||||
| Substernal or left chest pain | 22 (4.01%) | 38 (0.99%) | 4.15 (2.46 – 7.02) | <0.001 | 3.62 (2.13 – 6.16) | <0.001 |
| Other chest pain or neck/arm pain | 7 (2.17%) | 41 (1.71%) | 2.05 (0.92 – 4.59) | 0.081 | 1.44 (0.61 – 3.43) | 0.408 |
| Dyspnea | 7 (3.95%) | 17 (1.40%) | 4.08 (1.82 – 9.14) | <0.001 | 3.00 (1.32 – 6.84) | 0.009 |
| Other pain | 1 (1.10%) | 9 (1.28%) | 1.21 (0.17 – 8.83) | 0.849 | 0.88 (0.12 – 6.45) | 0.900 |
Adjusted Cox proportional hazards model controls for age, sex, race, diabetes mellitus, body mass index and hypertension
MI: Myocardial Infarction; UAH: Unstable angina Hospitalization; CV: Cardiovascular
Discussion
Using data from the PROMISE trial, we examined patient characteristics and outcomes based on the primary presenting symptom. We found that: 1) dyspnea as a the primary presenting symptom was associated with older age, higher burden of comorbidities, higher pre-test predicted risk of future events and increased burden of CAD; 2) presenting symptoms were only marginally associated with clinician risk assessment and did not change the odds of a positive test result or the risk of a clinical event and 3) presenting symptoms influenced the prognostic value of the noninvasive test. Specifically, the ability of a positive noninvasive test result to predict a future clinical event was greatest among those with substernal chest pain or dyspnea.
The diagnosis of a patient with symptoms suggestive of CAD has been a long studied clinical scenario in cardiovascular disease but the accurate identification of CAD remains a challenge.1–3 The broad possible range of symptoms contributes to the diagnostic challenge, and fewer data have existed for patients presenting with dyspnea.10 Women and older patients are more likely to report an absence of chest discomfort when presenting with an acute coronary syndrome11, 12 or with stable chest pain, a finding also highlighted in the PROMISE trial.13, 14 Similarly, patients with diabetes less often present with typical angina symptoms.15 In keeping with these prior reports, we found that fewer than half of PROMISE patients reported ‘typical’ symptoms or substernal/left-sided chest pain. The next largest group was other chest pain, followed by dyspnea, and finally a collection of widely varying symptoms prompting an evaluation. We also found significant baseline patient differences between the groups of presenting symptoms. Patients who presented with dyspnea were older with a higher burden of comorbidities and were more often referred for pharmacologic rather than exercise stress testing. In this setting, dyspnea patients also had a higher predicted risk for a future cardiovascular event.6, 7, 16 Additionally, we did not find any significant differences in symptom presentation between men and women. This is in contrast to prior literature, where women with coronary artery disease were less likely to present with typical chest pain symptoms11, 12, and may be reflective of the low-risk population of patients included. The majority of PROMISE participants had non-invasive tests results that did not indicate obstructive coronary artery disease.
Despite the differences in patient characteristics between symptom presentation groups, we observed similar NIT positivity across the four groups. In contrast to our findings, other reports found increased NIT positivity in patients with typical chest pain.17 We speculate that these may be related to differences in patient populations as well as the categorization of chest pain. Additionally, although substernal chest pain was considered typical angina in this analysis, our data did not allow for full characterization of typical angina, including provocative and relieving features. While we observed similar NIT positivity across the presentation groups, there were also important differences present, including a greater burden of non-obstructive CAD, based on CTA and CAC, among patients presenting with dyspnea. This is in alignment with prior work which showed that patients with dyspnea have a high burden of CAD, including a higher burden of severe, proximal stenosis and calcified lesions by coronary CTA, as compared with patients with typical angina.18 Despite the higher CAD burden, patients with dyspnea or other symptoms in our study were significantly less likely to be referred to cardiac catheterization, even after adjusting for age, risk factors, NIT type, and test positivity. When these patients were referred for invasive evaluation, we observed a similar burden of obstructive coronary artery disease, regardless of presentation symptoms, as has been previously described.19–23
In order to identify patients at highest risk for a clinical event and help guide clinicians in the management of patients with symptoms suggestive of CAD, validated risk scores have been developed which incorporate multiple aspects of a patient’s care – including symptoms, laboratory and diagnostic test findings. For example, the HEART score ranks clinician interpretation of the history as “slightly suspicious”, “moderately suspicious” and “highly suspicious”.24 Unlike these scores which assign higher risk to patients with more suspicious symptoms, in our cohort, there was no significant difference in clinical outcomes based on presenting symptom descriptions, despite the differing baseline risk between the symptom groups. Similarly, clinician assessment of risk did not modify the relationship between symptom presentation and clinical outcome. Prior work from the PROMISE trial similarly demonstrated the limitations associated with symptom-based assessment among the low risk patient population in the trial, noting the questionable value of symptom classification in the patient group.25 The differences observed in PROMISE may be due to a more stable outpatient patient population enrolled in the PROMISE trial. Further, given the pragmatic nature of the PROMISE trial, variations in processes of care based on symptom presentation, may have affected clinical outcomes.
While patients had similar clinical outcomes across the spectrum of symptoms at presentation, we found that the prognostic value of a positive NIT was significantly associated with the presenting symptom group. Consistent with prior literature, a positive NIT among patients presenting with substernal chest pain was prognostically meaningful.26, 27 However, we also found that a positive NIT among patients with dyspnea was indicative of an increased risk of a future event. As a group that is commonly characterized as having atypical symptoms, and in this setting undergoes variable management, our analysis suggests that patients with dyspnea may represent a unique group - one without classic chest pain symptoms, but at an increased risk for an event and in which NIT may provide important prognostic information during the course of work-up.
Among patients who present with symptoms suggestive of stable coronary artery disease, guideline recommendations would suggest the use of noninvasive testing to further risk stratify patients and to help guide decision making regarding invasive evaluation of coronary artery disease.27 However, we found that the prognostic value of a positive noninvasive test also differs based on symptom presentation. This suggests the incremental value of a positive NIT based on presenting symptoms may be helpful to clinicians when guiding discussions with patients.
We acknowledge several limitations associated with our study. First, the symptom groups were selected from a list based upon clinical judgment. These may be limited in their ability to fully reflect the complexities of clinical presentations and subjective assessment by the clinician. Next, the PROMISE trial did not randomize patients based on symptom presentation. However, similar numbers of patients in each symptom presentation group were randomized to undergo functional versus anatomic noninvasive testing. We were not able to perform additional subgroup analyses across combinations of symptom types due to the low clinical event rate. We adjusted our analyses for clinically important variables but were limited in the number of covariates we could include. Further, the lack of significant interactions observed for some of the analyses may reflect the small cell counts for some combinations. As a pragmatic study, clinical decision making beyond the initial randomization was left to the discretion of the site clinicians and may have affected clinical outcomes. Clinician rational for clinical decisions were also not available for inclusion in this study. Finally, as a sub-study of the PROMISE trial, our results should be viewed as hypothesis generating for the evaluation and management of patients presenting with a range of presenting symptoms.
Conclusion
Among low-risk patients with stable symptoms being evaluated for possible CAD in the PROMISE trial, presenting symptoms correlated with significant differences in baseline risk profiles and subsequent processes of care. Despite these differences, symptom presentation was not associated with a higher likelihood of a positive NIT result or adverse clinical outcomes. However, the prognostic value of a positive test was modified by symptom presentation, with the highest prognostic value among patients presenting with dyspnea or substernal chest pain. These findings underscore the difficulty of predicting obstructive CAD or outcomes based on presentation symptoms alone. They also highlight the importance of utilizing symptom presentation to help inform the positive predictive value of noninvasive testing and to guide subsequent management in this patient population.
Supplementary Material
What is Known.
Patients who are evaluated for coronary artery disease have a range of underlying risk levels and symptom presentations, including substernal chest pain and dyspnea, among others.
The relationships between the patient-described symptoms, clinician conclusions, non-invasive testing for coronary artery disease and outcomes remain incompletely described.
What the Study Adds.
Among low-risk outpatients evaluated for CAD in the PROMISE trial, typicality of symptoms was not closely associated with higher baseline risk or likelihood of a positive non-invasive test but was related to differences in processes of care.
The highest prognostic value of a positive non-invasive test was among patients presenting with dyspnea or substernal chest pain
Prediction of obstructive CAD or outcomes remains challenging based on presentation symptoms alone, but symptom presentation remains important to help inform the positive predictive value of noninvasive testing.
Funding
This project was supported by grants R01HL098237, R01HL098236, R01HL98305, and R01HL098235 from the National Heart, Lung, and Blood Institute (NHLBI). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. This paper does not necessarily represent the official views of NHLBI.
Disclosures
Lowenstern: none
Alexander: grants from Gilead, Sanofi-Aventis
Pagidipati: none
Hill: none
Alhanti: none
Pellikka: none
Cooper: none
Hoffmann: grants from HeartFlow and Kowa Pharmaceuticals
Mark: none
Douglas: grant support from HeartFlow and service on a data and safety monitoring board for GE HealthCare
Non-standard Abbreviations and Acronyms:
- BMI
Body mass index
- CAC
Coronary artery calcium
- CAD
Coronary artery disease
- CTA
Computer tomographic angiography
- CV
Cardiovascular
- MI
Myocardial infarction
- NIT
Noninvasive test
- UA
Unstable angina
Footnotes
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