Abstract
Aims
Individuals with suspected ischaemia but no obstructive coronary arteries (INOCA) experience persistent chest pain (PChP) at rates comparable to those with obstructive coronary artery disease (CAD). We analysed the National Heart, Lung, and Blood Institute-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) (NCT00000554) to compare patterns in chest pain persistence, cardiac medication use, and major adverse cardiovascular events (MACE) among women with INOCA and those with obstructive CAD.
Methods and results
There were 624 participants from WISE who met the inclusion criteria for this analysis (19% non-white, mean age = 58.0 years). Chest pain status was classified based on symptoms reported during the first 3 years of follow-up. Baseline predictors of 3-year chest pain status were assessed by Chi-square, and a log-rank test was used to compare 6-year outcomes by status. At 3 years, overall 26% of participants had persistent, 14% had intermediate, 27% had recurrent, and 34% had resolved chest pain. PChP prevalence was comparable in the INOCA group and the obstructive CAD groups (27% vs. 24%, P = 0.06). MACE occurrence was not significantly associated with 3-year chest pain status in either the INOCA or obstructive CAD groups. However, hospitalization for angina was associated with chest pain status (P < 0.001).
Conclusion
Women with INOCA experience a comparable burden of chest pain to those with obstructive CAD, yet lower rates of medical therapy at baseline and over time. Based on our findings, chest pain status at 3 years predicts angina hospitalizations but not MACE in women with or without obstructive CAD.
Keywords: INOCA, Persistent chest pain, Chronic angina, Women, Coronary artery disease
Graphical Abstract
Graphical Abstract.
Key Learning Points.
What is already known:
Women with INOCA experience comparable rates of chest pain to those with obstructive CAD.
What this study adds:
Despite comparable rates of chest pain to those with obstructive CAD, women with INOCA have lower rates of cardiac medication use and MACE occurrence.
Younger age, higher depression score, and lower functional status predict chest pain persistence in women with and without obstructive CAD.
Although persistent chest pain at 3 years is associated with greater angina hospitalizations, it does not predict MACE at 6-year follow-up.
Introduction
Chest pain is a common manifestation of cardiovascular disease, often due to insufficient oxygen supply from obstructed coronary arteries. However, approximately half of individuals with chest pain undergoing angiography for suspected ischaemic heart disease are found to have non-obstructive coronary arteries (<50% stenosis).1 This condition is termed ischaemia with no obstructive coronary arteries (INOCA). Estimates suggest that there are at least 3 to 4 million Americans living with INOCA.2 Individuals with INOCA often receive inaccurate or delayed diagnoses due to a lack of physician awareness and limited availability of diagnostic testing and expertise.3 It is likely that the lack of guideline-directed medical therapy for INOCA contributes to persistent symptoms, clinical inertia in advancing treatment, and increased morbidity.4
In addition to increased risk of cardiovascular death and recurrent myocardial infarction (MI), persistent chest pain (PChP) can limit functional capacity and adversely affect quality of life (QOL).5 It has been previously reported that PChP contributes more to adverse QOL than underlying obstructive coronary artery disease (CAD) status.6 Understanding the course of PChP among individuals with INOCA is necessary to improve knowledge and address the gap in effective treatments for this population.
Few studies have comparatively profiled chest pain prevalence and cardiac medication use among INOCA vs. obstructive CAD. A prior analysis of the Women’s Ischaemia Syndrome Evaluation (WISE) cohort demonstrated that PChP at 1 year was associated with a higher risk of major adverse cardiovascular events (MACE) but not mortality among women with INOCA.1 However, this prior analysis defined PChP as a dichotomous variable based on chest pain report at only 1-year follow-up. Our current analysis extends the duration of follow-up to 3 years and explores multiple patterns of chest pain persistence. We also evaluated baseline predictors, cardiac medication use, and association with 6-year MACE.
Methods
Study population
The National Heart, Lung, and Blood Institute (NHLBI)-sponsored WISE enrolled 936 women undergoing clinically indicated coronary angiography for chest pain symptoms or suspected myocardial ischaemia. Full methodology has been previously described.7 Recruitment was completed in 2000, while follow-up continued through March 2006, for a median duration of 9.5 years. Exclusion criteria included any contraindication to provocative myocardial stress testing; thus, enrolled subjects had stable symptoms. Study procedures were performed in accordance with guidelines and institutional review board approval at the respective WISE sites. All participants provided signed informed consent (see ClinicalTrials.gov NCT00000554).
Data collection
Baseline evaluation involved the collection of demographic information, risk factors for CAD, medication use, medical and reproductive history, detailed symptom history, psychosocial evaluation including the Beck Depression Inventory (BDI), physical examination, activity status assessment including the Duke Activity Status Index (DASI), and blood sampling as published.7 A core laboratory masked to patient data evaluated coronary angiograms to determine obstructive CAD status (≥50% diameter reduction in any coronary artery). Site nurses and physicians conducted follow-up evaluation at 6 weeks and then annually. Scripted interviews were used to query participants about symptoms, medication use, cardiovascular events since prior contact, hospitalizations, and revascularization procedures.
Definitions
Chest pain was determined by the question: ‘In the last 12 months, have you had chest pain or discomfort above your waist?’ Consistent with prior WISE findings,8 characterization of chest pain symptoms was not limited to ‘pain’ or location in the chest but included other descriptors and locations (e.g. shortness of breath, discomfort, shoulder location). Presence/absence of chest pain during the first 3 years of follow-up was used to categorize the pattern of chest pain. Chest pain was classified as persistent if it was reported for all 3 years of follow-up, intermediate if it persisted for ≥1 year but resolved by the third year, recurrent if it resolved for ≥1 year but recurred during the second or third follow-up year, and resolved if it was only reported at baseline and did not recur for all 3 follow-up years. In the case of missing follow-up chest pain values, the value for the prior year was imputed except for those who had myocardial infarction or revascularization during the year. Analysis was limited to participants with no missing chest pain values after imputation. Outcomes assessed were angina hospitalization, cardiovascular (CV) mortality, all-cause mortality, and composite MACE. MACE was defined as myocardial infarction (MI), heart failure (HF), stroke, death, or coronary intervention (angioplasty or coronary artery bypass surgery). Classification of deaths as CV was performed by WISE investigators masked to angiographic findings. Cardiac medications evaluated were aspirin, angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta-blockers, calcium-channel blockers, diuretics, statins, nitrates, and other vasodilators.
Statistical analysis
Frequency distributions are provided for chest pain categories. Time difference in medication use was tested using repeated measures logistic regression. Chi-square was used to assess which baseline demographic, risk factors, and medication variables were predictive of PChP at 3 years. A log-rank test was used to evaluate MACE occurrence by PChP status. An adjusted Cox proportional hazards regression model also compared time to MACE by PChP categories while adjusting for age, history of dyslipidemia, hypertension, diabetes, smoking, coronary severity score (a measure of the extent of coronary vessel stenosis),9 and baseline hypertension medication use (ACE-I, ARB, beta-blockers, calcium-channel blockers, vasodilators, diuretics). Fine and Gray competing risks models10 were made for the outcomes of CV death with non-CV death as a competing risk, as well as for angina hospitalization with all-cause mortality as a competing risk. These models had persistent chest pain categories as an explanatory variable and were adjusted for the same variables as the Cox proportional hazards models. Data were analysed using SAS version 9.4 (Cary, N.C).
Results
A total of 624 participants (Figure 1) who reported chest pain at baseline and had non-missing or imputed chest pain values for the first 3 follow-up years were included in this analysis. Mean age was 58.0 ± 11.2 years, participants with INOCA were younger (55.7 vs. 62.9, P < 0.0001), and had a lower prevalence of hypertension (55% vs. 64%, P = 0.02) compared to those with obstructive CAD (Table 1).
Figure 1.
Flowchart of participants included in analysis. Describes how the sample size for each analysis was derived. CAD, coronary artery disease; INOCA, ischaemia with no obstructive coronary artery disease.
Table 1.
Baseline demographics
| INOCA (n = 399) | Obstructive CAD (n = 225) | Total (n = 624) | P-value | |
|---|---|---|---|---|
| Agea (years) | 56.0 (10.5) | 61.6 (11.4) | 58.0 (11.2) | <0.0001 |
| BMIa | 29.7 (6.8) | 29.4 (6.4) | 29.6 (6.7) | 0.59 |
| Race | ||||
| White | 336 (84.2%) | 171 (76.0%) | 507 (81.3%) | 0.02 |
| Any history of cigarette smoking | 187 (47.1%) | 129 (57.3%) | 316 (50.8%) | 0.02 |
| History of alcohol use in past 6 months | 56 (14.1%) | 32 (14.3%) | 88 (14.1%) | 0.99 |
| Family history of coronary artery disease | 257 (65.7%) | 149 (68.3%) | 406 (66.7%) | 0.53 |
| History of diabetes | 64 (16.1%) | 79 (35.4%) | 143 (23.1%) | <0.0001 |
| History of hypertension | 217 (54.5%) | 143 (64.1%) | 360 (58.0%) | 0.02 |
| History of dyslipidemia | 170 (45.9%) | 138 (66.0%) | 308 (53.2%) | <0.0001 |
| History of frequent psychosocial stress | 246 (62.0%) | 138 (61.6%) | 384 (61.8%) | 0.93 |
| Baseline nitrate use | 92 (23.1%) | 120 (53.3%) | 212 (34.0%) | <0.0001 |
| Baseline antidepressant use | 78 (19.6%) | 35 (15.6%) | 113 (18.1%) | 0.23 |
| Beck Depression Inventory | 10.1 (7.5) | 10.9 (8.1) | 10.3 (7.7) | 0.27 |
Bold values indicate statistically significant P values (P < 0.05).
BMI, body mass index.
aMean (SD).
Chest pain status
At 3 years, 26% of participants had PChP, 14% had intermediate chest pain (IChP), 27% had recurrent chest pain (RChP), and 34% had resolved chest pain (ReChP). Figure 2 demonstrates the PChP prevalence from baseline to 3 years in the INOCA (Figure 2) and obstructive CAD (Figure 3) groups. PChP prevalence was comparable in the INOCA vs. obstructive CAD groups (persistent: 27% vs. 24%, resolved: 31% vs. 39%) (Table 2). Using the prior dichotomous stratification at 1 year, 46% had PChP, consistent with our previous publication of 45%.1
Figure 2.
Chest pain prevalence from baseline to 3 years among participants with INOCA in WISE. Sankey plot shows the changes in chest pain prevalence from baseline to 3 years in the INOCA cohort of WISE. WISE, women’s ischaemia syndrome evaluation; INOCA, ischaemia with no obstructive coronary artery disease.
Figure 3.
Chest pain prevalence from baseline to 3 years among participants with obstructive CAD in WISE. Sankey plot shows the changes in chest pain prevalence from baseline to 3 years in the obstructive CAD cohort of WISE. WISE, women’s ischaemia syndrome evaluation; CAD, coronary artery disease.
Table 2.
Chest pain status at 3 years by INOCA and obstructive CAD status
| Persistent chest pain n (%) | Intermediate chest pain n (%) | Recurrent chest pain n (%) | Resolved chest pain n (%) | |
|---|---|---|---|---|
| INOCA | 106 (26.6) | 50 (12.5) | 119 (29.8) | 124 (31.1) |
| Obstructive CAD | 54 (24.0) | 34 (15.1) | 49 (21.8) | 88 (39.1) |
| Total | 160 (25.6) | 84 (13.5) | 168 (26.9) | 212 (34.0) |
X2 = 7.27; P-value = 0.06.
Medication use
Differences in medication use between INOCA and obstructive CAD groups at baseline persisted at 3-year follow-up; women with INOCA reported less use of cardiac medications than those with obstructive CAD at each follow-up time. Over time, statin use increased in both groups (INOCA: P = 0.03; obstructive CAD: P < 0.001), aspirin use decreased in the INOCA group (P < 0.001), and nitrate use decreased in the obstructive CAD group (P = 0.002).
Predictors of chest pain status
In both INOCA and obstructive CAD groups, younger age at baseline, higher baseline BDI scores (more depressed), and lower baseline DASI scores (less functional capacity) were associated with higher PChP prevalence at 3 years (Tables 3 and 4).
Table 3.
Baseline factors associated with chest pain status at 3 years (INOCA group)
| Persistent Chest Pain (N = 106) | Intermediate chest pain (N = 50) | Recurrent chest pain (N = 119) | Resolved chest pain (N = 124) | P-value | |
|---|---|---|---|---|---|
| Age | 52.0 (45.7, 59.1) | 54.3 (48.9, 61.3) | 57.0 (50.3, 65.0) | 59.1 (50.4, 66.4) | <0.001 |
| Race | 0.54 | ||||
| White | 91 (85.8%) | 39 (78.0%) | 99 (83.2%) | 107 (86.3%) | |
| History of cigarette smoking | 54 (51.4%) | 24 (48.0%) | 55 (46.6%) | 54 (43.5%) | 0.70 |
| Alcohol use in prior 6 months | 14 (13.3%) | 10 (20.0%) | 7 (5.9%) | 25 (20.2%) | 0.01 |
| Frequent psychosocial stress | 75 (71.4%) | 32 (64.0%) | 79 (66.9%) | 60 (48.4%) | 0.002 |
| Antidepressants | 29 (27.6%) | 13 (26.0%) | 24 (20.2%) | 12 (9.7%) | 0.003 |
| ACE-inhibitors | 19 (18.1%) | 10 (20.0%) | 23 (19.3%) | 25 (20.2%) | 0.98 |
| Angiotensin receptor blockers | 2 (1.9%) | 1 (2.0%) | 4 (3.4%) | 5 (4.0%) | 0.82 |
| Diuretics | 24 (22.9%) | 13 (26.0%) | 33 (27.7%) | 31 (25.0%) | 0.87 |
| Vasodilators | 6 (5.7%) | 5 (10.0%) | 11 (9.2%) | 12 (9.7%) | 0.66 |
| Anxiolytics | 29 (27.4%) | 12 (24.0%) | 21 (17.6%) | 14 (11.3%) | 0.01 |
| Aspirin | 54 (51.4%) | 33 (66.0%) | 59 (49.6%) | 64 (52.0%) | 0.25 |
| Beta-blockers | 37 (35.2%) | 16 (32.0%) | 34 (28.6%) | 45 (36.3%) | 0.59 |
| Calcium-channel blockers | 41 (39.0%) | 13 (26.0%) | 25 (21.0%) | 21 (16.9%) | 0.001 |
| Lipid-lowering statins | 23 (21.9%) | 9 (18.0%) | 21 (17.6%) | 22 (17.7%) | 0.84 |
| Thyroid medications | 7 (6.6%) | 8 (16.0%) | 11 (9.2%) | 27 (21.8%) | 0.004 |
| Nitrates | 35 (33.3%) | 14 (28.0%) | 26 (21.8%) | 17 (13.7%) | 0.004 |
| Self-described general health | 0.001 | ||||
| Good—Excellent | 50 (47.6%) | 35 (70.0%) | 74 (62.2%) | 91 (73.4%) | |
| Patient-reported quality of life | 6.0 (5.0, 8.0) | 8.0 (6.0, 9.0) | 7.0 (5.0, 8.0) | 8.0 (7.0, 9.0) | <0.0001 |
| Satisfaction with quality of life | 7.0 (4.0, 8.0) | 8.0 (5.0, 9.0) | 7.0 (5.0, 9.0) | 8.0 (6.0, 9.0) | <0.001 |
| DASI Score | 12.5 (7.2, 24.7) | 18.7 (10.0, 37.7) | 18.7 (10.0, 34.7) | 26.3 (15.2, 36.7) | <0.0001 |
| Beck Depression Inventory | 12.0 (4.2, 19.0) | 9.5 (6.0, 14.0) | 9.0 (4.0, 14.0) | 6.0 (4.0, 11.0) | 0.003 |
Bold values indicate statistically significant P values (P < 0.05).
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BDI, Beck’s depression inventory.
Table 4.
Baseline factors associated with persistent chest pain at 3 years (obstructive CAD group)
| Persistent chest pain (N = 54) | Intermediate chest pain (N = 34) | Recurrent chest pain (N = 49) | Resolved chest pain (N = 88) | P-value | |
|---|---|---|---|---|---|
| Age | 56.8 (48.8, 65.8) | 64.9 (50.2, 68.9) | 63.8 (55.3, 73.3) | 64.8 (56.0, 71.2) | 0.01 |
| Race | 0.58 | ||||
| White | 43 (79.6%) | 25 (73.5%) | 34 (69.4%) | 69 (78.4%) | |
| History of cigarette smoking | 30 (55.6%) | 25 (73.5%) | 29 (59.2%) | 45 (51.1%) | 0.16 |
| Alcohol use in prior 6 months | 9 (16.7%) | 3 (8.8%) | 5 (10.4%) | 15 (17.0%) | 0.57 |
| Frequent psychosocial stress | 39 (72.2%) | 21 (61.8%) | 29 (59.2%) | 49 (56.3%) | 0.29 |
| Antidepressants | 12 (22.2%) | 4 (11.8%) | 6 (12.2%) | 13 (14.8%) | 0.49 |
| ACE-inhibitors | 19 (35.2%) | 8 (23.5%) | 20 (40.8%) | 27 (30.7%) | 0.39 |
| Angiotensin receptor blockers | 1 (1.9%) | 4 (11.8%) | 3 (6.1%) | 3 (3.4%) | 0.18 |
| Diuretics | 18 (33.3%) | 10 (29.4%) | 19 (38.8%) | 27 (30.7%) | 0.77 |
| Vasodilators | 2 (3.7%) | 2 (5.9%) | 4 (8.2%) | 6 (6.8%) | 0.81 |
| Anxiolytics | 12 (22.2%) | 6 (17.6%) | 10 (20.4%) | 9 (10.2%) | 0.20 |
| Aspirin | 37 (68.5%) | 29 (85.3%) | 34 (69.4%) | 69 (78.4%) | 0.21 |
| Beta-blockers | 27 (50.0%) | 14 (41.2%) | 22 (44.9%) | 44 (50.0%) | 0.80 |
| Calcium-channel blockers | 27 (50.0%) | 14 (41.2%) | 16 (32.7%) | 27 (30.7%) | 0.11 |
| Lipid-lowering statins | 24 (44.4%) | 12 (35.3%) | 15 (30.6%) | 25 (28.4%) | 0.25 |
| Thyroid medications | 7 (13.0%) | 2 (5.9%) | 11 (22.4%) | 17 (19.3%) | 0.16 |
| Nitrates | 28 (51.9%) | 19 (55.9%) | 26 (53.1%) | 47 (53.4%) | 0.99 |
| Self-described general health | 0.002 | ||||
| Good–Excellent | 22 (40.7%) | 21 (61.8%) | 24 (49.0%) | 63 (71.6%) | |
| Patient-reported quality of life | 7.0 (5.0, 8.0) | 7.0 (6.0, 9.0) | 7.0 (5.0, 8.0) | 8.0 (6.0, 9.0) | 0.01 |
| Satisfaction with quality of life | 7.0 (4.0, 8.0) | 7.0 (5.0, 9.0) | 6.0 (4.0, 8.0) | 8.0 (5.0, 9.0) | 0.01 |
| DASI Score | 9.0 (4.5, 18.7) | 11.6 (7.2, 25.5) | 13.5 (7.2, 21.5) | 18.6 (11.7, 24.1) | <0.001 |
| Beck depression inventory | 12.0 (6.0, 17.0) | 10.5 (6.0, 14.0) | 10.5 (6.0, 17.0) | 6.0 (4.0, 9.0) | 0.001 |
Bold values indicate statistically significant P values (P < 0.05).
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BDI, beck’s depression inventory.
In the INOCA group, a history of frequent psychosocial stress and use of antidepressants, anxiolytics, calcium-channel blockers, and nitrates at baseline were associated with higher PChP prevalence at 3 years. Baseline thyroid medication use was associated with a higher prevalence of resolved chest pain at 3 years.
Association between chest pain status and 6-year outcomes
Chest pain status at 3 years was associated with angina hospitalization (P < 0.001) but not with time to MACE, or CV- or all-cause mortality (log-rank P-values were 0.10 for time to MACE, 0.47 for CV-mortality, and 0.44 for all-cause mortality). After adjusting for age, history of dyslipidemia, hypertension, diabetes, coronary severity score, ever smoker, and baseline hypertension medication use, there was no difference in time to these outcomes among the PChP categories: P-values for adjusted Cox Hazards regression models were 0.13 for time to MACE, 0.59 for CV-mortality, and 0.58 for all-cause mortality. There was also no significant difference after stratification by obstructive CAD status. The adjusted Cox regression for the outcome of angina hospitalization showed significant overall differences among PCHP categories (P = 0.003). Compared to those with resolved chest pain, those with persistent (HR: 2.45, 95% CI (1.51, 3.98), P < 0.001) and recurrent chest pain (HR: 1.87, 95% CI (1.14, 3.08), P = 0.01) had more angina hospitalizations in adjusted Cox regression analyses. Adjusted competing risk models for CV death with non-CV death as a competing risk did not show significant differences in rates among PCHP categories (P = 0.38 for all subjects, P = 0.13 in obstructive CAD, P = 0.87 in INOCA). Adjusted competing risk models for angina hospitalization with death as a competing risk did show evidence of differences among PCHP categories (P = 0.004 in all subjects). Rate of angina hospitalizations with death as a competing risk were higher in persistent chest pain vs. resolved (HR: 2.38, 95% CI (1.48, 3.82)), and in recurrent vs. resolved (HR: 1.90, 95% CI (1.16, 3.10)) but intermediate did not show evidence of different rates compared to resolved (HR: 1.53 95% CI (0.84, 2.79)). When only CV-death was considered as a competing risk (non-cardiac deaths were censored), adjusted models for angina hospitalization showed varied evidence of differences among PCHP categories (P = 0.05 in INOCA, P = 0.009 in obstructive CAD).
In the INOCA group, participants with PChP had the highest rate of MACE (58.8%) and angina hospitalizations (27.1%). In the obstructive CAD group, participants with PChP had the highest rate of angina hospitalizations (48.4%) while those with intermediate chest pain had the highest rates of MACE, cardiovascular, and all-cause mortality (68.2%, 15.8%, and 24.6%, respectively, Figure 4). However, except for angina hospitalizations (INOCA: P = 0.01, obstructive CAD: P = 0.003, Figure 5), differences in time to events between the various chest pain categories were not statistically significant in either INOCA or obstructive CAD groups (all P > 0.1).
Figure 4.
Kaplan–Meier 6-year event rate estimates. Shows the event rate estimates at 6 years for participants in each chest pain category, stratified by CAD status. CAD, coronary artery disease; INOCA, ischaemia with no obstructive coronary artery disease; MACE, major adverse cardiovascular event.
Figure 5.
Kaplan–Meier curves for angina hospitalization stratified by chest pain status. Shows the Kaplan–Meier curves for survival without angina hospitalization by chest pain status for INOCA and obstructive CAD groups. INOCA, ischaemia with no obstructive coronary artery disease; CAD, coronary artery disease.
Discussion
Our findings indicate that individuals with INOCA had a similar prevalence of PChP at 3 years to those with obstructive CAD, while those with obstructive CAD had higher rates of cardiac medication use and MACE occurrence. Demographic and psychosocial variables predicted PChP at 3 years in women with and without obstructive CAD. PChP at 3 years was not significantly associated with 6-year MACE in either INOCA or obstructive CAD. PChP at 3 years was, however, associated with more angina hospitalizations in both groups.
Few studies have published data on longer-term outcomes in patients with INOCA, and to our knowledge, none have reported on trends in PChP prevalence beyond 1 year or compared these trends to those with obstructive CAD. However, we and others have reported increased rates of chest pain burden among INOCA patients with stable angina compared to reference groups.1,11 Compared to our study which showed a high burden of persistent or recurrent angina, the CIAO-ISCHEMIA study demonstrated that the majority (43%) of their INOCA participants experienced an improvement in angina symptoms over 1 year, with a smaller proportion (14%) reporting worsened symptoms based on the Seattle Angina Questionnaire.12 The lower burden of angina at 1-year follow-up in CIAO-ISCHEMIA may be due to a lower prevalence of baseline angina, as 55.6% of their INOCA participants reported no angina at baseline. Our current study reports chest pain resolution at 3-year follow-up among only 39% of participants with obstructive CAD and 31% of those with INOCA. The WISE study has previously demonstrated that women with INOCA and persistent chest pain have rates of angina hospitalization comparable to patients with obstructive CAD without persistent chest pain, highlighting the importance of studying the contributors to longer-term persistent chest pain.13
Medication use among participants with INOCA was lower than the obstructive CAD group for all cardiac medications, despite their similar prevalence of chest pain. This is not surprising, given that patients with INOCA are often not treated due to their non-obstructive CAD status.14 Although large clinical trials to determine optimal medical therapy for INOCA are still needed, statins and ACEIs/ARBs are now recommended for consideration in the treatment of INOCA, along with stratified antianginal treatment based on underlying pathophysiologic endotypes.15-17 Additionally, recent guidelines from the European Society of Cardiology recommend using a beta-blocker and/or a calcium-channel blocker (CCB) as initial drug therapy.16 Our study found varied baseline uptake of these medications (ACEs/ARBs—21.8%, statins—24.2%, beta-blockers—38%, and CCBs—29%). Future follow-up studies could determine changes to this pattern in accordance with the new guidelines.
The 1-year PChP proportion and its association with MACE in this cohort were similar to the original WISE cohort findings.6 Likewise, younger age at baseline, history of frequent psychosocial stress, higher BDI scores, and use of antidepressant medications predicted PChP status at 3 years in the INOCA group. Younger age at baseline and higher BDI scores also predicted PChP in the obstructive CAD group. Possibly, younger INOCA patients presenting with chest pain are even more likely to be undertreated, with their symptoms considered to be non-cardiac, resulting in higher rates of PChP. Studies have found that individuals with higher levels of psychological stress have a higher risk for CV death and all-cause mortality among patients with stable coronary artery disease.18 Potential strategies to modify this risk factor include education on stress management techniques, pharmacotherapy, and psychotherapy.16
PChP at 1 year has previously been associated with a higher risk of composite MACE but not mortality among women with INOCA in our cohort.1 However, the prior analysis defined PChP as a dichotomous variable based on chest pain reports at 1-year follow-up, representing a larger group with greater power to detect relations. The current analysis has smaller sample sizes because chest pain status was defined based on data from 3 years of follow-up, and we considered additional patterns of persistence (intermediate, recurrent). Composite MACE or mortality was not associated with PChP at 3-year status in both INOCA and obstructive CAD groups. Of note, 1-year PChP was associated with elevated MACE (adjusted HR—1.46, 95% CI (1.02, 2.10), χ2 P = 0.04), similar to what we previously published.1
This report lends credence to current literature suggesting similar symptom burden in INOCA and obstructive CAD. Chest pain persistence or recurrence in over 50% of our women supports the need for improved management techniques in INOCA as well as obstructive CAD.4 The Women's Ischemia Trial to Reduce Events In Non-Obstructive CAD (WARRIOR) is currently evaluating Intensive Medical Therapy vs. Usual Care strategies to inform guidelines about optimal medical therapy for INOCA.19 Future research should also explore other physiological and possibly environmental factors that contribute to chest pain persistence among individuals with obstructive CAD.
Study limitations
Our assessment of chest pain was based on responses to a single question because our study predated widespread adoption of standardized questionnaires such as the SAQ. However, prior analysis1 has determined this measure to be representative of actual symptoms, and using the same measure across several years of follow-up ensures consistency. Although we attempted to address confounding by adjusting for relevant variables in the model, unmeasured confounding may still affect the associations. Additionally, our study population was limited to women, so these findings may not be generalizable to men. Finally, subgroup analyses pose a risk of inadequate power to detect relations. Also, the risk of attrition bias exists, as in many long-term follow-up studies.
Conclusions
Women with INOCA experience a comparable burden of chest pain to those with obstructive CAD, yet lower rates of medical therapy at baseline and over time. Based on our findings, chest pain status at a longer follow-up period of 3 years does not predict MACE in women with or without obstructive CAD. Increased awareness about the natural history of INOCA will help clinicians make informed decisions in the management of these patients. More so, targeted research to determine effective treatment options will be critically important to reduce morbidity and improve QOL in both populations.
Contributor Information
Okezi Obrutu, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 321 S San Vicente Blvd, A3212, Los Angeles, CA 90048, USA.
Martha Gulati, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 321 S San Vicente Blvd, A3212, Los Angeles, CA 90048, USA.
Steven Reis, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Vera Bittner, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Eileen Handberg, Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Galen Cook-Wiens, Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Tara Sedlak, Women’s Heart Center, University of British Columbia, British Columbia, V5Z 1M9, Canada.
Odayme Quesada, Women’s Heart Center, The Christ Hospital, Cincinnati, OH 45219, USA.
Carl J Pepine, Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
C Noel Bairey Merz, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 321 S San Vicente Blvd, A3212, Los Angeles, CA 90048, USA.
Janet Wei, Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, 321 S San Vicente Blvd, A3212, Los Angeles, CA 90048, USA.
Funding
This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23 HL105787, K23 HL125941, K23 HL127262, K23HL151867 T32 HL69751, finals, 1R03 AG032631, R01 HL146158, R01 HL153500, R01HL124649, PR150224P1 (CDMRP-DoD), U54 AG065141, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, the Linda Joy Pollin Women’s Heart Health Program, the Erika Glazer Women’s Heart Health Project, and the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, California.
This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.