Invasive versus non-invasive management in non-ST segment elevation myocardial infarction patients with pulmonary hypertension

Abstract

Background

Non–ST-segment elevation myocardial infarction (NSTEMI) represents a substantial proportion of acute coronary syndrome and is associated with considerable morbidity and mortality. Pulmonary hypertension (PH) is linked to adverse cardiovascular outcomes and may complicate management decisions in NSTEMI. However, evidence regarding the optimal treatment strategy for NSTEMI patients with PH remains limited. This study evaluated the association between invasive versus conservative management and short- and long-term outcomes in a real-world multicenter cohort.

Materials and methods

This retrospective multicenter cohort study used data from the Tianjin Health and Medical Big Data Super Platform. Adult patients hospitalized with NSTEMI and concomitant PH between January 2010 and March 2023 were included. Patients were categorized according to treatment strategy during the index hospitalization (invasive vs. conservative management). The primary outcome was 1-year major adverse cardiovascular events (MACE), defined as cardiac death, recurrent myocardial infarction, ischemic stroke, or repeat revascularization. Propensity scores were estimated using logistic regression. The primary analysis used inverse probability of treatment weighting with doubly robust Cox regression models, with additional sensitivity analyses.

Results

Among 985 patients with NSTEMI and PH, 243 (24.7%) received invasive management and 742 (75.3%) conservative treatment. In doubly robust Cox models, invasive management was associated with a lower risk of 1-year MACE (adjusted hazard ratio [aHR] 0.60, 95% CI 0.41–0.88, P = 0.009) and cardiac death (aHR 0.54, 95% CI 0.34–0.87, P = 0.011). However, bleeding risk was higher in the invasive group (aHR 2.86, 95% CI 1.34–6.11, P = 0.007).

Conclusion

Invasive management was associated with fewer ischemic events but a higher risk of bleeding in patients with NSTEMI and PH, highlighting the need for individualized treatment strategies.

Keywords

non-ST segment elevation myocardial infarction pulmonary hypertension invasive management prognosis

Introduction

Non–ST-segment elevation myocardial infarction (NSTEMI) represents a substantial proportion of acute coronary syndrome presentations and is associated with significant short- and long-term morbidity and mortality. Despite advances in pharmacotherapy and revascularization strategies, risk stratification remains essential due to the marked heterogeneity within the NSTEMI population. Current guidelines recommend an early invasive strategy for high-risk patients^1,2; however, the clinical benefit of routine invasive management may vary across specific subgroups.^3–6

Pulmonary hypertension (PH) is a progressive condition characterized by elevated pulmonary arterial pressure and increased right ventricular afterload. Patients with PH often exhibit impaired coronary perfusion, right ventricular ischemia, and systemic congestion, all of which may adversely influence outcomes in the setting of myocardial infarction.^7–10 Prior observational studies have demonstrated that the presence of PH is associated with worse prognosis among patients with acute myocardial infarction and higher mortality following percutaneous coronary intervention (PCI).^11–13

The coexistence of NSTEMI and PH poses unique clinical challenges. On one hand, invasive coronary evaluation may alleviate ischemia related to obstructive coronary disease.⁷ On the other hand, patients with PH are more vulnerable to bleeding complications.¹⁴

Despite these considerations, evidence guiding the optimal management strategy for NSTEMI patients with concomitant PH remains limited. Current guidelines do not provide specific recommendations for this subgroup, largely due to the absence of dedicated studies. Therefore, the present study aimed to evaluate the association between invasive versus conservative management and 1-year clinical outcomes in patients with NSTEMI and concomitant pulmonary hypertension using a large real-world multicenter database.

Methods

Study design

This retrospective multicenter cohort study was conducted using data from the Coronary Artery Disease (CAD) Database of the Tianjin Health and Medical Big Data Super Platform (hereinafter referred to as the “Platform”). The details of the platform have been described in previous publications.^15,16 The CAD specialized database includes all patients hospitalized at least once between January 1, 2010 and March 31, 2024 with a discharge diagnosis of CAD. The Platform integrates demographic characteristics, diagnoses, medication prescriptions, laboratory results, procedural information, cost data, community medical records, and public health mortality information within Tianjin municipality.

The study protocol adhered to the ethical principles of the 1975 Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of Tianjin Medical University Second Hospital (KY2023052-01). Given the retrospective design and use of de-identified administrative data, the requirement for written informed consent was waived.

Study population

Patients aged ≥18 years who were hospitalized with a discharge diagnosis of non–ST-segment elevation myocardial infarction (NSTEMI) (ICD-10 code I21.4x) and a concomitant diagnosis of pulmonary hypertension (PH) (ICD-10 code I27.2x).^17,18 between January 1, 2010 and March 31, 2023 were eligible for inclusion, ensuring that all individuals had the opportunity to complete at least 1 year of follow-up. To avoid duplication and clustering effects from recurrent hospitalizations, only the first NSTEMI admission during the study period was considered the index hospitalization. Patients with duplicate records or insufficient follow-up information were excluded.

Patients were categorized according to the management strategy received during the index hospitalization. Invasive management was defined as coronary angiography performed after admission, with revascularization undertaken when clinically indicated. Conservative management referred to treatment with medical therapy without invasive coronary evaluation during the index hospitalization.^3,19,20 Classification was based on the initial treatment strategy during the index admission according to the intention-to-treat principle, irrespective of subsequent procedures during follow-up.

Comorbidities were identified using ICD-10 codes recorded during hospitalization. All ICD-10 codes used in this study are listed in Supplementary Table S1.^21,22 Pulmonary hypertension was identified solely based on ICD-10 codes. Hemodynamic measurements, echocardiographic parameters, PH etiology, and PH-specific treatment regimens were not available in the database.

Follow-up and endpoints

All follow-up information was obtained from the Platform, which integrates outpatient, emergency, inpatient records and public health mortality data within Tianjin municipality.

Follow-up was calculated from the date of the index hospitalization until the occurrence of an endpoint, death, or completion of the 1-year follow-up period, whichever occurred first. Follow-up was administratively censored at 1 year for the primary analysis.

The primary outcome was 1-year major adverse cardiovascular events (MACE), defined as the composite of cardiac death (CD), recurrent myocardial infarction, ischemic stroke (IS), or repeat revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]). Cardiac death was determined according to the cause of death recorded in public health mortality data, and recurrent myocardial infarction was identified using ICD-10 codes during follow-up hospitalizations.^23,24

Secondary outcomes included all-cause mortality, the individual components of MACE, and net adverse clinical events (NACE), which were defined as the composite of recurrent myocardial infarction, all-cause mortality, ischemic stroke, repeat revascularization, and bleeding events.

The safety endpoint was bleeding events. Major bleeding events were identified using ICD-10 codes and included gastrointestinal bleeding, intracranial hemorrhage (including hemorrhagic stroke), and other major bleeding (e.g., ocular or respiratory bleeding).²⁵ The ICD-10 codes used to identify all outcomes were predefined (Supplementary material online, Table S1).

Considering that NSTEMI represents an acute clinical condition in which early adverse events are common, 30-day outcomes were additionally assessed to evaluate short-term risk.²⁶

Statistical analyses

Continuous variables are presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables are expressed as frequencies and percentages. Group comparisons were performed using Student’s t-test or Mann–Whitney U test for continuous variables and χ² test or Fisher’s exact test for categorical variables.

To address potential confounding, inverse probability of treatment weighting (IPTW) based on propensity scores was used as the primary analytic approach. Propensity scores were estimated using logistic regression modeling the probability of receiving invasive management according to baseline covariates (Supplementary material online, Table S2). Stabilized weights were applied to reduce variability, with weights calculated as the inverse of the propensity score for patients in the invasive management group and the inverse of one minus the propensity score for those in the conservative management group.

Covariate balance before and after weighting was assessed using standardized mean differences (SMD), with SMD <0.10 considered indicative of adequate balance, while SMD <0.20 was considered acceptable. Time-to-event outcomes were analyzed using Kaplan–Meier survival curves and compared using log-rank tests. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). To further minimize residual confounding, multivariable Cox regression models adjusting for baseline covariates were performed in the weighted cohort (doubly robust approach). For outcomes with limited numbers of events, Cox regression models were not performed due to concerns about model instability, and IPTW-adjusted event rates were compared descriptively as exploratory analyses. Subgroup analyses were conducted for the primary outcome, and interaction terms were tested to evaluate the consistency of treatment effect across predefined subgroups.

To assess the robustness of the primary findings, a sensitivity analysis was performed using a stabilized inverse probability of treatment weighting (SIPTW) approach.

All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. Analyses were performed using R version 4.2.2.

Results

Baseline characteristics

As shown in Figure 1, (a) total of 985 patients with NSTEMI and PH were included. Among these, 243 patients received invasive management (58.85% male) and 742 patients accepted conservative management (50.94% male). In the invasive group, 197 patients had received PCI during the hospital. The baseline characteristics are shown in Table 1 and Table 2. Before weighting, significant differences were observed between the two groups. Patients in the invasive group exhibited fewer risk factors for poor prognosis, such as younger age (70.11±11.31 vs. 75.40±10.76, SMD = 0.479), male (58.85% vs. 50.94%, SMD = 0.159), lower Killip class (Killip class I: 48.56% vs. 33.42%; Killip class II: 33.33% vs. 29.11%; Killip class III: 11.11% vs. 24.26%; Killip class IV: 7% vs. 13.21%, SMD = 0.456), milder frailty (6.47±3.55 vs. 9.25±4.27, SMD = 0.707), and less comorbidity [cerebrovascular disease (28.81% vs. 40.97%, SMD = 0.159), atrial fibrillation (31.69% vs. 47.17%, SMD = 0.321), respiratory failure (4.94% vs. 17.12%, SMD = 0.396)]. Additionally, patients in the invasive group were more likely to be prescribed drugs during hospitalization except for diuretics.

Figure 1.

Study flow chart.

Table 1.

Baseline and clinical characteristics of patients before IPTW.

Characteristics	Conservative strategy (n = 742)	Invasive strategy (n = 243)	SMD
Female (%)	364 (49.06)	100 (41.15)	0.159
Age (years) (mean±SD)	75.40 (10.76)	70.11 (11.31)	0.479
HRFS	9.25 (4.27)	6.47 (3.55)	0.707
HFRS category (%)			0.606
Low risk (<5)	124 (16.71)	101 (41.56)
Intermediate risk (5-15)	546 (73.58)	135 (55.56)
High risk (>15)	72 (9.70)	7 (2.88)
KILLIP (%)			0.456
I	248 (33.42)	118 (48.56)
II	216 (29.11)	81 (33.33)
III	180 (24.26)	27 (11.11)
IV	98 (13.21)	17 (7.00)
Comorbidity
PVD (%)	113 (15.23)	35 (14.40)	0.023
CVD (%)	304 (40.97)	70 (28.81)	0.257
COPD (%)	121 (16.31)	32 (13.17)	0.089
GIB (%)	24 (3.23)	10 (4.12)	0.047
DM (%)	295 (39.76)	95 (39.09)	0.014
SKD (%)	200 (26.95)	28 (11.52)	0.399
Cancer (%)	27 (3.64)	4 (1.65)	0.124
AF (%)	350 (47.17)	77 (31.69)	0.321
Hypertension (%)	522 (70.35)	183 (75.31)	0.112
ARF (%)	127 (17.12)	12 (4.94)	0.396
Drugs
Aspirin (%)	458 (61.73)	231 (95.06)	0.886
P2Y12 Inhibitor (%)	537 (72.37)	239 (98.35)	0.790
CCB (%)	204 (27.49)	69 (28.40)	0.020
BB (%)	432 (58.22)	181 (74.49)	0.349
ACEI/ARB (%)	333 (44.88)	175 (72.02)	0.573
Statins (%)	559 (75.34)	237 (97.53)	0.685
Diuretics (%)	637 (85.85)	167 (68.72)	0.418
Oral Anticoagulants (%)	104 (14.02)	39 (16.05)	0.057
Nitrates (%)	583 (78.57)	214 (88.07)	0.257
PA/PRA (%)	25 (3.37)	6 (2.47)	0.053

IPTW, Inverse Probability of Treatment Weighting; HRFS, Hospital Frailty Risk Score; PVD, Peripheral Vascular Disease; CVD, Cerebrovascular Disease; COPD, Chronic Obstructive Pulmonary Disease; GIB, Gastrointestinal Bleeding; DM, Diabetes Mellitus; SKD, Severe Kidney Disease; AF, Atrial Fibrillation; ARF, Acute Respiratory Failure; CCB, Calcium Channel Blocker; BB, Beta-Blocker; ACEI/ARB, Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker; PA/PRA, Prostacyclin analogues/prostacyclin receptor agonists.

Table 2.

Baseline and clinical characteristics of patients after IPTW.

Characteristics	Conservative strategy (n = 1119.38)	Invasive strategy (n = 1119.38)	SMD
Female (%)	488.01 (43.60)	488.01 (43.60)	<0.001
Age (years) (mean±SD)	72.93 (11.70)	72.93 (10.05)	<0.001
HRFS	8.37 (4.51)	7.43 (4.20)	0.218
HFRS category (%)			<0.001
Low risk (<5)	311.84 (27.86)	311.84 (27.86)
Intermediate risk (5-15)	719.77 (64.30)	719.77 (64.30)
High risk (>15)	87.78 (7.84)	87.78 (7.84)
KILLIP (%)			<0.001
I	458.43 (40.95)	458.43 (40.95)
II	315.66 (28.20)	315.66 (28.20)
III	218.75 (19.54)	218.75 (19.54)
IV	126.54 (11.30)	126.54 (11.30)
Comorbidity
PVD (%)	205.16 (18.33)	205.16 (18.33)	<0.001
CVD (%)	404.39 (36.13)	404.39 (36.13)	<0.001
COPD (%)	160.36 (14.33)	133.09 (11.89)	0.072
GIB (%)	47.53 (4.25)	47.53 (4.25)	<0.001
DM (%)	444.81 (39.74)	444.81 (39.74)	<0.001
SKD (%)	265.66 (23.73)	140.92 (12.59)	0.292
Cancer (%)	34.50 (3.08)	27.75 (2.48)	0.037
AF (%)	457.73 (40.89)	457.73 (40.89)	<0.001
Hypertension (%)	831.56 (74.29)	831.56 (74.29)	<0.001
ARF (%)	135.77 (12.13)	135.77 (12.13)	<0.001
Drugs
Aspirin (%)	814.18 (72.74)	814.18 (72.74)	<0.001
P2Y12 Inhibitor (%)	913.55 (81.61)	913.55 (81.61)	<0.001
CCB (%)	318.49 (28.45)	318.49 (28.45)	<0.001
BB (%)	682.10 (60.94)	682.10 (60.94)	<0.001
ACEI/ARB (%)	597.79 (53.40)	597.79 (53.40)	<0.001
Statins (%)	925.90 (82.72)	925.90 (82.72)	<0.001
Diuretics (%)	814.91 (72.80)	814.91 (72.80)	<0.001
Oral Anticoagulants (%)	156.16 (13.95)	201.60 (18.01)	0.111
Nitrates (%)	867.65 (77.51)	867.65 (77.51)	<0.001
PA/PRA (%)	37.18 (3.32)	17.11 (1.53)	0.117

Clinical outcomes

1-Year clinical outcomes

In the original cohort before weighting, the invasive group exhibited a significantly lower incidence of primary outcomes: MACE (26.34% vs. 34.37%, adjusted hazard ratio [aHR]: 0.73, 95% CI: 0.54 to 0.99, P = 0.043). Regarding secondary endpoints, the invasive group exhibited a lower risk of all-cause death (13.99% vs. 35.85%, aHR: 0.51, 95% CI: 0.35 to 0.75, P < 0.001), CD (11.52% vs. 26.28%, aHR: 0.59, 95% CI: 0.38 to 0.90, P = 0.015) and recurrent MI (4.94% vs. 5.93%, aHR: 0.45, 95% CI: 0.22 to 0.89, P = 0.021) in one year. There was no significant difference in 1-year revascularization risk (8.23% vs. 3.10%, aHR: 1.08, 95% CI: 0.56 to 2.08, P = 0.819), IS (3.70% vs. 2.29%, aHR: 3.02, 95% CI: 0.71 to 12.81, P = 0.134) and NACE (35.80% vs. 48.11%, aHR: 0.83, 95% CI: 0.64 to 1.08, P = 0.170) between the two groups. For the safety endpoint, there were no significant differences in bleeding events (9.88% vs. 8.49%, aHR: 1.51, 95% CI: 0.86 to 2.67, P = 0.154) between the two groups (Figure 2).

Figure 2.

Results of multivariate Cox analyses before IPTW IPTW, inverse probability of treatment weighting; aHR, adjusted hazard ratio; CI, confidence interval; MACE, major cardiovascular adverse events; NACE, net adverse clinical events; CD, cardiac death; MI, myocardial infarction; IS, ischemic stroke.

After doubly robust adjustment, the invasive group remained a significantly lower incidence of MACE (aHR: 0.60, 95% CI: 0.41 to 0.88, P = 0.009), all-cause death (aHR: 0.58, 95% CI: 0.38 to 0.86, P = 0.008), CD (aHR: 0.54, 95% CI: 0.34 to 0.87, P = 0.011), recurrent MI (aHR: 0.42, 95% CI: 0.23 to 0.77, P = 0.005). There were no significant differences in 1-year revascularization (aHR: 0.61, 95% CI: 0.30 to 1.25, P = 0.181), IS (aHR: 1.03, 95% CI: 0.43 to 2.45, P = 0.954) and NACE (aHR: 0.94, 95% CI: 0.64 to 1.38, P = 0.747) between the two groups. However, the invasive group had a significantly higher incidence of bleeding events (aHR: 2.86, 95% CI: 1.35 to 6.11, P = 0.007) (Figure 3, Table 3). In bleeding events, gastrointestinal bleeding occurs most frequently. However, both before and after IPTW, the proportion of respiratory tract bleeding in the invasive group was higher than that in the conservative treatment group, with statistical significance. No differences were observed between the two groups in other types of bleeding (Supplementary material online, Table S3-5). The Kaplan-Meier survival curves for 1-year outcomes are presented in Figure 4.

Figure 3.

Results of multivariate Cox analyses after IPTW. IPTW, inverse probability of treatment weighting; aHR, adjusted hazard ratio; CI, confidence interval; MACE, major cardiovascular adverse events; NACE, net adverse clinical events; CD, cardiac death; MI, myocardial infarction; IS, ischemic stroke.

Table 3.

1-Year Results of multivariate Cox analyses after IPTW.

Outcomes	Events		aHR (95% CI)	P Value
Outcomes	Conservative strategy (n = 742)	Invasive strategy (n = 243)	aHR (95% CI)	P Value
MACE	229 (34.37%)	64 (26.34%)	0.60 (0.41-0.88)	0.009
NACE	357 (48.11%)	87 (35.80%)	0.94 (0.64-1.38)	0.747
Death	266 (35.85%)	34 (13.99%)	0.58 (0.38-0.86)	0.008
CD	195 (26.28%)	28 (11.52%)	0.54 (0.34-0.87)	0.011
MI	44 (5.93%)	12 (4.94%)	0.42 (0.23-0.77)	0.005
IS	17 (2.29%)	9 (3.70%)	1.03 (0.43-2.45)	0.954
Revascularization	23 (3.1%)	20 (8.23%)	0.61 (0.30-1.25)	0.180
Bleeding Events	63 (8.49%)	24 (9.88%)	2.86 (1.34-6.11)	0.007

IPTW, Inverse Probability of Treatment Weighting; aHR, Adjusted Hazard Ratio; CI, Confidence Interval; MACE, Major Cardiovascular Adverse Events; NACE, Net Adverse Clinical Event; CD, Cardiac Death; MI, Myocardial Infarction; IS, Ischemic Stroke.

Figure 4.

Kaplan-Meier curves for 1-year MACE (A), NACE (B), Death (C) and CD (D) after IPTW. Adjustment MACE, Major Adverse Cardiovascular Events; NACE, Net adverse clinical events; CD, Cardiac Death; IPTW, Inverse Probability of Treatment Weighting.

30-Day clinical outcomes

After doubly robust adjustment, the invasive strategy was associated with a significantly lower risk of MACE (aHR: 0.52, 95% CI: 0.30 to 0.89, P = 0.019) and all-cause mortality (aHR: 0.51, 95% CI: 0.28 to 0.92, P = 0.026). No significant differences were observed between the two groups in NACE (aHR: 0.73, 95% CI: 0.44 to 1.20, P = 0.216) or CD (aHR: 0.58, 95% CI: 0.32 to 1.06, P = 0.076). Due to the limited number of events, additional outcomes were evaluated as exploratory analyses based on IPTW-adjusted event rates. No significant differences were observed between the invasive and conservative groups in IS (0% vs. 0.27%, P = 0.163), MI (0.82% vs. 1.48%, P = 0.163) or repeat revascularization (1.65% vs. 1.08%, P = 0.303), whereas bleeding events occurred more frequently in the invasive group (1.65% vs. 2.16%, P = 0.025) (Table 4). The Kaplan-Meier survival curves for 30-days outcomes are presented in Figure 5.

Table 4.

30-days Results of multivariate Cox analyses after IPTW.

Outcomes	Events		aHR (95% CI)	P Value
Outcomes	Conservative strategy (n = 742)	Invasive strategy (n = 243)	aHR (95% CI)	P Value
MACE	143 (19.27%)	21 (8.64%)	0.52 (0.30-0.89)	0.019
NACE	175 (23.58%)	24 (9.88%)	0.73 (0.44-1.20)	0.216
Death	145 (19.54%)	15 (6.17%)	0.51 (0.28-0.92)	0.026
CD	124 (16.71%)	15 (6.17%)	0.58 (0.32-1.06)	0.076
MI	11 (1.48%)	2 (0.82%)	0.42 (0.23-0.77)	0.005
IS	2 (0.27%)	0 (0.00%)	1.03 (0.43-2.45)	0.954
Revascularization	8 (1.08%)	4 (1.65%)	0.61 (0.30-1.25)	0.180
Bleeding Events	16 (2.16%)	4 (1.65%)	2.86 (1.34-6.11)	0.007

Figure 5.

Kaplan-Meier curves for 30-days MACE (A), NACE (B), Death (C) and CD (D) after IPTW adjustment. MACE, Major adverse cardiovascular events; NACE, net adverse clinical events; CD, cardiac death; IPTW, inverse probability of treatment weighting.

Subgroup analysis

The results of the subgroup analyses demonstrated that the association between invasive management and the risk of 1-year MACE was generally consistent across the predefined subgroups. No significant interactions were observed, suggesting that the potential benefit of invasive management was broadly consistent among different patient subgroups (Figure 6).

Figure 6.

Result of MACE in prespecified subgroups after IPTW MACE, Major Adverse Cardiovascular events; IPTW, inverse probability of treatment weighting; PVD, peripheral vascular disease; CVD, cerebrovascular disease; COPD, chronic obstructive pulmonary disease; GIB, gastrointestinal bleeding; DM, diabetes mellitus; SKD, severe kidney disease; AF, atrial fibrillation; ARF, acute respiratory failure.

Sensitivity analyses

The association between invasive management and outcomes remained consistent in the SIPTW analysis (Supplementary material online, Table S6).

Discussions

In this retrospective cohort study, several key findings were observed. (1) Invasive management showed a lower incidence of MACE in patients with NSTEMI and PH during the first year, with similar trends observed for cardiac death and myocardial infarction. (2) A reduction in all-cause mortality within one year was also observed in the invasive group. (3) No significant difference in repeat revascularization risk was observed between groups. (4) Invasive management was associated with an increased risk of bleeding events.

Our study has several strengths. (1) Our data were derived from metropolitan secondary and tertiary hospital records encompassing over a decade of comprehensive clinical encounters and the inclusion of discharge diagnoses ensured diagnostic validity across the cohort of patients. This can truly reflect the clinical and prognostic characteristics of patients with NSTEMI and PH and the efficacy of invasive management in the real world. (2) We used the invasive management, rather than coronary revascularization, to contrast with conservative treatment. Compared to coronary revascularization, invasive management is more in line with guideline recommendations,^2,27 while also reducing the confounding bias in retrospective studies that may result from angiography outcomes. (3) Despite better healthcare, the number of frail patients is increasing due to an aging population and more known health issues.²⁸ Specifically, These patients have a higher incidence of adverse events.²⁹ Therefore, we used the Hospital Frailty Risk Score (HFRS) score at baseline to stratify patients, in order to adjust for confounding factors caused by frailty.³⁰ Furthermore, our prespecified subgroup analyses explicitly incorporated HFRS-defined frailty levels to evaluate potential effect modification.

Patients selected for invasive management tended to have more favorable baseline characteristics, including younger age, lower frailty burden, lower Killip class, and fewer comorbidities, suggesting the presence of treatment-selection bias. Although IPTW and doubly robust adjustment were applied to mitigate confounding, residual confounding from unmeasured variables cannot be excluded. In particular, important clinical factors such as the severity and etiology of pulmonary hypertension, hemodynamic parameters, echocardiographic findings, coronary anatomical complexity, and detailed antithrombotic therapy were not available in the present dataset and may have influenced both treatment selection and outcomes.

Currently, there are limited data directly comparing invasive management with conservative treatment in patients with NSTEMI and concomitant pulmonary hypertension (PH). The study by Galiè et al. described outcomes in patients who underwent PCI for angina or angina-like symptoms attributed to left main coronary artery (LMCA) compression secondary to pulmonary arterial hypertension. Their findings demonstrated that PCI could alleviate mechanical compression and improve angina symptoms, and during a mean follow-up of 22 months, no cardiac death, myocardial infarction, stroke, or stent thrombosis was observed. These observations suggest that relief of coronary compression may improve ischemic outcomes in selected patients with PH.⁷ One potential mechanism underlying the observed ischemic benefit of invasive management in our study may therefore involve the relief of LMCA compression secondary to pulmonary artery dilation. However, pulmonary hypertension in our cohort was identified using ICD-10 codes without hemodynamic measurements (e.g., mean pulmonary artery pressure) or imaging confirmation (e.g., pulmonary artery diameter). As a result, the true prevalence of LMCA compression in this population remains unknown, and this proposed mechanism should be considered hypothetical rather than definitive.

Furthermore, Galiè et al. also reported that some patients required repeat revascularization due to mechanical recoil from recurrent pulmonary artery compression or in-stent restenosis caused by neointimal proliferation. This phenomenon may partly explain why invasive management in our study did not significantly reduce the need for repeat revascularization compared with conservative treatment. Nevertheless, given the absence of detailed angiographic and imaging data in our database, these interpretations remain speculative and warrant further prospective investigation.

In addition to the mechanical compression of the LMCA, patients with PH have increased right ventricular load and lactate metabolism, which further increases myocardial oxygen consumption.^31,32 Moreover, coronary disease further compounds the already unfavorable myocardial conditions and limited cardiac reserve in these patients. Therefore, invasive treatment can better assess and improve coronary blood flow conditions, thereby bringing better outcomes for patients with PH.

The invasive strategy was associated with an increased risk of bleeding events at 1-year follow-up, with exploratory analyses identifying respiratory tract bleeding as the principal contributor, potentially attributable to more aggressive antiplatelet regimens in this group. Previous studies have shown that pulmonary arterial hypertension is associated with bronchial artery enlargement, aneurysms or pseudo-aneurysms of the pulmonary artery and pulmonary artery dilation, which may lead to respiratory tract bleeding.^14,33–35 In addition to that, a meta-analysis reported that, in the elderly population with NSTEMI, patients undergoing invasive treatment are at a higher risk of major bleeding.³⁶ Since our study population has an average age of over seventy, they are classified as elderly patients. These studies can explain why NSTEMI patients with concomitant pulmonary hypertension are at an increased risk of bleeding after invasive management.

When ischemic and bleeding events are considered together within a net clinical framework, the increased bleeding burden may attenuate part of the ischemic benefit associated with invasive treatment.

In summary, pulmonary hypertension is associated with a worse prognosis in patients with AMI. In this study, invasive management was associated with improved ischemic outcomes but also a higher risk of bleeding in patients with NSTEMI and PH. Given the observational nature of the study and the potential for residual confounding, these findings should be considered hypothesis-generating and warrant further prospective investigation.

Limitations

Several limitations should be acknowledged in the present study. First, as this was an electronic health record–based study, there is potential for information bias related to miscoding. Although outcome events were validated through physician review of medical records, misclassification cannot be entirely excluded.

Second, pulmonary hypertension was identified using ICD-10 diagnostic codes without access to hemodynamic measurements, echocardiographic parameters, or etiological classification. In addition, no information on disease severity was available. Given the substantial heterogeneity of pulmonary hypertension across different etiologies and severity stages, grouping all PH phenotypes into a single category may limit the interpretability of the findings and restrict their generalizability. Furthermore, the absence of detailed clinical characterization precludes assessment of whether the observed associations differ across PH subtypes or severity levels.

Third, the database did not provide information regarding the etiology of pulmonary hypertension or disease-specific therapies such as long-term anticoagulation, pulmonary vasodilators, corticosteroids, or immunosuppressive agents. Given that PH represents a heterogeneous syndrome—including PH due to left heart disease, chronic thromboembolic PH, and connective tissue disease–associated PH—differences in underlying mechanisms and treatment regimens may independently influence both ischemic and bleeding risks. This heterogeneity may have confounded the observed associations and contributed to the attenuation of net clinical benefit after statistical adjustment.

Finally, because this was a retrospective study based on an existing real-world healthcare database, no formal sample size calculation was performed and the study population was determined by the number of eligible patients available during the study period. In addition, as with any observational study, residual confounding from unmeasured variables cannot be entirely excluded despite the use of doubly robust models and additional sensitivity analyses using propensity score–adjusted and stabilized IPTW approaches.

Conclusions

For NSTEMI patients with concomitant pulmonary hypertension, although invasive management was associated with reductions in all-cause mortality and MACE in certain analyses, the overall clinical impact must be interpreted within the context of increased bleeding risk and the absence of consistent net benefit after adjustment.

Rather than universally endorsing an invasive strategy, our findings support consideration of this approach in selected NSTEMI patients with PH, with particular attention to individual bleeding risk. Achieving a favorable balance between ischemic protection and hemorrhagic harm requires careful patient selection and thoughtful antithrombotic management.

Importantly, these observations are derived from observational data and should be regarded as hypothesis-generating. Prospective, adequately powered randomized controlled trials are required to confirm causality and to identify subgroups most likely to derive true net clinical benefit.

Supplemental material

Supplemental material - Invasive versus non-invasive management in non-ST segment elevation myocardial infarction patients with pulmonary hypertension

Supplemental material for Invasive versus non-invasive management in non-ST segment elevation myocardial infarction patients with pulmonary hypertension by Ze Zhang, Tianshu Gu, Haonan Xu, Yukun Zhang, Sutao Hu, MD, Huaying Fu, Weiding Wang, Xing Liu, Xian Shao, Lin Wang, Yongjian Li, Tong Liu and Kang-Yin Chen in Sage Open Medicine.

Footnotes

Acknowledgments

The authors thank the staff and participant of the Tianjin Health and Medical Big Data Super Platform for their important contributions.

ORCID iD

Kang-Yin Chen

Ethical considerations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

The study protocol was approved by The Institutional Review Board of the Second Hospital of Tianjin Medical University (#KY2023052-01), the requirement for written informed consent was waived.

Author contributions

Study conception and design: Kang-Yin Chen, Tianshu Gu and Ze Zhang; Acquisition, analysis, or interpretation of data: Tianshu Gu, Ze Zhang, Yukun Zhang and Sutao Hu; Draft manuscript preparation: Ze Zhang, Tianshu Gu, Haonan Xu and Xian Shao. All authors reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the National Science and Technology Innovation 2030, Noncommunicable Chronic Diseases-National Science and Technology Major Project (Grant No. 2024ZD0524300, 2024ZD0524301), Tianjin Municipal Key Research Project in Priority Areas of Traditional Chinese Medicine (2022011), National Natural Science Foundation of China (82470527), Science and Technology Project of Tianjin Municipal Health Committee (TJWJ2024RC004, TJWJ2022MS009), and the Key Science and Technology Support Project of Tianjin Science and Technology Bureau (24ZXGZSY00130), Key Research Project of Tianjin Education Commission (2024ZD031), Tianjin Key Medical Discipline Construction (TJYXZDXK-3-006B), Academic Backbone of “Clinical Talent Training and Climbing Plan” of Tianjin Medical University, “Jinmen Medical Talent” of Tianjin Health Industry High-Level Talent Selection and Training Project (TJSJMYXYC-D2-046), National Health Commission Hospital Management Research Project of China (NIHA23JXH009).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Please contact the corresponding authors for access to the data.*

Supplemental material

Supplemental material for this article is available online.

Appendix

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