Efficacy of nitroglycerin vs labetalol in hypertensive emergency among patients with a history of coronary artery disease

Abstract

BACKGROUND

Hypertensive emergencies, characterized by severe blood pressure elevation (> 180/120 mmHg) with end-organ damage, pose significant risks in patients with coronary artery disease (CAD), where rapid yet safe reduction is crucial to prevent ischemia and complications. Nitroglycerin and labetalol are common intravenous agents, but comparative data in CAD are limited.

AIM

To compare efficacy and safety of nitroglycerin vs labetalol in hypertensive emergencies among CAD patients, assessing blood pressure control, reductions, adverse events, outcomes, and utilization.

METHODS

Retrospective cohort of 563 CAD patients with hypertensive emergency (2018-2024) receiving IV nitroglycerin (n = 282) or labetalol (n = 281). Primary: Time to target blood pressure [systolic blood pressure (SBP) < 160 mmHg, diastolic blood pressure < 100 mmHg]. Secondary: Blood pressure reductions, major adverse cardiovascular event, safety, utilization. Analyzed via t-tests, χ², multivariable logistic regression adjusting for age, gender, myocardial infarction/heart failure history, diabetes, baseline SBP, chest pain.

RESULTS

Baseline characteristics were balanced. Labetalol achieved target blood pressure faster (25.14 ± 4.92 minutes vs 30.38 ± 5.16 minutes; P < 0.0001), but nitroglycerin yielded greater SBP (50.78 ± 9.45 mmHg vs 45.20 ± 10.46 mmHg; P < 0.0001) and diastolic blood pressure reductions (29.86 ± 8.63 mmHg vs 28.02 ± 7.74 mmHg; P = 0.0079). Nitroglycerin showed trends toward lower major adverse cardiovascular event [adjusted odds ratio (AOR): 0.72; 95% confidence interval (CI): 0.42-1.24], reduced bradycardia (AOR: 0.14; 95%CI: 0.05-0.38), shorter intensive care unit (2.99 ± 1.04 days vs 3.54 ± 1.02 days; P < 0.0001) and hospital stays (6.92 ± 1.93 days vs 7.99 ± 2.06 days; P < 0.0001), lower 30-day readmissions (AOR: 0.49; 95%CI: 0.27-0.88), and smaller biomarker increases (delta troponin: 0.10 ± 0.05 ng/mL vs 0.21 ± 0.10 ng/mL; P < 0.0001).

CONCLUSION

While labetalol offers faster blood pressure control, nitroglycerin is associated with greater reductions, fewer adverse events like bradycardia, and improved utilization (shorter stays, fewer readmissions) in CAD-associated hypertensive emergencies, supporting its use in ischemic contexts.

Key Words: Hypertensive emergency; Coronary artery disease; Nitroglycerin; Labetalol; Blood pressure control; Cardiovascular outcomes

Core Tip: This retrospective study uniquely compares intravenous nitroglycerin and labetalol for managing hypertensive emergencies in a large South Asian cohort of patients with established coronary artery disease. Although labetalol achieved target blood pressure more rapidly, nitroglycerin provided greater magnitude of blood pressure reduction, significantly lower rates of bradycardia, smaller rises in cardiac biomarkers, shorter intensive care unit and hospital stays, and reduced 30-day readmissions. These findings highlight nitroglycerin’s potential advantages in ischemic contexts and support its preferential use in high-risk coronary artery disease patients within resource-constrained settings.

INTRODUCTION

Hypertensive emergency represents a critical medical condition characterized by a severe elevation in blood pressure, typically exceeding 180/120 mmHg, coupled with acute end-organ damage[1]. This differs from hypertensive urgency, where blood pressure is similarly elevated but without immediate organ compromise[1,2]. The prevalence of hypertensive emergencies is relatively low, accounting for approximately 0.5% of all emergency department visits, though it rises to 3.2% among patients presenting with markedly elevated blood pressure[3]. Globally, hypertensive crises affect 1%-2% of the population, with emergencies posing a higher risk of morbidity and mortality, particularly in underserved regions[3,4]. Patients with a history of coronary artery disease (CAD) are especially vulnerable[5]. In this subgroup, the incidence of hypertensive emergencies may be higher due to underlying vascular pathology, with studies reporting up to 45% of emergency department patients experiencing transient hypertensive episodes[2].

The management of hypertensive emergencies requires prompt, controlled blood pressure reduction to mitigate organ damage[5-7]. American Heart Association (AHA) guidelines emphasize tailored therapy based on the clinical presentation, recommending intravenous agents for rapid titration[5]. Nitroglycerin, a nitrovasodilator, acts primarily by releasing nitric oxide, leading to smooth muscle relaxation and predominant venodilation at low doses[8]. However, tolerance can develop with prolonged infusion, and side effects like headache or reflex tachycardia may occur[8]. In contrast, labetalol is a non-selective beta-blocker with alpha-1 blocking properties, exerting a 3:1 to 7:1 beta-to-alpha ratio depending on the route of administration[9]. It reduces heart rate, contractility, and peripheral vascular resistance, making it effective for acute hypertension without significantly increasing coronary flow[9]. Labetalol is favored in scenarios requiring heart rate control, such as in aortic dissection or post-operative hypertension, and has a faster onset than some alternatives[9,10]. Potential drawbacks include bradycardia or bronchospasm in susceptible patients.

Comparative studies on nitroglycerin vs labetalol in hypertensive emergencies are limited, with mixed results[11,12]. One trial in general hypertensive crises found labetalol achieved target blood pressure faster (96% vs 44% at 1 hour) with fewer add-on medications required[11]. However, in specific contexts like pre-eclampsia, nitroglycerin demonstrated superior efficacy (96% vs 87% success rate)[11]. In CAD patients, nitroglycerin’s coronary vasodilatory effects may confer advantages, though direct head-to-head data are scarce[12]. Guidelines suggest nitroglycerin for CAD-associated emergencies to improve myocardial perfusion, while labetalol is a viable alternative for broader use[13]. This gap highlights the need for targeted research.

The present retrospective study aims to evaluate the efficacy of nitroglycerin compared to labetalol in managing hypertensive emergencies among patients with a documented history of CAD. Unlike prior studies in general hypertensive crises or stroke, this research targets CAD patients in a real-world South Asian setting, assessing not only blood pressure control but also biomarkers and utilization to guide ischemic-specific management. By analyzing real-world data, this investigation seeks to provide evidence-based insights to optimize treatment strategies in this high-risk population, potentially informing future guidelines and reducing cardiovascular complications.

MATERIALS AND METHODS

Study design and population

This retrospective cohort study was conducted at Northwest General Hospital and Research Centre in Peshawar, Pakistan. We reviewed electronic medical records (EMR) of adult patients (≥ 18 years) admitted with a hypertensive emergency [systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 120 mmHg with end-organ damage] from January 1, 2018 to December 31, 2024. Eligible patients had a confirmed history of CAD and received either intravenous nitroglycerin or labetalol as the primary antihypertensive agent within the first hour of presentation. This study included all eligible patients identified from the EMR during the specified period; no formal sample size calculation was performed given the retrospective design. To address potential indication bias (e.g., clinicians selecting nitroglycerin for ischemic presentations or labetalol for tachycardia), multivariable models adjusted for presenting symptoms like chest pain, and baseline characteristics were balanced between groups.

Dosing regimens

Nitroglycerin was administered as a continuous IV infusion starting at 5 μg/minute, titrated by 5 μg/minute every 3-5 minutes up to 200 μg/minute based on blood pressure response. Labetalol was given as IV boluses of 10-20 mg every 10 minutes (max 300 mg) or infusion at 2 mg/minute, titrated to target. Protocols followed institutional guidelines aligned with AHA recommendations.

Data collection

A standardized form was used to extract data on baseline demographics, cardiovascular history, comorbidities, and presenting clinical and hemodynamic parameters. Data extraction used a standardized EMR form by two trained reviewers, with inter-rater reliability verified (kappa > 0.8). Blood pressure was measured non-invasively via automated cuff every 5 minutes during initial treatment, verified by nursing records and physician notes. To address potential information bias from EMR data, data extraction was performed by trained reviewers using predefined criteria.

Outcomes

The primary efficacy outcome was the time to achieve target blood pressure (SBP < 160 mmHg and DBP < 100 mmHg). Secondary efficacy outcomes included the magnitude of blood pressure reduction and the proportion of patients achieving target blood pressure within 60 minutes. The primary safety outcome was a composite of major adverse cardiovascular events (MACEs), including all-cause mortality, non-fatal myocardial infarction (MI), non-fatal stroke, and urgent revascularization. Other safety outcomes included the incidence of hypotension (SBP < 90 mmHg), bradycardia (heart rate < 50 bpm), new or worsening heart failure (HF), and acute kidney injury. We also assessed healthcare utilization metrics, such as intensive care unit and hospital length of stay and 30-day readmission rates.

Statistical analysis

All statistical analyses were performed using R software (version 4.3.1). Continuous variables were presented as means with standard deviations and compared using independent t-tests (assuming normality based on data distribution). Categorical variables were presented as n (%) and analyzed with χ² or Fisher’s exact tests. To assess the association between treatment and outcomes, both unadjusted (crude) and multivariable-adjusted logistic regression models were constructed. The adjusted models controlled for age, gender, history of MI, history of HF, diabetes mellitus, baseline SBP, and presenting with chest pain. Results are presented as odds ratios with 95% confidence intervals (CIs). Patients with missing data on key variables were excluded from the analysis (complete-case approach); there was no imputation as data were complete post-exclusion. Loss to follow-up for 30-day outcomes was minimal, as readmissions were captured via linked EMR and hospital records. A two-sided P < 0.05 was considered statistically significant.

RESULTS

Baseline characteristics of the study population

A total of 563 patients were included in the final analysis, with 282 allocated to the nitroglycerin group and 281 to the labetalol group, as detailed in the participant flow diagram (Figure 1). The baseline demographic and clinical characteristics were well-balanced between the two treatment arms (Table 1). There were no missing data for the variables reported. The mean age was 64.79 ± 10.25 years in the nitroglycerin group and 64.52 ± 9.80 years in the labetalol group (P = 0.718). Key cardiovascular comorbidities, including prior MI (38.7% vs 42.0%, P = 0.454) and HF (24.8% vs 20.3%, P = 0.233), were comparable. Baseline hemodynamics were also similar, with a mean initial SBP of 199.20 ± 20.03 mmHg in the nitroglycerin group and 198.54 ± 21.33 mmHg in the labetalol group (P = 0.727). Notably, a significantly higher proportion of patients in the labetalol group presented with chest pain (45.2% vs 36.5%, P = 0.039).

Figure 1  Participant flow diagram.

Table 1 Baseline demographic and clinical characteristics of the study population, n (%)/mean ± SD.

Variable	Nitroglycerin (n = 282)	Labetalol (n = 281)	P value
Age (years)	64.79 ± 10.25	64.52 ± 9.80	0.718
Male	176 (62.4)	178 (63.3)	0.847
South Asian	268 (95.0)	269 (95.7)	0.719
History of MI	109 (38.7)	118 (42.0)	0.454
History of PCI/CABG	94 (33.3)	85 (30.2)	0.469
History of HF	70 (24.8)	57 (20.3)	0.233
LVEF (%)	45.09 ± 9.84	45.07 ± 9.79	0.978
History of stroke/TIA	51 (18.1)	45 (16.0)	0.545
PAD	27 (9.6)	21 (7.5)	0.413
AF	58 (20.6)	60 (21.4)	0.833
DM	154 (54.6)	142 (50.5)	0.372
eGFR (mL/min/1.73 m2)	69.48 ± 20.45	71.86 ± 18.85	0.162
Baseline SBP (mmHg)	199.20 ± 20.03	198.54 ± 21.33	0.727
Baseline DBP (mmHg)	111.21 ± 14.60	110.22 ± 15.54	0.462
Baseline HR (bpm)	90.45 ± 14.11	90.08 ± 15.12	0.771
Chest pain	103 (36.5)	127 (45.2)	0.039
Dyspnea	92 (32.6)	75 (26.7)	0.138
Neurological deficit	52 (18.4)	45 (16.0)	0.494
Initial creatinine (mg/dL)	1.19 ± 0.52	1.19 ± 0.55	0.999
Initial troponin (ng/mL)	0.51 ± 0.32	0.53 ± 0.30	0.399
ST changes on ECG	82 (29.1)	91 (32.4)	0.443
Home antihypertensives	205 (72.7)	187 (66.5)	0.124
Home antiplatelets	174 (61.7)	166 (59.1)	0.559
Home statins	154 (54.6)	142 (50.5)	0.372

P values were calculated using independent t-tests for continuous variables and χ² or Fisher’s exact tests for categorical variables. MI: Myocardial infarction; PCI: Percutaneous coronary intervention; CABG: Coronary artery bypass grafting; HF: Heart failure; LVEF: Left ventricular ejection fraction; TIA: Transient ischemic attack; PAD: Peripheral artery disease; AF: Atrial fibrillation; DM: Diabetes mellitus; eGFR: Estimated glomerular filtration rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: Heart rate; ECG: Electrocardiogram.

Efficacy of blood pressure control as illustrated in Figure 2A, labetalol was associated with a significantly faster time to achieve target blood pressure compared to nitroglycerin (mean 25.14 ± 4.92 minutes vs 30.38 ± 5.16 minutes, respectively; P < 0.0001). However, as shown in Figure 2B, treatment with nitroglycerin resulted in a greater mean reduction in both SBP (50.78 ± 9.45 mmHg vs 45.20 ± 10.46 mmHg; P < 0.0001) and DBP (29.86 ± 8.63 mmHg vs 28.02 ± 7.74 mmHg; P = 0.0079). The proportion of patients achieving target blood pressure within 60 minutes was similar between the two groups (Table 2).

Figure 2 Comparative efficacy of nitroglycerin vs labetalol on blood pressure. A: Time to achieve target blood pressure; B: Magnitude of blood pressure reduction. BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

Table 2 Comparison of clinical outcomes and healthcare utilization, n (%)/mean ± SD.

Outcome	Nitroglycerin (n = 282)	Labetalol (n = 281)	P value
Time to target BP (minute)	30.38 ± 5.16	25.14 ± 4.92	< 0.0001
Achievement of target BP	245 (86.9)	246 (87.5)	0.9124
SBP reduction (mmHg)	50.78 ± 9.45	45.20 ± 10.46	< 0.0001
DBP reduction (mmHg)	29.86 ± 8.63	28.02 ± 7.74	0.0079
MACE	27 (9.6)	35 (12.5)	0.3384
All-cause mortality	12 (4.3)	20 (7.1)	0.199
Non-fatal MI	9 (3.2)	17 (6.0)	0.1571
Non-fatal stroke	14 (5.0)	6 (2.1)	0.1128
Urgent revascularization	2 (0.7)	8 (2.8)	0.1094
Hypotension	14 (5.0)	8 (2.8)	0.2806
Bradycardia	5 (1.8)	28 (10.0)	< 0.0001
New/worsening HF	11 (3.9)	19 (6.8)	0.1857
AKI	17 (6.0)	19 (6.8)	0.8546
Intensive care unit LOS (days)	2.99 ± 1.04	3.54 ± 1.02	< 0.0001
Hospital LOS (days)	6.92 ± 1.93	7.99 ± 2.06	< 0.0001
30-day readmission	20 (7.1)	36 (12.8)	0.0335
Delta troponin (ng/mL)	0.10 ± 0.05	0.21 ± 0.10	< 0.0001
Delta NT-proBNP (pg/mL)	191.42 ± 101.72	287.63 ± 149.26	< 0.0001

P values were calculated using independent t-tests for continuous variables and χ² tests for categorical variables. BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; HF: Heart failure; AKI: Acute kidney injury; LOS: Length of stay; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

Cardiovascular and safety outcomes

The overall incidence of MACE did not differ significantly between the groups, as detailed in Table 2. After adjusting for baseline covariates, nitroglycerin was associated with a non-significant trend toward lower odds of MACE [adjusted odds ratio (AOR): 0.72; 95%CI: 0.42-1.24], as shown in the forest plot in Figure 3. This trend was driven by numerically lower odds of all-cause mortality (AOR: 0.49; 95%CI: 0.23-1.05) and non-fatal MI (AOR: 0.45; 95%CI: 0.19-1.06), although these findings did not reach statistical significance. Conversely, nitroglycerin use was associated with higher odds of non-fatal stroke compared to labetalol (AOR: 2.16; 95%CI: 0.80-5.81).

Figure 3 Crude and adjusted odds ratios for clinical outcomes. MACE: Major adverse cardiovascular event; OR: Odds ratio; CI: Confidence interval; MI: Myocardial infarction; HF: Heart failure; AKI: Acute kidney injury.

Regarding the safety profile, patients receiving labetalol had a significantly higher incidence of bradycardia (10.0% vs 1.8%, P < 0.0001). The adjusted analysis confirmed that treatment with nitroglycerin was strongly protective against bradycardia (AOR: 0.14; 95%CI: 0.05-0.38) (Figure 3). Rates of hypotension, new or worsening HF, and acute kidney injury were not significantly different between the two groups (Table 2).

Healthcare utilization and biomarkers

Patients treated with nitroglycerin had significantly shorter intensive care unit and hospital lengths of stay (Table 2). Furthermore, the 30-day readmission rate was significantly lower in the nitroglycerin group (7.1% vs 12.8%, P = 0.0335), a finding that remained significant after multivariable adjustment (AOR: 0.49; 95%CI: 0.27-0.88) (Figure 3). Treatment with nitroglycerin was also associated with significantly smaller increases in cardiac biomarkers, including delta troponin and delta N-terminal pro-B-type natriuretic peptide (NT-proBNP), compared to labetalol (Table 2).

DISCUSSION

This retrospective cohort study provides valuable real-world evidence on the comparative efficacy and safety of intravenous nitroglycerin vs labetalol for managing hypertensive emergencies in patients with a history of CAD. This study builds on prior comparisons by focusing on CAD in an underrepresented population, incorporating biomarkers and utilization metrics to highlight nitroglycerin's potential in ischemic emergencies. Analyzing data from 563 patients at a single center in Peshawar, Pakistan, from 2018 to 2024, our findings reveal that labetalol achieves target blood pressure more rapidly (mean 25.14 ± 4.92 minutes vs 30.38 ± 5.16 minutes; P < 0.0001), while nitroglycerin offers greater overall blood pressure reductions (systolic: 50.78 ± 9.45 mmHg vs 45.20 ± 10.46 mmHg, P < 0.0001; diastolic: 29.86 ± 8.63 mmHg vs 28.02 ± 7.74 mmHg, P = 0.0079), MACE rates were similar (9.6% vs 12.5%; P = 0.338), with no significant differences in components after adjustment, fewer bradycardic events (1.8% vs 10.0%, P < 0.0001), lower biomarker elevations (delta troponin: 0.10 ± 0.05 ng/mL vs 0.21 ± 0.10 ng/mL, P < 0.0001; absolute change NT-proBNP: 191.42 ± 101.72 pg/mL vs 287.63 ± 149.26 pg/mL, P < 0.0001), and improved healthcare utilization metrics, including shorter intensive care unit (2.99 ± 1.04 days vs 3.54 ± 1.02 days, P < 0.0001) and hospital lengths of stay (6.92 ± 1.93 days vs 7.99 ± 2.06 days, P < 0.0001) and lower 30-day readmission rates (7.1% vs 12.8%, P = 0.0335). These results underscore the nuanced trade-offs in pharmacologic choices for this vulnerable population, emphasizing the need for individualized therapy to balance expeditious blood pressure control with cardioprotection.

The superior speed of blood pressure reduction with labetalol aligns with its dual alpha- and beta-adrenergic blockade, enabling rapid vasodilation and heart rate modulation without pronounced reflex tachycardia[14]. This finding is consistent with prior comparative trials in general hypertensive crises, where labetalol achieved target blood pressure faster than nitroglycerin (e.g., 96% vs 44% at 1 hour) with minimal additional agents required[15]. In acute stroke settings, labetalol has similarly demonstrated quicker hemodynamic stabilization[16]. In our CAD-focused cohort, this rapidity may be especially pertinent for mitigating immediate end-organ damage in patients presenting with neurological deficits or dyspnea, though the approximately 5-minute difference’s clinical impact remains debatable in resource-constrained environments like Pakistan, where delays in care access could amplify its relevance[17]. Nonetheless, labetalol’s higher bradycardia incidence (AOR: 0.14 for nitroglycerin protection; 95%CI: 0.05-0.38) highlights potential risks in CAD patients with conduction issues or impaired ventricular function, warranting cautious use[18].

In contrast, nitroglycerin’s advantages in blood pressure magnitude and cardioprotective profile stem from its nitric oxide-mediated venodilation, which reduces preload and myocardial oxygen demand while enhancing coronary perfusion - critical in ischemic contexts[19]. MACE rates were similar (9.6% vs 12.5%; P = 0.338), with no significant differences in components after adjustment, as do the attenuated biomarker rises indicative of reduced cardiac strain[20]. These benefits resonate with evidence from perfusion studies showing nitroglycerin preserves peripheral and coronary flow better than labetalol during induced hypotension[21]. Comparable hypotension rates (5.0% vs 2.8%, P = 0.2806) challenge concerns over nitroglycerin’s vasodilatory risks, suggesting tolerability in CAD[22]. However, the numerically elevated non-fatal stroke rate (5.0% vs 2.1%, P = 0.1128; AOR: 2.16, 95%CI: 0.80-5.81) warrants investigation, potentially linked to cerebral autoregulation vulnerabilities or unadjusted confounders like baseline stroke history[23].

From a healthcare perspective, nitroglycerin's association with reduced resource use aligns with literature on agents that optimize myocardial outcomes, potentially lowering costs in low- and middle-income settings amid rising CAD burdens[24]. In Pakistan, where epidemiological shifts exacerbate hypertension-CAD overlap, these efficiencies could guide policy toward preferential nitroglycerin use in cardiac-dominant emergencies[25].

Our findings contextualize within contemporary guidelines. The 2025 AHA/American College of Cardiology guideline advocates individualized therapy, prioritizing nitroglycerin in CAD or acute coronary syndromes for its vasodilatory benefits[26]. The 2024 European Society of Cardiology guideline recommends labetalol for general crises but favors nitroglycerin in ischemia[27], while hypertension Canada’s 2025 updates emphasize lifestyle integration post-emergency to sustain control[28]. Emerging 2025 data on nitroglycerin-labetalol combinations suggest hybrid approaches for enhanced efficacy without compounded risks[29], meriting exploration in CAD.

Strengths include a large, real-world cohort with balanced baselines and multivariable adjustments for confounders like age, gender, and chest pain presentation. Limitations encompass retrospective biases, such as selection (e.g., clinician drug choice) and information inaccuracies from EMRs, despite trained extraction. Single-center design limits generalizability beyond South Asia, and short follow-up precludes long-term insights. Non-significant MACE trends may reflect underpowering, and unmeasured factors (e.g., dosing variations) could introduce residual confounding. Additional limitations include selection bias from retrospective design (e.g., non-randomized drug assignment) and indication bias, where nitroglycerin may have been preferred for chest pain (higher in labetalol group, P = 0.039), potentially confounding outcomes despite adjustments. Single-center data may not generalize beyond South Asia.

Future studies should employ prospective, multicenter randomized designs with propensity matching to address biases[30]. Deeper biomarker analyses, including serial troponin/NT-proBNP, could clarify mechanisms[31]. Investigating combinations[29] or alternatives like nicardipine, which systematic reviews show are comparable to labetalol in crises[32], may refine algorithms.

CONCLUSION

In conclusion, while labetalol excels in speed, nitroglycerin appears preferable for CAD-associated hypertensive emergencies, offering superior reduction, safety, and efficiency. Clinicians should tailor selections to ischemia presence, aligning with guidelines to enhance global cardiovascular care in high-risk groups.