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INTRODUCTION
Peptic ulcer disease (PUD) remains a prevalent global health concern, affecting approximately 4 million individuals annually, with an estimated incidence ranging from 1.5% to 3% in the general population [1]. Among these patients, perforation—a life-threatening complication characterized by full-thickness gastrointestinal wall disruption—occurs in approximately 2% to 14% of cases, leading to a lifetime prevalence of perforated PUD of approximately 5% [12]. The associated mortality of perforated peptic ulcer varies widely, reported to be between 1.3% and 20%, underscoring the critical need for optimal management strategies [2].
Despite significant advancements in the medical treatment of PUD, including the widespread use of proton pump inhibitors (PPIs) and Helicobacter pylori eradication therapy, pyloroduodenal ulcer perforation (PUP) continues to present a major clinical challenge, particularly in high-risk populations [34]. H. pylori infection plays a pivotal role in ulcer pathogenesis by inducing chronic inflammation, increasing acid secretion, impairing epithelial regeneration, and aggravating reperforation [4]. Additionally, factors such as advanced age and smoking have been associated with compromised gastric microcirculation, leading to impaired mucosal perfusion, delayed healing, and increased oxidative stress, all of which may exacerbate ulcer disease and contribute to adverse clinical outcomes [345].
Surgical intervention remains the cornerstone of treatment for PUP, with primary closure (PC) being the standard approach [67]. The role of highly selective vagotomy (HSV) has been proposed to lower acid secretion and decrease the risk of recurrent ulceration, however its long-term clinical efficacy in the era of modern medical therapy, particularly with the widespread use of PPIs, remains uncertain [68].
This study aimed to evaluate the long-term outcomes of patients who underwent laparoscopic PC for the management of PUP and identify the risk factors associated with PUP recurrence following PC.
METHODS
Ethics statement
A single-arm observational study was designed and carried out according to the principles of the Declaration of Helsinki, 1989. All data was obtained after consent from all participants before inclusion in the data recruitment. This study was approved by the Institutional Review Board of Gyeongsang National University Hospital (No. GNUH 2019-11-035-001).
Primary outcome
The primary outcome was event time to recurrence, defined as the interval from surgery to the first documented esophagogastroduodenoscopy (EGD) confirmed ulcer or clinical event of PUP recurrence. Patients who died or were lost to follow-up were excluded from the study.
Data collection
We retrospectively analyzed data from patients who underwent laparoscopic PC and omentopexy (PC only) or laparoscopic PC and omentopexy with HSV (PC + HSV) for PUP at a regional tertiary hospital between January 2010 and December 2019. The details of surgical techniques and treatment strategies were published in previous reports [67].
Demographic and clinical data—including age, sex, smoking history, comorbidities, surgical outcomes, early postoperative EGD findings (performed within 1 month after surgery), and H. pylori status—were extracted from a prospectively maintained institutional database.
Smoking history was determined at the time of admission. Patients who reported active smoking or recent smoking were classified as smokers, while those with no history of smoking or who had quit more than 1 year prior were classified as nonsmokers. Postoperative smoking status (e.g., cessation or continuation) was not consistently documented and was therefore not included in the analysis. Data on NSAID use was retrospectively obtained from medical records and patient interviews where available. Long-term NSAID use was defined as regular intake for ≥5 days per week over 4 weeks or for a total duration of ≥3 months. Postoperative medication history, including PPI use, was also reviewed.
Postoperative management and long-term follow-up
The urea breath test (UBT) was performed in the emergency department for all patients with suspected peptic ulcer perforation at admission. Patients with a positive UBT result were administered standard triple therapy (PPI + clarithromycin/metronidazole + amoxicillin) for approximately 14 days, beginning before discharge, in accordance with previously published guidelines [9]. All patients received PPI therapy for at least 2 months postoperatively, regardless of H. pylori status. Follow-up endoscopy was recommended at 3–6 months postoperatively and H. pylori treatment success was confirmed in follow-up UBTs or antigen tests.
Long-term follow-up data were collected through outpatient clinic visits and telephone interviews over a period of 5 years. Follow-up EGD findings were obtained via the National Health Screening Program, which routinely provides biennial endoscopic evaluation. Clinical events including ulcer recurrence, perforation recurrence, reinitiation of PPI therapy, and follow-up EGD findings were recorded.
Patients who died during follow-up or were lost to follow-up were excluded from the final analysis.
Statistical analysis
Continuous data are expressed as mean with standard deviation, with calculation of the probability value to measure the significance of differences. The Student t-test was used for comparisons of continuous variables. Categorical and binary variables were tested by the 2-tailed Pearson chi-square test. Survival analysis was performed using the Cox proportional hazards regression model to identify independent risk factors for recurrence. Univariate regression was initially conducted, and variables with a significance level of P < 0.1 were included in the multivariate model. The proportional hazards assumption was assessed using Schoenfeld residuals. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. Statistical significance was set at P < 0.05. All statistical analyses were performed with IBM SPSS Statistics ver. 28.0 (IBM Corp.)
RESULTS
A total of 206 patients underwent PC with or without HSV for PUP. Of these, 25 patients were excluded due to death, and 42 were lost to follow-up. Consequently, data from 139 patients were eligible for analysis (Fig. 1).
A total of 139 patients were included in the analysis, with a mean age of 59.44 ± 18.33 years. The cohort consisted of 109 males and 30 females. Based on the American Society of Anesthesiologists physical status classification, 14.4% of patients were class I, 62.6% were class II, 20.1% were class III, and 2.9% were class IV (Table 1). Hypertension was the most prevalent, observed in 56 patients (40.3%), followed by diabetes mellitus in 41 patients (29.5%), pulmonary diseases in 29 patients (20.9%), and liver cirrhosis in 14 patients (10.1%).
Regarding smoking history, 76 patients (54.7%) had a history of smoking. Among all patients, only 2 reported NSAID use that met the predefined criteria for long-term use. Due to the limited number, this variable was not included in the statistical analysis. In terms of surgical approach, 95 patients (68.3%) underwent PC alone (PC only), while 44 (31.7%) underwent PC with HSV (PC + HSV).
All patients received postoperative PPI therapy, with a mean duration of 10.5 ± 7.6 months. H. pylori infection was detected in 54 patients (38.8%), and eradication therapy was successful in 46 (33.1%). H. pylori eradication success rate was 85%.
During the follow-up period (mean, 55.4 ± 12.7 months), ulcer recurrence occurred in 19 patients (13.7%), while perforation recurrence was observed in 9 (6.5%).
Risk factors and survival analysis for ulcer and perforation recurrence
Ulcer recurrence
In the multivariate Cox regression analysis for ulcer recurrence, smoking (HR, 6.476; 95% CI, 1.834–22.873; P = 0.004) and older age (HR, 1.049; 95% CI, 1.012–1.088; P = 0.009) were identified as significant risk factors (Table 2). Other variables, including sex (P = 0.343), PPI duration (P = 0.683), H. pylori eradication (P = 0.273), and surgical approach (P = 0.733) were not significantly associated with ulcer recurrence.
Kaplan-Meier survival analysis further supported these findings, showing that cumulative recurrence-free survival was significantly lower in the smoker group over the 60-month follow-up period (P < 0.001, log-rank test) (Fig. 2).
Peptic ulcer perforation recurrence
Similarly, in the multivariate Cox regression analysis for peptic ulcer perforation recurrence, smoking (HR, 19.129; 95% CI, 2.048–178.702; P = 0.010) and older age (HR, 1.062; 95% CI, 1.009–1.118; P = 0.021) were significantly associated with an increased risk of recurrence (Table 3). Other variables, including sex (P = 0.313), PPI duration (P = 0.898), H. pylori eradication (P = 0.138), and surgical approach (P = 0.279), were not significantly associated with perforation recurrence.
Kaplan-Meier analysis similarly showed a significantly lower cumulative perforation-free survival in smokers compared to nonsmokers (P < 0.001, log-rank test) (Fig. 3).
Characteristics of smoking patients
To investigate the impact of smoking on PUP, a comparative analysis between smokers and nonsmokers was performed.
A subgroup analysis comparing smokers (n = 76) and nonsmokers (n = 63) revealed several notable differences. The proportion of male patients was significantly higher in the smoker group (71/76, 93.4%) compared to the nonsmoker group (38/63, 60.3%) (P < 0.001). The mean age of smokers (53.0 ± 14.3 years) was lower than that of nonsmokers (67.0 ± 19.5 years) (P < 0.001). H. pylori positivity was more frequent among smokers (35/76, 46.1%) than nonsmokers (19/63, 30.2%), although this difference did not reach statistical significance (P = 0.080). Similarly, H. pylori eradication therapy was more commonly administered in smokers (30/76, 39.5%) than in nonsmokers (16/63, 25.4%), but the difference was not statistically significant (P = 0.103).
The mean duration of postoperative PPI therapy was similar between the 2 groups (10.1 ± 7.1 months for smokers vs. 10.0 ± 8.2 months for nonsmokers, P = 0.287). Importantly, both ulcer recurrence (15/76, 19.7% vs. 4/63, 6.3%; P = 0.026) and perforation recurrence (8/76, 10.5% vs. 1/63, 1.6%; P = 0.040) were significantly more common in the smoker group (Table 4).
DISCUSSION
This study highlights the significant role of smoking as a major risk factor for PUP recurrence following PC. Our findings demonstrate that smoking is associated with younger age at presentation, male predominance, and increased ulcer and perforation recurrence rates. These results reinforce existing evidence suggesting that smoking exacerbates PUD by impairing mucosal defense mechanisms, reducing gastric blood flow, and increasing gastric acid secretion.
The Cox proportional hazards regression analysis identified smoking and older age as independent predictors of ulcer and PUP recurrence. Despite previous studies suggesting a strong link between H. pylori infection and PUD, our results indicate that H. pylori status and eradication therapy were not significantly associated with recurrence. This finding aligns with prior reports indicating that the role of H. pylori in ulcer recurrence may be less pronounced in perforated cases, where smoking and NSAID use play a more dominant role [1011]. The fact that H. pylori eradication therapy did not significantly influence recurrence rates suggests that factors beyond infection contribute to long-term outcomes. This also implies that a more comprehensive approach, including lifestyle modifications such as smoking cessation, may be crucial for preventing recurrence.
Although HSV has traditionally been considered an effective strategy to reduce acid secretion and prevent ulcer recurrence, our findings suggest that its role in the management of perforated duodenal ulcers may be limited. In our cohort, no significant difference in recurrence rates was observed between patients who underwent PC alone and those who underwent additional HSV. This may indicate that acid-reducing procedures alone are insufficient in the context of perforation, where other factors such as mucosal ischemia and delayed healing may predominate. It is important to note, that the absence of statistical significance does not necessarily imply the absence of true effect, particularly given the limited sample size in this subgroup. Therefore, our findings should not be interpreted as definitive evidence against HSV and prospective studies with larger cohorts are required to clarify its role.
Analysis of HSV usage trends in our cohort revealed a clear decline over time: HSV was performed in 100% of cases during 2010–2014, but the rate decreased to 32% during 2015–2019 and further declined to 19.7% in 2020–2021. This trend reflects a shift in clinical practice toward more selective use of HSV, as medical therapy has advanced with effective acid suppression and H. pylori eradication.
The mechanisms by which smoking influences ulcer recurrence are well established in the literature [1213]. Smoking is known to impair the gastric mucosal barrier by reducing prostaglandin synthesis, leading to decreased mucosal blood flow and impaired healing of the ulcerated tissue [14]. Additionally, smoking promotes increased gastric acid secretion and inhibits bicarbonate production, further contributing to mucosal damage [14]. These pathophysiological mechanisms align with our findings, which indicate a strong association between smoking and ulcer recurrence [1215]. Taken together, these mechanisms provide a plausible explanation for why smoking is a significant predictor of both ulcer and PUP recurrence.
The influence of age on ulcer recurrence is another note-worthy finding in our study. Older age has been associated with impaired mucosal defense mechanisms, reduced regenerative capacity, and an increased likelihood of comorbidities that may affect healing [161718]. Our findings support the notion that elderly patients may be at a heightened risk for ulcer recurrence following PC. This emphasized the importance of individualized postoperative management strategies tailored to older patients, including stricter follow-up protocols, optimized medication regimens, and nutritional support to enhance mucosal healing [19]. Additionally, older patients are more likely to be on long-term NSAID therapy for comorbid conditions such as arthritis, further increasing their risk for ulcer recurrence [202122]. Future research should focus on exploring whether modifying NSAID use in elderly patients can further reduce recurrence rates.
Due to the retrospective nature of our study, we were unable to distinguish between current and former smokers regarding the time point of PUP recurrence, as detailed postoperative smoking history was not consistently documented. Future prospective studies should consider stratifying patients based on smoking cessation status to better elucidate its impact on recurrence.
The present study has several limitations. First, the retrospective design and reliance on follow-up data introduce potential biases, including selection bias and loss of follow-up. Second, smoking history was based on medical records and patient interviews. Self-reported smoking status may not accurately reflect actual tobacco exposure, and biochemical verification methods such as nicotine/cotinine levels could provide a more objective assessment in future studies. Third, NSAID use is recognized as a potential risk factor for PUD; however, only 2 patients in our cohort met the predefined criteria for long-term use. Given the small number of applicable cases and limitations inherent to retrospective data collection, particularly with regard to medication history, we were unable to reliably assess its clinical impact in this study. Fourth, the study population was limited to a single regional tertiary hospital, which may affect the generalizability of the findings. Although our results are consistent with prior research, multicenter studies with a more diverse patient population are needed to confirm our conclusions.
Despite its limitations, this study highlights the need for targeted postoperative strategies to reduce ulcer recurrence, particularly through smoking cessation interventions. Given the strong association between smoking and recurrence risk, integrating structured cessation programs, including counseling and nicotine replacement therapy, into postoperative care may be beneficial. Public health efforts to reduce smoking in high-risk populations could also contribute to lowering the overall burden of PUD.
Future studies with larger cohorts and longer follow-ups are needed to better understand the impact of smoking on PUP recurrence and refine prevention strategies. In particular, randomized trials assessing intensive smoking cessation programs and alternative medical therapies, such as cytoprotective agents or advanced acid suppression, could provide valuable insights.
These findings emphasize the importance of patient education on modifiable risk factors, especially smoking cessation, to improve outcomes after PC of perforated pyloroduodenal ulcers. A multidisciplinary approach involving surgeons, gastroenterologists, and primary care providers may be key to optimizing long-term care.
In this long-term observational study, we identified smoking and advanced age as the most significant risk factors for ulcer and perforation recurrence following laparoscopic PC for PUP. Despite the widespread use of PPIs and H. pylori eradication therapy, neither H. pylori status nor eradication success was significantly associated with recurrence. Similarly, the addition of HSV did not demonstrate a clear benefit over PC alone in preventing long-term recurrence. These findings highlight the dominant role of modifiable lifestyle factors—particularly smoking—over traditional ulcer-related parameters in determining recurrence risk.
Our results underscore the importance of comprehensive postoperative strategies, including structured smoking cessation support and tailored surveillance protocols, particularly for older patients. Given the strong association between smoking and recurrence, clinicians should prioritize risk factor modification as a cornerstone of long-term management. Future prospective, multicenter studies are warranted to validate these findings and further optimize recurrence prevention in this population.
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