Abstract
Background and aims:
Cirrhosis patients are at increased risk for postoperative complications. It remains unclear whether preoperative nonsurgical clinician visits improve postoperative outcomes. We assessed the impact of preoperative primary care physician (PCP) and/or Gastroenterologist/Hepatologist (GI/Hep) visits on postoperative mortality in cirrhosis patients undergoing surgery and explored differences in medication changes and paracentesis rates as potential mediators.
Methods:
This was a retrospective cohort study of cirrhosis patients in the Veterans Health Administration who underwent surgery between 2008 and 2016. We compared 1982 patients with preoperative PCP and/or GI/Hep visits with 1846 propensity matched patients without preoperative visits. We used Cox regression and Fine and Gray competing risk regression to evaluate the association between preoperative visit type and postoperative mortality at 6 months.
Results:
Patients with preoperative GI/Hep and PCP visits had a 45% lower hazard of postoperative mortality compared to those without preoperative visits (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.87). A smaller effect size was noted with GI/Hep preoperative visit alone (HR, 0.69; 95% CI, 0.48–0.99) or PCP visit alone (HR, 0.70; 95% CI, 0.53–0.93). Patients with preoperative PCP/GI/Hep visits were more likely to have diuretics, spontaneous bacterial peritonitis prophylaxis, and hepatic encephalopathy medications newly initiated and/or dose adjusted and more likely to receive preoperative paracentesis as compared to those without preoperative visits.
Conclusion:
Preoperative PCP/GI/Hep visits are associated with a reduced risk of postoperative mortality with the greatest risk reduction observed in those with both PCP and GI/Hep visits. This synergistic effect highlights the importance of a multidisciplinary approach in the preoperative care of cirrhosis patients.
Keywords: Cirrhosis, surgical risk, postoperative complications, preoperative visits, preoperative optimization
Graphical Abstract
Introduction
The prevalence of cirrhosis is rising given high rates of alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD).1 Accordingly, there has also been a rise in the volume of surgeries performed in these patients.2 Patients with cirrhosis have increased risk of post-operative morbidity and mortality due to pathophysiological changes including portal hypertension increasing the risk of bleeding, immune dysregulation increasing risk for infections, and increased susceptibility to hemodynamic effects of anesthetic agents.3 Recent literature has focused on developing more accurate prediction models for postoperative outcomes through incorporation of unique patient and surgery risk factors, such as the Veterans Outcomes and Costs Associated With Liver Disease (VOCAL)–Penn score.4–7 However, despite these advancements, there are limited data evaluating the role of preoperative medical optimization and interventions that may mitigate post-operative risk in patients with cirrhosis.
Preoperative medical optimization is an essential process to address modifiable risk factors for patients undergoing surgical interventions and may entail medication adjustment, volume status optimization, infection prevention measures, and identification of issues that may require anticipatory perioperative management.3 Existing literature suggest that preoperative nonsurgical clinician visits in patients with various comorbidities may lower rates of postoperative complications, yet it is unclear if these findings translate to patients with cirrhosis who have unique pathophysiologic considerations and operative challenges.8 To address this knowledge gap, we used national data from the Veterans Health Administration (VHA) to assess the impact of preoperative primary care physician (PCP) and/or gastroenterology/hepatology (GI/Hep) visits on postoperative outcomes in patients with cirrhosis undergoing surgery.
Methods
Study Design, Data Source, and Cohort Creation
We performed a propensity-matched retrospective cohort study of patients with cirrhosis using the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) cohort, which contains data on >129,000 patients with cirrhosis from 128 VHA hospitals identified between 2008 and 2016, and has been used for numerous studies of chronic liver disease.9–11 We merged VOCAL with the Veterans Affairs Surgical Quality Improvement Program (VASQIP) dataset, which contains prospectively adjudicated data on VHA surgical procedures.12 We included all patients ≥18 years of age with cirrhosis, defined using a validated algorithm based on International Classification of Diseases codes,13 who underwent major surgeries of interest (Supplemental Table 1). This list notably did not comprise hepatic surgeries, minor surgeries, or those with accepted low risk, and was adapted from prior categorizations in the VOCAL-Penn Score derivation cohort.4 We excluded patients who received liver transplantation prior to surgery, those with missing preoperative American Society of Anesthesiology (ASA) classification, and those with ASA classes of 1 or 5 as these extremes of risk would be unlikely to be meaningfully impacted by preoperative medical optimization. We also excluded surgery events beyond the first temporal surgery of interest, thereby isolating first major surgeries and arriving at a cohort of unique patients.
Ascertainment of Exposure Variables
We collected data on demographics (age, sex, and race/ethnicity), comorbidities (diabetes, obesity, atrial fibrillation, coronary artery disease [CAD], heart failure), and preoperative laboratory data (aspartate aminotransferase [AST], alanine aminotransferase [ALT], platelet count, total bilirubin, sodium, creatinine, and INR). Preoperative laboratory values closest to the day of surgery were used, with a maximum window of 30 days prior to surgery. Comorbidities were ascertained using previously described methods.10 Etiology of liver disease was classified using a validated algorithm and categorized as hepatitis C virus (HCV), hepatitis B virus (HBV), ALD, HCV and ALD, MASLD, or other.24 MELD and MELD-Na were computed from preoperative laboratory parameters, and preoperative Child-Turcotte-Pugh (CTP) class was determined using a well-validated VHA algorithm.17 The primary exposure of interest was preoperative PCP and/or GI/Hep appointment in the 60 days prior to the surgery; completed visits of interest were obtained using VHA stop codes from the outpatient visits table in the VHA Clinical Data Warehouse (CDW). The primary exposure was classified into four levels: PCP visit alone, GI/Hep visit alone, both PCP and GI/Hep visits, and no preoperative visits. We used Common Procedure Terminology (CPT) codes to categorize surgical procedure types as abdominal wall, vascular, major orthopedic, chest/cardiac, major abdominal, spine/central nervous system (CNS), or rectal/genitourinary/retroperitoneal. These categories were decided based on guidance from the literature, as well as through expert opinion. ASA classification was determined preoperatively by anesthesiologist assessment, as adjudicated in the VASQIP. An emergency modifier was denoted in cases where delay in surgery would lead to a significant increase in the likelihood of death or loss of body part (e.g., ASA 4E was emergent whereas ASA 4 was non-emergent).
Outcomes
The primary outcome was postoperative mortality through 6 months, which we ascertained using the Vital Status File and manually-adjudicated VASQIP death data. Exploratory outcomes included the frequency of medication changes (new initiation or dose changes) of non-selective beta-blockers (NSBB; carvedilol, propranolol, nadolol), diuretics (amiloride, bumetanide, eplerenone, furosemide, spironolactone, torsemide), hepatic encephalopathy (HE) medications (lactulose, rifaximin), or spontaneous bacterial peritonitis prophylaxis (SBP PPx; cefpodoxime, fluoroquinolones, trimethoprim-sulfamethoxazole), as well as performance of paracentesis in the 60 days prior to surgery. Granular medication data were obtained from pharmacy tables in the VHA CDW and paracenteses were identified using CPT codes.
Primary Statistical Analysis
Baseline preoperative characteristics were reported as percentages for categorical variables and medians and interquartile ranges (IQRs) for continuous variables. These data were stratified by patients with or without preoperative PCP and/or GI/Hep visits in the 60 days prior to the surgery, and comparisons were made using Wilcoxon rank-sum and chi-square tests, as indicated. A propensity score (PS) was estimated using logistic regression with the outcome of outpatient preoperative visit using the following variables: age, sex, race, etiology of liver disease, surgery type, ASA class, platelet count, CTP class, diabetes mellitus, obesity, atrial fibrillation, CAD, heart failure. PS matching (PSM) was then performed using maximum 3:1 matching without replacement and a caliper width of 0.003. Adequacy of PSM was demonstrated through kernel density plots of propensity scores in unmatched and matched groups. Standardized mean differences (SMDs) were also computed and adequate balance was indicated by values between −0.1 and 0.1. To evaluate the association between preoperative outpatient visit and post-operative mortality through 6 months in the PSM cohort we used a survival analysis approach. Index time was the day of surgery, and patients were right-censored at maximum follow-up or liver transplantation. Kaplan-Meier analysis was used to estimate the cumulative incidence of postoperative mortality, and associated Kaplan-Meier plots were presented for each level of the primary exposure. Log-rank testing was performed to compare survival distributions. Cox regression was then used to estimate the hazard ratio (HR) of postoperative mortality for each group. In a sensitivity analysis, Fine and Gray competing risk regression was used to estimate the subhazard ratio (SHR) accounting for the competing event of liver transplantation. Survival curves were presented for both models, along with 95% confidence intervals (CIs). In the primary Cox regression model, we also tested for a priori interactions between preoperative outpatient visit and (1) emergency surgery status and (2) surgery type. We also performed an a priori subgroup analysis limited to patients with CTP B/C cirrhosis to test the hypothesis that preoperative outpatient care may have a larger impact in patients with more advanced liver disease, as well as an analysis of CTP A patients to determine if the relative effect of PCP versus GI/Hep care may be more salient in such patients. Finally, to explore potential risk reduction through preoperative visits relative to predicted postoperative risk, we computed average observed probabilities of post-operative mortality by surgery type and primary exposure category (from Fine and Gray competing risk regression models) and then computed average predicted probabilities of postoperative mortality using the VOCAL-Penn Score (VPS).4 The difference (delta) between observed and predicted probabilities of postoperative mortality was then plotted for each surgery type and primary exposure category. Of note, this was only done for surgeries included in the initial VPS model, and thus spine/CNS and rectum/genitourinary/retroperitoneal surgeries were excluded. For all hypothesis testing, an alpha level of 5% was used to determine statistical significance.
Exploratory Analysis
In an exploratory analysis of management changes mediated through preoperative visits, we computed the proportion of patients with (1) new initiations of diuretics, NSBBs, HE medications, or SBP PPx, (2) dose adjustments in diuretics, NSBBs, HE medications, or SBP PPx, and (3) performance of preoperative paracentesis. These statistics were evaluated across each preoperative visit category and comparisons made using the chi-square test. We also evaluated proportions of patients who received any of the above management changes, stratified by outpatient visit categories as well as CTP A vs. CTP B/C cirrhosis.
Other Considerations
This study received institutional review board approval at the Corporal Michael J. Crescenz Philadelphia Veterans Affairs Medical Center. All data management and analyses were performed using a combination of structured query language and STATA/BE 18.0 (StataCorp LP, College Station, TX).
Results
Cohort Characteristics
After application of selection criteria (Supplemental Figure 1), the unmatched cohort included 6,180 unique patients with cirrhosis, among which 2,830 (46%) had preoperative PCP/GI/Hep visits, while 3,350 (54%) had no preoperative visits (Supplemental Table 2). In the unmatched cohort, there were significant patient differences in preoperative visit groups in terms of etiology of liver disease (P<.001, Table 1) where patients without preoperative visits were more likely to have ALD (34.7% vs 30.1%), and in terms of surgery type (P=.001) and emergency status (p=0.04), where patients without preoperative visits had a higher proportion of orthopedic surgeries (31.7% vs 27.1%) and emergent surgeries (10.2% vs 8.7%). Patients without preoperative visits were also more likely to have cardiac comorbidities including atrial fibrillation (17.1% vs 14.1%, P=.001), CAD (33.1% vs 30.4%, P=.02), and heart failure (26.3% vs 22.8%, P=.002).
Table 1 -.
Cohort Characteristics of the Unmatched and Propensity Matched Cohort
| Unmatched Cohort | Propensity Matched Cohort | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| Factor | No PCP/GI/Hep Visit Prior N=3350 | PCP/GI/Hep Visit Prior N=2830 | P-value | No PCP/GI/Hep Visit Prior N=1846 | PCP/GI/Hep Visit Prior N=1982 | SMD |
| Recipient Age at Transplant (years), median (IQR) | 64 (59, 69) | 64 (60, 68) | .72 | 64 (59, 68) | 64 (59, 68) | 0.040 |
|
| ||||||
| Male Sex, No. (%) | 3257 (97.2) | 2766 (97.7) | .20 | 1802 (97.6) | 1943 (98.0) | 0.013 |
|
| ||||||
| Race/Ethnicity, No. (%) | .62 | -0.013 | ||||
| White | 2023 (60.4) | 1712 (60.5) | 1135 (61.5) | 1280 (64.6) | ||
| Black | 612 (18.3) | 502 (17.7) | 355 (19.2) | 342 (17.3) | ||
| Hispanic | 254 (7.6) | 236 (8.3) | 173 (9.4) | 171 (8.6) | ||
| Asian | 33 (1.0) | 35 (1.2) | 23 (1.2) | 31 (1.6) | ||
| Other | 428 (12.8) | 345 (12.2) | 160 (8.7) | 158 (8.0) | ||
|
| ||||||
| Etiology of Liver Disease, No. (%) | <.001 | 0.004 | ||||
| Hepatitis C Virus | 463 (13.8) | 422 (14.9) | 312 (16.9) | 347 (17.5) | ||
| Hepatitis B Virus | 87 (2.6) | 57 (2.0) | 31 (1.7) | 33 (1.7) | ||
| Alcohol-Related Liver Disease | 1161 (34.7) | 851 (30.1) | 527 (28.5) | 545 (27.5) | ||
| HCV + ALD | 924 (27.6) | 943 (33.3) | 711 (38.5) | 778 (39.3) | ||
| Metabolic dysfunction-associated steatotic liver disease | 465 (13.9) | 346 (12.2) | 212 (11.5) | 220 (11.1) | ||
| Other | 250 (7.5) | 211 (7.5) | 53 (2.9) | 59 (3.0) | ||
|
| ||||||
| Surgery Type, No. (%) | .002 | 0.035 | ||||
| Spine/CNS | 233 (7.0) | 192 (6.8) | 122 (6.6) | 122 (6.2) | ||
| Rectum/GU/RP | 180 (5.4) | 151 (5.3) | 90 (4.9) | 102 (5.1) | ||
| Orthopedic | 1063 (31.7) | 766 (27.1) | 456 (24.7) | 461 (23.3) | ||
| Abdominal Wall | 649 (19.4) | 634 (22.4) | 448 (24.3) | 517 (26.1) | ||
| Vascular | 304 (9.1) | 238 (8.4) | 146 (7.9) | 150 (7.6) | ||
| Chest/Cardiac | 279 (8.3) | 254 (9.0) | 168 (9.1) | 185 (9.3) | ||
| Major Abdominal – Open | 360 (10.7) | 347 (12.3) | 230 (12.5) | 254 (12.8) | ||
| Major Abdominal – Laparoscopic | 282 (8.4) | 248 (8.8) | 186 (10.1) | 191 (9.6) | ||
|
| ||||||
| Emergency Surgery, No. (%) | 343 (10.2) | 246 (8.7) | .04 | 196 (10.6) | 179 (9.0) | -0.052 |
|
| ||||||
| ASA Class, No. (%) | .56 | 0.007 | ||||
| 2 | 143 (4.3) | 137 (4.8) | 103 (5.6) | 108 (5.4) | ||
| 3 | 2298 (68.6) | 1932 (68.3) | 1258 (68.1) | 1332 (67.2) | ||
| 4 | 909 (27.1) | 761 (26.9) | 485 (26.3) | 542 (27.3) | ||
|
| ||||||
| AST, median (IQR), (U/L) | 33 (23, 54) | 34 (23.5, 54) | .16 | 35 (23, 57) | 35 (24, 56) | -0.017 |
|
| ||||||
| ALT, median (IQR), (U/L) | 29 (19, 46) | 29 (19, 47) | .30 | 29 (19, 48) | 29 (19, 47) | -0.005 |
|
| ||||||
| Platelet Count, median (IQR), ×103/μL | 154 (109, 210) | 147 (102, 201) | <.001 | 143 (102, 194) | 142 (99, 194) | -0.016 |
|
| ||||||
| Creatinine, median (IQR), mg/dL | 0.9 (0.8, 1.2) | 1.0 (0.8, 1.2) | .046 | 0.9 (0.8, 1.2) | 1.0 (0.8, 1.2) | 0.024 |
|
| ||||||
| Sodium, median (IQR), mEq/L | 138 (136, 140) | 138 (136, 140) | .09 | 138 (136, 140) | 138 (136, 140) | 0.055 |
|
| ||||||
| Total Bilirubin, median (IQR), mg/dL | 0.7 (0.5, 1.1) | 0.8 (0.5, 1.2) | .11 | 0.8 (0.5, 1.2) | 0.8 (0.5, 1.2) | -0.026 |
|
| ||||||
| Albumin, median (IQR), mg/dL | 3.7 (3.3, 4.1) | 3.7 (3.2, 4.1) | .96 | 3.7 (3.2, 4.1) | 3.7 (3.2, 4.1) | 0.029 |
|
| ||||||
| INR, median (IQR) | 1.1 (1.0, 1.2) | 1.1 (1.0, 1.2) | .29 | 1.1 (1.0, 1.2) | 1.1 (1.0, 1.2) | 0.036 |
|
| ||||||
| MELD-Na, median (IQR) | 10 (8, 14) | 10 (8, 14) | .80 | 10 (8, 14) | 10 (8, 14) | 0.009 |
|
| ||||||
| CTP Class, No. (%) | .11 | 0.011 | ||||
| A | 3015 (90.0) | 2502 (88.4) | 1627 (88.1) | 1734 (87.5) | ||
| B | 323 (9.6) | 313 (11.1) | 210 (11.4) | 238 (12.0) | ||
| C | 12 (0.4) | 15 (0.5) | 9 (0.5) | 10 (0.5) | ||
|
| ||||||
| Ascites Classification | .01 | 0.098 | ||||
| Absent | 2973 (88.7%) | 2441 (86.3%) | 1630 (88.3%) | 1683 (84.9%) | ||
| Slight | 291 (8.7%) | 296 (10.5%) | 162 (8.8%) | 222 (11.2%) | ||
| Moderate | 86 (2.6%) | 93 (3.3%) | 54 (2.9%) | 77 (3.9%) | ||
|
| ||||||
| Encephalopathy Classification | .49 | 0.016 | ||||
| No encephalopathy | 3271 (97.6%) | 2756 (97.4%) | 1797 (97.3%) | 1929 (97.3%) | ||
| Grade 1-2 | 74 (2.2%) | 66 (2.3%) | 45 (2.4%) | 49 (2.5%) | ||
| Grade 3-4 | 5 (0.1%) | 8 (0.3%) | 4 (0.2%) | 4 (0.2%) | ||
|
| ||||||
| Diabetes, No. (%) | 1686 (52.1) | 1392 (51.2) | .52 | 954 (51.7) | 990 (49.9) | -0.033 |
|
| ||||||
| Obesity, No. (%) | 2385 (73.7) | 2048 (75.4) | .13 | 1429 (77.4) | 1497 (75.5) | -0.063 |
|
| ||||||
| Atrial Fibrillation, No. (%) | 573 (17.1) | 399 (14.1) | .001 | 225 (12.2) | 225 (11.4) | -0.040 |
|
| ||||||
| Coronary Artery Disease, No. (%) | 1109 (33.1) | 860 (30.4) | .02 | 525 (28.4) | 561 (28.3) | -0.050 |
|
| ||||||
| Heart Failure, No. (%) | 881 (26.3) | 646 (22.8) | .002 | 382 (20.7) | 386 (19.5) | -0.032 |
ALD = alcohol-related liver disease; CTP = Child-Turcotte-Pugh; HCV = hepatitis C virus; INR = international normalized ratio; IQR = interquartile range; MELD = model for end-stage liver disease; SMD = standardized mean difference
After PSM, we identified 1,982 patients with preoperative PCP/GI/Hep visits matched to 1,846 patients without preoperative visits. Adequate balance and bias reduction were achieved across all included baseline covariates (each SMD between −0.1 and 0.1; Table 1), and kernel density plots confirmed excellent matching of propensity scores (Figure 1). The PSM cohort was predominantly male (97.8%) and White (63.1%), with a median age 64 years (IQR 59, 68). Most patients were CTP A (87.8%) or CTP B (11.7%), ASA Class 3 (67.7%) or 4 (26.8%), with HCV and ALD as the most common etiology of liver disease (38.9%; Table 1). The most common surgeries were abdominal wall (22.5%) and major orthopedic (24.0%), and the least common were rectal/genitourinary/retroperitoneal (5.0%), with 9.8% of the surgeries being performed on an emergent basis.
Figure 1 –
Propensity Matching for Preoperative PCP/GI/Hep visits with (A) Pre-Matching and (B) Post-Matching
Impact of Preoperative Outpatient Visits on Postoperative Mortality
Over median follow-up 6.0 months (IQR 2.4, 6.0), the cumulative incidence of postoperative mortality in groups was as follows: 11.5% no preoperative visit, 8.1% PCP visit alone, 8.2% GI/Hep visit alone, and 6.7% both PCP and GI/Hep visits. There was a significant difference in survival curves in log-rank testing of Kaplan-Meier curves (P=.006, Figure 2A) as well as in Cox regression models of the primary exposure (joint P =.006, Table 2). Preoperative visits with both PCP and GI/Hep providers were associated with a 45% reduced hazard of postoperative mortality (HR 0.55, 95% CI 0.35–0.87, P=.01) versus those with no preoperative visits. Effect sizes were more modest for GI/Hep visit only (HR 0.69, 95% CI 0.48–0.99, P =.04) and PCP visit only (HR 0.70, 95% CI 0.53–0.93, P=.01) though differences remained statistically significant. Similar results were obtained when accounting for the competing risk of liver transplantation, where patients with both PCP and GI/Hep preoperative visits had a 51% lower subhazard of post-operative mortality relative to no preoperative visit (SHR 0.49; 95% CI, 0.31–0.79; P=.003), with more modest effects with GI/Hep visit only (SHR 0.67, 95% CI 0.47–0.96, P=.03) or PCP visit only (SHR 0.70, 95% CI 0.53–0.93, P=.02; Table 2, Figure 2B). In primary Cox regression modeling, there was no interaction between preoperative visit category and emergency surgery status (P=.13) or surgery type (P=.97). Finally, in a subgroup analysis limited to patients with CTP B/C cirrhosis (n=467), we observed an intensified association between PCP and GI/Hep preoperative visits and post-operative mortality. For instance, in competing risk analysis patients with both PCP and GI/Hep visits prior to surgery had an 81% reduced subhazard of postoperative mortality relative to patients with no preoperative visit (SHR 0.19, 95% CI 0.06–0.62, P=.006; Supplemental Table 3). By contrast, in CTP A patients with cirrhosis, there remained a significant association between pre-operative visits and post-operative mortality (P=.048), however PCP visits appeared to be a stronger driver of this association (e.g., SHR 0.68 PCP alone vs. no visits, 95% CI 0.48–0.95, P=.03 vs. SHR 0.62 both PCP and GI/Hep vs. no visits, 95% CI 0.37–1.04, P=.07; Supplemental Table 4).
Figure 2 –
Association between Preoperative Outpatient Visits and Post-operative Mortality in (A) Kaplan-Meier and (B) Competing Risk Analyses* in the Propensity Matched Cohort
Panel B accounts for the competing risk of liver transplantation in the postoperative period.
Table 2 –
Association between Preoperative Outpatient Visits and Postoperative Mortality in Cox Regression and Competing Risk Models in the Propensity Matched Cohort
| Outpatient Visit Category | Cox Regression | Fine and Gray Competing Risk Model | ||
|---|---|---|---|---|
| Hazard Ratio (95% CI) | P-value | Subhazard Ratio (95% CI) | P-value | |
| No visit | (ref) | .006 | (ref) | .002 |
| PCP visit only | 0.70 (0.53-0.93) | .01 | 0.70 (0.53-0.93) | .02 |
| GI/Hep visit only | 0.69 (0.48-0.99) | .04 | 0.67 (0.47-0.96) | .03 |
| Both PCP and GI/Hep visit | 0.55 (0.35-0.87) | .01 | 0.49 (0.31-0.79) | .003 |
As an illustration of differences in risk by surgery type across preoperative visit categories, chest/cardiac surgeries had the highest observed risk of six-month postoperative mortality followed by major abdominal surgery, regardless of preoperative visit exposure classification (Figure 3A), though the mortality risk for all surgeries was reduced with preoperative visits, especially in patients with both PCP and GI/Hep visits. For each surgery, the predicted risk of postoperative mortality per the VPS was generally similar across preoperative visit categories (Figure 3B), and again chest/cardiac surgeries had the highest predicted risk of all surgeries. The delta between observed and predicted mortality demonstrated an absolute risk reduction for all surgeries with preoperative visits, especially both PCP and GI/Hep visits, ranging between 2.8% for major vascular surgeries and 5.1% for chest/cardiac surgeries (Figure 3C).
Figure 3 –
Average (A) Observed Probabilities of Six-Month Post-operative Mortality, (B) Predicted Probabilities of Post-operative Mortality per VOCAL-Penn Score, and (C) Delta between Observed and Predicted, Stratified by Surgery Type and Preoperative Visit Classification
Exploratory Analyses
Across preoperative visit classifications, there were several differences in the proportion of patients newly initiated on cirrhosis-related medications or receiving dose adjustment, as well as in receipt of preoperative paracenteses. Patients with preoperative visits were significantly more likely to be newly initiated on diuretics (e.g., 11.6% PCP and GI/Hep vs. 5.7% no visit, P<.001; Table 3) and SBP PPx (e.g., 10.7% PCP vs. 7.5% no visit, P=.04) and to have dose adjustments to diuretics (11.4% PCP and GI/Hep vs. 5.5% no visit, P<.001) and HE medications (4.4% PCP and GI/Hep vs. 1.9% no visit, P=.005). Patients with preoperative visits were also more likely to receive preoperative paracentesis (7.2% PCP and GI/Hep vs. 1.4% no visit, P<.001). Finally, any management changes (inclusive of medication initiation, dose changes, paracentesis) were most commonly observed in patients with both PCP and GI/Hep visits (e.g., 40.2% vs. 27.4% no visits, P<.001). The proportion of patients with any management changes was higher in those with CTP B/C cirrhosis as compared to CTP A cirrhosis (55.5% vs. 28.1%, respectively, P<.001).
Table 3 –
Exploratory Analysis: Medication Changes and Paracentesis in 60 Days Prior to Surgery
| Factor | No Visit (N=1846) | PCP Visit (N=1020) | GI/Hep Visit (N=557) | Both PCP and GI/Hep Visit (N=405) | P-value |
|---|---|---|---|---|---|
| New Medication Initiation | |||||
| Diuretics, No. (%) | 106 (5.7) | 85 (8.3) | 36 (6.5) | 47 (11.6) | <.001 |
| NSBBs, No. (%) | 50 (2.7) | 31 (3.0) | 18 (3.2) | 13 (3.2) | .88 |
| HE Meds, No. (%) | 60 (3.3) | 41 (4.0) | 23 (4.1) | 23 (5.7) | .13 |
| SBP prophylaxis, No. (%) | 139 (7.5) | 109 (10.7) | 52 (9.3) | 35 (8.6) | .04 |
| Medication Dose Adjustment | |||||
| Diuretics, No. (%) | 101 (5.5) | 63 (6.2) | 29 (5.2) | 46 (11.4) | <.001 |
| NSBBs, No. (%) | 43 (2.3) | 16 (1.6) | 8 (1.4) | 14 (3.5) | .08 |
| HE Meds, No. (%) | 35 (1.9) | 38 (3.7) | 18 (3.2) | 18 (4.4) | .005 |
| SBP prophylaxis, No. (%) | 98 (5.3) | 55 (5.4) | 33 (5.9) | 17 (4.2) | .70 |
| Paracentesis Performed, No. (%) | 26 (1.4) | 31 (3.0) | 28 (5.0) | 29 (7.2) | <.001 |
| Any Management Change*, No. (%) | 506 (27.4%) | 347 (34.0%) | 186 (33.4%) | 163 (40.2%) | <.001 |
Encompasses any new medication initiation, medication dose adjustment, or performance of paracentesis
Discussion
Recent efforts have improved our ability to risk stratify patients with cirrhosis in need of surgery. However, the risk of surgery is both a reflection of the patient’s disease severity, the inherent risks of surgery, and the extent to which the patient is optimized for surgery. Given limited data elucidating specific strategies for preoperative optimization to mitigate the risk of surgery, we conducted this study of a national cohort of patients with cirrhosis undergoing diverse surgeries. We found that completing preoperative visits (PCP, GI/Hep, or both) was significantly associated with reduced risk of postoperative mortality. Importantly, we also demonstrated an absolute risk reduction in six-month post-operative mortality with preoperative visits relative to predictions from the validated VOCAL-Penn Score, highlighting PCP and GI/Hep preoperative visits as modifiable risk factors that may mitigate perioperative risk and improve patient candidacy for surgery, especially for high-risk procedures such as chest/cardiac surgeries.
A potential synergistic effect was observed in patients seen by both PCP and GI/Hep providers prior to surgery, as these patients had the lowest postoperative mortality risk as compared to all other groups. This observation was consistent across stratifications of surgery type, emergency status of the surgery, and the CTP class of patients. This suggests that each provider may be optimizing different aspects of patient health, including cirrhosis-related and non-cirrhosis-related factors, that may impact operative risk. This may be especially salient in the Veterans’ population, which generally carries a higher burden of metabolic, cardiovascular, substance use, and mental health-related comorbidities as compared to the general population.26 In this context, PCP management of non-hepatic comorbidities and coordination with other specialists may be critically important to mitigate postoperative risk, separate from the impact of GI/Hep providers on cirrhosis-related care. Additionally, though somewhat limited by small sample size, it is important to highlight that preoperative outpatient visits with both PCP and GI/Hep appear to have a greater impact on operative outcomes in patients who are sicker at baseline from a liver standpoint, as was observed in the subgroup analysis of patients with CTP B/C cirrhosis. By contrast, in CTP A patients the impact of PCP visits may be relatively more impactful on post-operative risk mitigation than GI/Hep visits.
It is notable that a protective association was observed with preoperative visits in both emergency and elective surgical scenarios. This indicates that some of the visits captured in this study may not have been dedicated to address preoperative risk stratification, and that engagement in routine care for cirrhosis and non-cirrhosis-related management may help to ensure medical optimization even when an indication for surgery arises unexpectedly. Here it is relevant to note that we intentionally did not adjust for baseline engagement in care (which might otherwise address a “healthy user” bias), as the primary exposure of interest (outpatient preoperative visits) is itself a marker of engagement. Thus, healthy usership may in fact serve as a mediator of the outcome for the research question addressed in this study.
An important feature of this study is the exploration of potential mechanisms through which preoperative visits may impact postoperative outcomes. We found that patients with preoperative visits were more likely to be newly initiated on key medications including diuretics and SBP PPx, more likely to have dose adjustments made to diuretics and HE medications, and more likely to undergo preoperative paracentesis to address ascites. Importantly, these findings were observed with PCP alone and GI/Hep alone categories but were generally intensified in patients who were seen by both PCP and GI/Hep providers, again highlighting the potential synergistic effects noted previously. Additionally, as these aspects of management were concentrated in patients with more advanced cirrhosis (i.e., CTP B/C), the importance of preoperative visits is likely especially critical in these patients.
Previous studies have addressed the importance of preoperative sampling and managing ascites in patients with cirrhosis undergoing surgery. This may help to (1) rule out SBP which might otherwise worsen postoperative morbidity and mortality, (2) identify indications for SBP Ppx including in patients with low-protein ascites, and (3) minimize the risk of wound dehiscence and infection that may occur after abdominal surgery in patients with significant ascites.3 Given that patients with cirrhosis are at increased risk for postoperative HE that may be triggered by infections, acute kidney injury (AKI), bleeding, and intraoperative anesthetics or postoperative analgesics, appropriate preoperative titration of HE medications is critical to ensure patients have controlled HE going into surgery. Finally, dose adjustment in some instances included discontinuation of medications, highlighting that even if medications such as diuretics were indicated previously, they may need to be held preoperatively if patients manifest AKI, electrolyte derangements, or refractory ascites as this may indicate reduced hemodynamic reserve and increased risk with surgery and anesthesia.3 In light of these considerations, it is plausible that these key medication initiations/adjustments and paracentesis may contribute to the observed reduction in postoperative mortality in patients with preoperative visits. Nevertheless, these findings are exploratory in nature and should be evaluated in detail in future studies.
Our data must be interpreted in the context of the study design. First, although we used PSM and demonstrated excellent covariate balance, there is potential for residual confounding. In particular, we did not explore the effect of outpatient specialist visits apart from GI/Hepatology clinic visits; this may be an area of inquiry in future studies as specialists such as cardiologists and nephrologists may plausibly impact operative risk in a highly comorbid cohort of patients. Second, there are external validity limitations to using VHA data given that the cohort is predominantly male and of white race. However, this is unlikely to impact the observed associations in this study as there were no significant differences in these variables between patients with and without preoperative visits in the unmatched cohort. Third, a significant proportion of patients in this study had ALD (~30%) and given data limitations we were unable to evaluate the impact of prolonged alcohol abstinence on the postoperative mortality risk in these patients. Fourth, there is potential misclassification of exposure data resulting from administrative coding errors or variable ascertainment algorithms with imperfect diagnostic parameters. We used validated algorithms wherever possible to minimize this bias. Additionally, we would expect this misclassification bias to impact patients with and without preoperative visits similarly, thus representing a non-differential bias with respect to postoperative mortality. Fifth, as our cohort was comprised of patients who underwent surgery, we could not account for patients who were evaluated for surgery but ultimately did not receive it. Based on historic practice our cohort is skewed towards CTP A patients, however our subgroup analysis of patients with CTP B/C cirrhosis suggests that preoperative outpatient visits likely have as much or more impact on postoperative outcomes in these patients. Finally, we did not explore mechanisms of postoperative mortality due to data limitations, nor did we evaluate costs associated with preoperative visits and potential cost savings with reduction in post-operative complications. These are important areas of future research.
In summary, preoperative PCP and/or GI/Hep visits were significantly associated with lower postoperative mortality in patients with cirrhosis undergoing surgery as compared to those without preoperative visits. The greatest risk reduction was found in those with both PCP and GI/Hep preoperative visits, suggesting a potential synergistic effect. Mitigation of operative risk may potentially be mediated through preoperative medication management and paracentesis, in particular in patients with more advanced cirrhosis. This study adds to the growing body of literature emphasizing the benefits of a multidisciplinary approach to managing patients with liver cirrhosis in the preoperative setting.
Supplementary Material
What You Need to Know.
Background:
The impact of preoperative primary care physician (PCP) and/or Gastroenterologist/Hepatologist (GI/Hep) visits on postoperative mortality in cirrhosis patients undergoing surgery remains unclear.
Findings:
Preoperative PCP/GI/Hep visits were associated with a reduced postoperative mortality risk compared to patients without preoperative visits. The greatest risk reduction was in patients with both PCP and GI/Hep visits.
Implications for patient care:
Preoperative visits can improve postoperative outcomes in cirrhosis patients undergoing surgery. There is a possible synergistic effect to seeing both PCP and GI/Hep, highlighting the importance of a multidisciplinary approach.
Acknowledgments
This work was supported by resources and facilities available through the Philadelphia Veterans Affairs Healthcare System as well as the central data repositories maintained by the Veterans Affairs Information Resource Center. The views expressed in this article do not reflect position or policy of the Department of Veterans Affairs of the United States government.
Grant support:
Dr. Kaplan reported receiving grants from the US Department of Veterans Affairs, AstraZeneca, Gillead Sciences, Glycotest, Exact Sciences, and Bayer Healthcare outside the submitted work. Dr. Serper reported receiving grants from the National Institutes of Health (NIH) and personal fees from Gillead Sciences outside the submitted work. Dr. Mahmud reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases (K08-DK124577, R03-DK134794) and investigator-initiated funding from Grifols unrelated to this work.
Abbreviations
- ALD
Alcohol related liver disease
- ASA
American Society of Anesthesiologists
- BMI
Body mass index
- CAD
Coronary Artery Disease
- CI
Confidence interval
- CNS
Central nervous system
- CPT
Current procedure terminology
- CTP
Child-Turcotte-Pugh
- GU
Genitourinary
- HBV
Hepatitis B virus
- HCV
Hepatitis C virus
- HE
Hepatic encephalopathy
- HR
Hazard Ratio
- ICD
International Classification of Diseases
- INR
International normalized ratio
- IQR
Interquartile range
- MASLD
Metabolic dysfunction-associated steatotic liver disease
- MELD
Model for end-stage-liver disease
- MELD-Na
Model for end-stage-liver disease-sodium
- NSBB
Non-selective beta blockers
- NSQIP
National Surgery Quality Improvement Program
- PCP
Primary care physician
- SBP
Spontaneous bacterial prophylaxis
- SHR
Subhazard Ratio
- VASQIP
Veterans Affairs Surgical Quality Improvement Program
- VHA
Veterans Health Administration
- VOCAL
Veterans Outcomes and Costs Associated with Liver Disease
Footnotes
Disclosures: The authors reports no disclosures relevant to the content of this manuscript
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Data Transparency Statement:
Data and study materials will not be made available to other researchers as the data are not publicly available and are maintained by the VHA.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data and study materials will not be made available to other researchers as the data are not publicly available and are maintained by the VHA.