Short-term vasoactive agent treatment driven by physicians’ preference in acute esophageal variceal bleeding in a tertiary center

Background

Rupture of esophageal varices that results in variceal hemorrhage is a major complication associated with high mortality rate (Garceau & Chalmers, 1963; Graham & Smith, 1981). Despite initial control of bleeding, early rebleeding rate may be as high as 30–50% among the survived patients and the mortality rate can be up to 40% (Garcia-Tsao et al., 2007). Therefore, it is recommended that treatment goals should aim for bleeding arrest and prevention of early rebleeding (D’Amico, Pagliaro & Bosch, 1995).

Vasoactive drugs may reduce portal hypertension which lead to a reduction in variceal pressure to achieve better control of hemorrhage (Garcia-Pagan et al., 1999; Villanueva et al., 2001). In general, vasoactive agents including somatostatin and terlipressin were highly effective in control of variceal bleeding if compared to the placebo (D’Amico, Pagliaro & Bosch, 1999). On the other hand, the efficacy of somatostatin for early rebleeding control has been reported to be similar to terlipressin (D’Amico, Pagliaro & Bosch, 1999; Burroughs et al., 1990; Cales et al., 2001; Chen et al., 2006; Feu et al., 1996; Levacher et al., 1995). In suspected acute variceal bleeding (EVB), vasoactive drugs should be started as soon as possible and are generally prescribed for 5 days to prevent against very early rebleeding (Lo, 2010; De Franchis, 2005). Endoscopic variceal ligation (EVL) is recommended in patients with EVB and is best used in combination with vasoactive drugs according to the Baveno IV consensus. Short-course administration (2-day or 3-day) of vasoactive drugs have been shown to be as effective as a 5-day course for the control of acute EVB when used as an adjuvant therapy to EVL (Chitapanarux et al., 2015; Rengasamy et al., 2015).

The management of acute EVB in real-world clinical practice may be different from clinical trials or from available guidelines. In Taiwan, the National Health Insurance (NHI) program uses a single-payer system and covers 99.9% of the nation’s population and therefore provides their physicians a high degree of freedom in their choice of medications (Li et al., 2015). The Taiwan NHI program approves short-course (3 days) administration of any two vasoactive drugs i.e., somatostatin or terlipressin in treating acute EBV. The aim of study was to assess the physicians’ preference of vasoactive agents, their reasons of preference and efficacy and safety of short-course regimen of these agents in the real-world clinical practice.

Methods

Results

Of the 352 patients screened, 202 patients were excluded owing to HCC BCLC ≥ C (n = 43), >80 or <20 years old (n = 32), other malignancies (n = 17), uremia (n = 14), prior TIPS (n = 9), prior EIS or EVL (n = 42), pregnancy (n = 1) and refusal to participate (n = 44). Finally, a total of 150 patients were enrolled in the trial, with 41 in group S and 109 in group T (Fig. 1).

The baseline demographic characteristics including gender, age, etiology of cirrhosis, symptoms, Child Pugh’s scores and MELD scores were comparable in both treatment groups, all P > 0.05 (Table 1). Likewise, the endoscopic findings were not different in terms of variceal size, red color signs and presence of gastric varix and portal hypertensive gastropathy between the two study groups (Table 1).

Convenient administration (77.1%, n = 84) followed by a good safety profile (13.8%, n = 15) were the main reasons for physician drug choice in group T (Fig. 2). On the other hand, good safety profile (73.2%, n = 30) was a major consideration for physicians in group S. Inconvenient administration (4.9%, n = 2) was a major limitation for physician choice in group S.

Main clinical treatment results and adverse events are shown in Table 2. No participants were lost during follow up. Only one patient in each study group was considered as treatment failure as per definition. Very early rebleeding within 49–120 h occurred in one patient in each group (p = 0.469). Four patients (10.0%) in group S and 14 patients (13.0%) in group T had EV rebleeding episodes within 6–42 d (p = 0.781). No significant differences were observed in 6-week mortality rate (9.8% vs. 12.8%, p = 0.419), blood transfusion (4.6 ± 5.7 vs. 4.0 ± 3.6 units, p = 0.421) and hospital stay (8.1 ± 2.8 vs. 8.9 ± 4.0 days, p = 0.240).

Overall adverse events were classified into two subgroups, either vasoactive agent-related or EVL-associated (Table 2). In the former subgroup, chest tightness/pain (14.6% vs. 21.1%), hypertension (12.2% vs. 23.9%), abdominal pain (4.9 vs. 11.0%), arrhythmia (2.4% vs. 3.7%), lymphangitis (0% vs. 5.5%), hyperglycemia (4.9% vs. 3.7%) and flushing (2.4% vs. 2.8%) were comparable in both groups S and T. Patients in group S vs. group T had shown a trend of having more renal failure (group S: 9.8% vs. group T: 2.8%, p = 0.089) but group T vs. group S had shown a trend towards more hyponatremia (group S: 4.9% vs. group T: 16.5%, p = 0.103). In the later subgroup, all the EVL-associated symptoms, such as chest tightness/pain (group S: 14.6% vs. group T: 21.1%), retrosternal pain (12.2% vs. 16.5%), dysphagia/odynophagia (2.4% vs. 1.8%), post-EVL ulcer (9.8% vs. 11.9%) and esophageal stricture (0% vs. 0%) were similar between groups S and T (all P values >0.05).

Discussion

Rebleeding is a major determinant of poor outcome following initial control of acute EVB. Nowadays, combined pharmacological and endoscopic therapy is key to management of acute EVB in real-world clinical practice. Vasoactive drug therapy should be given as soon as possible and ideally before endoscopy. A few studies have been conducted thus far that compares the efficacy of terlipressin vs. somatostatin vs. octreotide in acute EBV with a short infusion duration of 3 days up to 5 days (Seo et al., 2014; Abid et al., 2009). The current study shows that a 3-day terlipressin treatment was as effective as a 3-day somatostatin treatment in controlling initial bleeding but also preventing early rebleeding. Besides, we have demonstrated that most clinicians would choose terlipressin over somatostatin because of convenience. However, safety profile was a major consideration of physicians who preferred somatostatin.

Most guidelines, including the Baveno IV guidelines, have suggested the use of vasoactive agents for 2–5 days (De Franchis, 2005; Farooqi et al., 2007). The most recent Baveno VI guidelines recommended a 5-day use of vasoactive agents (De Franchis, 2015). However, the optimal duration for the use of vasoactive agents in acute EVB remains inconclusive thus far. Previous clinical trials have shown that three days of somatostatin and two days of octreotide were not inferior to five days of both drugs in preventing early rebleeding (Rengasamy et al., 2015; Li et al., 2015). On the other hand, early administration of vasoactive agents especially the first two days of acute EVB is probably preferred. This is because of a greater increase of portal pressure after acute EVB as observed by Avgerinos A et al. with subsequent return to pretreatment level after the first two days after EVB (Avgerinos et al., 2004). In Taiwan, all patients with acute EVB would be given a 3-day course of vasoactive agents because this is the maximal duration that is fully covered by the NHI system. However, the current study showed that despite giving a shorter 3-day course it did not affect initial hemostatic control and also early rebleeding. Our findings support the Avgerinos observation that control of portal pressure for the first two days is most important.

The most recent meta-analysis did not show a difference with either vasopressin/terlipressin or somatostatin/octreotide in the prevention of very early rebleeding and early rebleeding (Wang et al., 2015). The 5-day variceal rebleeding rates of our current study were 0.9% in group T and 2.5% in group S, and these rates were similarly to previous studies (Seo et al., 2014; Wang et al., 2015). However, very early rebleeding rate was lower in our study if compared to Seo et al. (2014) despite a shorter duration (3-day vs. 5-day) of therapy. Two probable reasons may explain this difference. First, the recruitment of patients with gastric variceal bleeding may result in a higher very early rebleeding rate because the treatment success of gastroesophageal varices type 2 and isolated gastric varices was known to be lower compared to esophageal varices and gastroesophageal varices type 1, i.e., 55–87% versus 88–91% respectively (Seo et al., 2014). Secondly, the treatment effect of EVL is far more prominent than vasoactive agents if both are used in combination (Lo et al., 2009; Kumar et al., 2015).

Terlipressin is currently the only drug that has been shown to have survival benefit with a 34% relative risk reduction in mortality, unlike somatostatin (Lo, 2010; Ioannou, Doust & Rockey, 2003; Abraldes & Bosch, 2002). It is for this reason that terlipressin is considered as the first choice based on a number of expert opinions (Abraldes & Bosch, 2002; Dell’Era, De Franchis & Iannuzzi, 2008). Besides that, a randomized trial from the South Korea had reported that the effect of terlipressin in reducing portal hypertension was more sustained compared to octreotide (Baik et al., 2005). Furthermore, when compared with somatostatin, terlipressin has been shown to improve thoracic blood volume, liver reserve blood volume and also improve the hyperdynamic state in cirrhosis (Kalambokis et al., 2010). These effects are particularly beneficial in patients with advanced liver diseases and acute EVB episode. Indirect evidence suggested that terlipressin might prevent hemorrhage-induced renal impairment, and its liver protection effect has been reported in cases of septic shock in an animal model (Moreau et al., 2002).

A global study found that 55% of physicians preferred terlipressin compared to 38% who favored octreotide (p < 0.001)  (Rahimi, Guntipalli & Rockey, 2014). Approximately two-thirds of the patients were prescribed with terlipressin in our current study. Noticeably, the current unavailability of terlipressin is the issue of why most physicians worldwide do not prescribe it, and overall 93% of those physicians would have like to use it if it is readily offered, particularly in the North America  (Rahimi, Guntipalli & Rockey, 2014). The actual reason why physicians were more willing to use terlipresin in the global study is unclear and our study aimed to address this.

Convenience of administration was the main consideration by our clinicians who chose terlipressin in the current study. Terlipressin infusion using slow intravenous push every 6 hourly is relatively easier and is more favored by nurses if compared to continuous infusion with somatostatin. Conversely, side effects of terlipressin may be an issue in daily clinical practice of physicians (approximately one third had side effects in the current study). Terlipressin two mg every four hours in the first 1–2 days followed by one mg for the following 2–5 day is the current recommendation, whereas the two mg bolus injection followed by one mg infusion every six hours in our current protocol resulted in a lower total dosage given but with comparable efficacy and less side effects (Augustin, Gonzalez & Genesca, 2010).

The safety profile is a top priority of clinicians who chose somatostatin. For patients with ischemic heart diseases or uncontrolled hypertension, somatostatin may be a good alternative to terlipressin. Somatostatin has the advantage of having lesser side-effects including hypertension and hyponatremia. A previous study also showed that compared to terlipressin, somatostatin had fewer side effects (21% vs. 29%, not statistically significant (D’Amico, Pagliaro & Bosch, 1999).

Comparing the costs of drugs for the duration of three days, the total cost of terlipressin and somatostatin were USD 621.32 and USD 496.43 respectively. An additional USD 124.89 or 20% of expenditures are needed for terlipressin. The cost factor may be neglected by clinicians in real-world medical practice because expenditure of both drugs is fully subsidized by the health care plan in Taiwan. Therefore, convenience of use outweighs the cost factor in real world in Taiwan.

There were limitations in our study. Firstly, selection bias might exist in both treatment groups due to clinicians’ preference of one drug over the other although this reflects the real-world clinical practice. Secondly, although a single institution study might not reflect the practice of other institutions in Taiwan but the similar NHI program implemented country-wide provided some consistencies in management across different institutions. Lastly, referral bias might occur in any tertiary referral centers where only patients with a greater tendency to stop bleeding spontaneously were able to arrive at the tertiary hospital.

Conclusion

In real-world clinical practice, most of the physicians preferred terlipressin over somatostatin because of convenience in administration although terlipressin is more expensive and its safety remains a concern. Yet, the efficacy on hemostasis and safety does not seem to differ significantly between patients with acute EVB who received short three-day course of either somatostatin or terlipressin as an adjuvant to EVL.

Supplemental Information