Efficacy of combination terazosin and nifedipine therapy in postoperative treatment of distal ureteral stones after transurethral ureteroscopic lithotripsy.

Introduction

Ureteral stones represent a common urinary system disease with an incidence of approximately 5% to 12% in Europe and the United States, which affects men more frequently than women.[1,2] Many factors contribute to the incidence of ureteral stones, such as metabolic disorder, nutritional mechanisms, levels of calcium salts, and levels of uric acid.[3] Both shock wave lithotripsy and ureteroscopy are common therapeutic methods for the treatment of ureteral stones; many studies have shown successful ureteroscopic lithotripsy outcomes.[4-7] Shock wave lithotripsy reportedly leads to 82% stone-free outcomes for the proximal ureter and 74% stone-free outcomes for the distal ureter.[8]

In addition to surgical methods, several types of medicines are used in treatment of ureteral stones, including allopurinol for uric acid stones and thiols for cystine calculi.[9] Nifedipine is widely used to promote stone discharge.[10] Nifedipine continues to be used for clinical treatment of ureteral stones.[11,12] Several studies have shown that terazosin, an α-receptor antagonist for benign prostatic hyperplasia,[13] can be used to promote stone discharge in treatment of ureteral stones.[14,15] Moreover, terazosin is reportedly safe and effective in treatment of distal ureteral stones, especially stones >5 mm.[16] However, to the best of our knowledge, no studies have focused on combination use of both terazosin and nifedipine in postoperative treatment of ureteral stones after transurethral ureteroscopic lithotripsy.

In the present study, we investigated the effects of combination terazosin and nifedipine therapy on stone discharge rate, discharge time, postoperative pain, and prostatic function. The results of this study may provide clinical evidence to support combination terazosin and nifedipine therapy in treatment of ureteral stones.

Methods and materials

Patients

This prospective single-blinded randomized study enrolled consecutive patients who underwent transurethral ureteroscopic lithotripsy in our hospital from April 2016 to December 2017. All patients who met the following inclusion criteria during the study period were included in the analyses: diagnosis of distal ureteral stones by imaging methods including computed tomography, kidney and upper bladder X-ray, or intravenous pyelography; stone location at the inner wall segment of the ureter and bladder, or near the bladder wall; distance between stone center and ureteral orifice of >3 cm; and sinus disjunction of >3 cm on the affected side. Exclusion criteria were as follows: stone diameter >1 cm; renal insufficiency; bilateral ureteral calculi or multiple ureteral calculi; history of pelvic or ureteral surgery; other diseases of the urinary system (e.g., infection and/or tumor); treatment with an α-receptor antagonist or calcium antagonist within 1 month prior to the study; and/or loss to follow-up during the study. Written informed consent to participate was obtained from all patients. The study protocol was approved by the Ethics Committee of The First Hospital of China Medical University.

Treatment strategy

All patients were randomized divided into three groups by a computer-generated list using SPSS Statistics, version 20.0 (IBM Corp., Armonk, NY, USA): control, terazosin, and combination. For sample size calculation, the formula: was used. Visual Analogue Scale (VAS) score reduction >1 point at 3 days postoperatively was considered effective. Generally, the mean postoperative VAS score has been 4 ± 1.5 in our hospital. Thus, the parameters for the sample size calculation were as follows: δ = 1, s = 1.5, α = 0.05, and β = 0.10; the minimum number of patients per group was 23. All patients underwent transurethral ureteroscopic lithotripsy by the same surgical team, using the same surgical protocol. Briefly, intravertebral anesthesia was induced in all patients by administration of 0.5% bupivacaine 10 mg (Shanghai Hefeng Pharmaceutical Co., Ltd., Shanghai, China). A Wolf 8.0/9.8-F ureteroscope (Richard Wolf, Knittlingen, Germany) was inserted through the urethra into the bladder. A safety guide wire was advanced into the urethra to the location of the stone and a Swiss LithoClast Master (EMS, Nyon, Switzerland) was used to crush the stones to <3 mm. An F14–16 nephrostomy tube (Richard Wolf) was placed and kidney and upper bladder X-rays were conducted to assess the outcome of surgery. A double J stent (Zhangjiagang Huamei Medical equipment Co., Ltd., Zhangjiagang, China) was placed after surgery and removed at 4 weeks postoperatively.

For postoperative treatment and monitoring, all patients were asked to drink 2000 to 3000 mL water each day and were prescribed ciprofloxacin (0.5 g, twice daily; Zhejiang Xinchang Pharmaceutical Co., Ltd, Xinchang, China) for 7 days. In addition, all patients were asked to collect their urine to observe potential stone discharge; kidney and upper bladder X-rays were performed weekly. Patients in the terazosin group were prescribed terazosin (2 mg, once daily; Abbott Laboratories, Lake Bluff, IL, USA) for 7 days. Patients in the combination group were prescribed both terazosin (2 mg, once daily) and nifedipine (10 mg, three times per day; Shanghai Shikangte Pharmaceutical Co., Ltd., Shanghai, China) for 7 days.

Data collection and measurement

Patient characteristics including age, sex, and stone diameter were recorded. The stone discharge rate and time were recorded. VAS scores were used to evaluate pain at 1, 3, 5, and 7 days postoperatively. The International Prostatic Symptoms Score (IPSS) was used to evaluate prostatic function; the quality of life (QOL) score was used to measure patient QOL preoperatively and at 7 days postoperatively. The VAS scores were regarded as the primary outcome; IPSS and QOL scores were regarded as secondary outcomes. Side effects and complications were also recorded. All patients were followed up for 1 month postoperatively.

Statistical analysis

The measurement data are expressed as mean ± standard deviation. Stone discharge rates were compared by chi-squared analysis. Comparisons among the three groups were conducted using one-way analysis of variance, followed by the Tukey post hoc test. Differences with P < 0.05 were considered statistically significant. All calculations were performed using SPSS Statistics, version 20.0.

Results

Baseline patient characteristics

In total, 165 patients were included in this study: control group (n = 55), terazosin group (n = 55), and combination group (n = 55). The patient characteristics are shown in Table 1. The flowchart for patient enrollment is shown in Figure 1. No significant differences were observed in baseline characteristics among the groups of patients.

Table 1.

Baseline characteristics of 165 patients with distal ureteral stones who underwent transurethral ureteroscopic lithotripsy.

Variable	Combined group, n = 55	Terazosin group, n = 55	Control group, n = 55	P
Age, years	43.6 ± 12.9	42.8 ± 12.2	44.2 ± 12.2	0.829
Sex, female (%)	19 (34.5)	17 (30.9)	20 (36.4)	0.706
BMI, kg/m2	21.0 ± 1.7	21.0 ± 1.7	20.8 ± 1.5	0.755
Stone diameter, mm	6.6 ± 2.3	7.2 ± 2.4	6.7 ± 2.4	0.424

Comparisons among three or more groups were conducted using one-way analysis of variance, followed by post hoc Tukey tests for pairwise comparisons. Sex proportions were analyzed using the chi-squared test.

Abbreviation: BMI, body mass index.

Figure 1.

Flowchart for patient enrollment in the study.

Differences in stone discharge rates and times

The stone discharge rate was significantly higher in the combination group than in the terazosin and control groups, while the stone discharge rate was remarkably lower in the control group than in the other groups (P < 0.05, Table 2). The mean discharge time of the combination group was 6.9 ± 2.1 days, dramatically shorter than the times of the other groups; the discharge time was significantly longer in the control group than in the combination and terazosin groups (P < 0.05). These results indicated that combination terazosin and nifedipine therapy could reduce the discharge rates and times after transurethral ureteroscopic lithotripsy in patients with distal ureteral stones.

Table 2.

Stone discharge rates and times among patients with distal ureteral stones who underwent transurethral ureteroscopic lithotripsy.

Variable	Combined group,n = 55	Terazosin group,n = 55	Control group,n = 55
Stone discharge rate, n (%)	52 (94.5)b,c	45 (81.8)a,c	36 (65.5)a,b
Discharge time, days	6.9 ± 2.1b,c	8.3 ± 2.8a,c	10.2 ± 3.0a,b

Stone discharge rates were compared by chi-squared analysis. Discharge times were compared by one-way analysis of variance, followed by the Tukey post hoc test. aP<0.05, compared with the combination group; bP<0.05, compared with the terazosin group; cP<0.05, compared with the control group.

Differences in VAS, IPSS, and QOL scores

To further investigate the efficacy of combination terazosin and nifedipine therapy, the VAS and PISS scores were used to evaluate pain and prostatic function. As shown in Figure 2a–c, beginning at 3 days postoperatively, VAS scores were dramatically lower in the combination group than in the terazosin and control groups (P < 0.05); moreover, the control group had the highest VAS scores (P < 0.05). In addition, both IPSS and QOL scores were significantly lower in the combination group than in the terazosin and control groups (P < 0.05), indicating that combination terazosin and nifedipine therapy could improve postoperative pain and prostatic function after transurethral ureteroscopic lithotripsy in patients with distal ureteral stones.

Figure 2.

(a) VAS scores among patient groups at 1, 3, 5, and 7 days postoperatively. *P<0.05, compared with the terazosin group, #P<0.05, compared with the combination group, &P<0.05, compared with the control group. (b) IPSS and (c) QOL scores among patient groups, preoperatively (Before treatment) and at 7 days postoperatively (After treatment). *P<0.05 between groups, as indicated in the figure.

Abbreviations: IPSS, International Prostatic Symptoms Score; QOL, Quality of Life; VAS, Visual Analogue Scale.

Side effects and complications

Finally, side effects and complications were compared among the groups. Observed side effects included weakness (eight patients), dizziness (six patients), tachycardia (two patients), and gastrointestinal discomfort (four patients). No Clavien–Dindo grade III side effects were observed, and no significant differences were observed among the three groups. In addition, 20 patients showed recurrence of edema; this complication was significantly less frequent in the combination and terazosin groups than in the control group (P < 0.05, Table 3). However, no significant difference was observed between the combination and terazosin groups. These results indicated that combination terazosin and nifedipine therapy reduced the recurrence of edema and did not increase the rate of side effects after transurethral ureteroscopic lithotripsy in patients with distal ureteral stones.

Table 3.

Side effects and complications among patients with distal ureteral stones who underwent transurethral ureteroscopic lithotripsy.

Variable	Combined group,n = 55	Terazosin group,n = 55	Control group,n = 55	P value
Side effect
Weakness	3 (5.5)	4 (7.3)	1 (1.8)
Dizziness	3 (5.5)	2 (3.6)	1 (1.8)
Tachycardia	1 (1.8)	1 (1.8)	0 (0)
Gastrointestinal discomfort	1 (1.8)	1 (1.8)	2 (3.6)
All side effects	8 (14.5)	8 (14.5)	4 (7.3)	0.197
Recurrence of edema	4 (7.3)	5 (9.1)	11 (20.0)	0.012

Note: data are shown as n (%).

Discussion

Treatment of ureteral stones using transurethral ureteroscopic lithotripsy is a common clinical practice.[17] Postoperative treatment is an important consideration for enhancement of surgical efficacy, improvement of patient recovery, and reduction of surgical pain. Both terazosin and nifedipine have been widely used in treatment of many diseases; however, there have been few studies regarding the use of terazosin in treatment of ureteral stones or the use of combination terazosin and nifedipine therapy in postoperative treatment of ureteral stones after transurethral ureteroscopic lithotripsy. To the best of our knowledge, the present study is the first to show that combination terazosin and nifedipine therapy could enhance the stone discharge rate, reduce the stone discharge time, improve postoperative pain and prostatic function, and reduce the recurrence of edema after transurethral ureteroscopic lithotripsy in patients with distal ureteral stones.

In this study, combination terazosin and nifedipine therapy improved patient recovery after transurethral ureteroscopic lithotripsy, consistent with the findings of previous investigations regarding treatment with nifedipine alone. In 2004, Porpiglia et al.[18] reported that nifedipine could be used in treatment of lower ureteral stones. In a subsequent randomized controlled study, Gandhi and Agrawal[19] demonstrated that nifedipine and alfuzosin were effective in treatment of ureteral stones. Cao et al.[20] then reported that tamsulosin was more effective than nifedipine in treatment of patients with ureteral stones. Moreover, combination alfuzosin and nifedipine therapy was reportedly effective as a medical expulsive therapy for distal ureteric stones; this combination therapy could increase the rate of stone expulsion, reduce the rates of pain attacks, and decrease the number of hospital readmissions.[21] However, Gottlieb and Nakitende recently performed a meta-analysis of tamsulosin, nifedipine, and placebo in treatment of ureteric colic; they found that combination tamsulosin and nifedipine therapy was not more effective than placebo in reducing the need for urologic intervention after 4 weeks of treatment among patients with acute ureteric colic.[12] Thus, additional clinical studies are needed to confirm the efficacy of nifedipine in treatment of ureteric stones.

Terazosin has mainly been used in treatment of prostatic diseases. Okada et al.[22] found that terazosin was effective in treatment of symptomatic benign prostatic hyperplasia in Japanese patients. Miyazato et al.[23] also demonstrated that terazosin could improve urine storage function in the spinal cord in rats with spinal cord injury. In 2006, it was reported that terazosin could facilitate the expulsion of lower ureteral stones.[14] However, few studies have since shown clinical evidence for the use of terazosin in treatment of ureteral stones. In the present study, we demonstrated that terazosin could be used in postoperative treatment of ureteral stones; moreover, combination terazosin and nifedipine therapy could provide better efficacy. Nonetheless, the present study had some limitations. First, the sample size was limited in this study and additional patients are needed in future studies. Second, long-term efficacy and side effects have not been established; additional studies are needed to address these aspects.

In conclusion, this prospective study investigated the efficacy of combination terazosin and nifedipine therapy in treatment of distal ureteral stones after transurethral ureteroscopic lithotripsy. The findings demonstrated that terazosin could be used in postoperative treatment of ureteral stones, and that combination terazosin and nifedipine therapy provided better efficacy, enhanced the stone discharge rate, reduced the stone discharge time, and improved both postoperative pain and prostatic function.