Intention to Treat Laparoscopic Versus Open Hemi-Hepatectomy: A Paired Case-Matched Comparison Study.

BACKGROUND: The benefits of laparoscopic hemi-hepatectomy compared to open hemi-hepatectomy are not clear. OBJECTIVE: This study aims to share our experience with the laparoscopic hemi-hepatectomy compared to an open approach. METHODS: A total of 40 consecutive laparoscopically started hemi-hepatectomy (intention-to-treat analysis) cases between August 2012 and October 2015 were matched against open cases using the following criteria: laterality of surgery and pathology (essential criteria); American Society of Anesthesiologists score, body mass index, pre-operative bilirubin, neo-adjuvant chemotherapy, additional procedures, portal vein embolization, and presence of cirrhosis/fibrosis on histology (secondary criteria); age and gender (tertiary criteria). Hand-assisted and extended hemi-hepatectomy cases were excluded from the study. The two groups were compared for blood loss, operative time, hospital stay, morbidity, mortality, and oncological outcomes. All complications were quantified using the Clavien-Dindo classification. RESULTS: Two groups were well matched (p = 1.00). In the two groups, 10 patients had left and 30 had right hemi-hepatectomy. Overall conversion rate was 15%. Median length of hospital and high dependency unit stay was less in the intention to treat laparoscopic hemi-hepatectomy group: 6 versus 8 days, p = 0.025 and 1 versus 2 days, p = 0.07. Median operative time was longer in the intention to treat laparoscopic hemi-hepatectomy group: 420 min (range: 389.5-480) versus 305 min (range: 238.8-348.8; p = 0.001). Intra-operative blood loss was equivalent, but the overall blood transfusions were higher in the intention to treat laparoscopic hemi-hepatectomy (50 vs 29 units, p = 0.36). The overall morbidity (18 vs 20 patients, p = 0.65), mortality (2.5%), and the positive resection margin status were similar (18% vs 21%, p = 0.76). The 1- (87.5% vs 92.5%, p = 0.71) and 3-year survival (70% vs 72.5%, p = 1.00) was also similar. CONCLUSIONS: We observed lower hospital and high dependency unit stay in the laparoscopic group. However, the laparoscopic approach was associated with longer operating time and a non-significant increase in blood transfusion requirements. There was no difference in morbidity, mortality, re-admission rate, and oncological outcomes.

Comparison of risk-scoring systems in the prediction of outcome after liver resection.

BACKGROUND: Risk prediction techniques commonly used in liver surgery include the American Society of Anesthesiologists (ASA) grading, Charlson Comorbidity Index (CCI) and cardiopulmonary exercise tests (CPET). This study compares the utility of these techniques along with the number of segments resected as predictive tools in liver surgery. METHODS: A review of a unit database of patients undergoing liver resection between February 2008 and January 2015 was undertaken. Patient demographics, ASA, CCI and CPET variables were recorded along with resection size. Clavien-Dindo grade III-V complications were used as a composite outcome in analyses. Association between predictive variables and outcome was assessed by univariate and multivariate techniques. RESULTS: One hundred and seventy-two resections in 168 patients were identified. Grade III-V complications occurred after 42 (24.4%) liver resections. In univariate analysis of CPET variables, ventilatory equivalents for CO2 (VEqCO2) was associated with outcome. CCI score, but not ASA grade, was also associated with outcome. In multivariate analysis, the odds ratio of developing grade III-V complications for incremental increases in VEqCO2, CCI and number of liver segments resected were 1.09, 1.49 and 2.94, respectively. CONCLUSIONS: Of the techniques evaluated, resection size provides the simplest and most discriminating predictor of significant complications following liver surgery.

An experimental technique to assess the immunologic consequences of segmental small bowel transplantation.

BACKGROUND: The amount of native small bowel required for adequate nutrition is variable, but lies between 10% and 20% of full length. Currently, for patients requiring small bowel transplantation (SBT), standard practice is to transplant the entire small bowel if space permits. Few experimental studies have addressed the effect of the length of small bowel transplanted on immune responses and in those that have, the amount of mesenteric lymph node (MLN) transplanted has always been a potential confounding factor, as have differences between jejunum and ileum. METHODS: Full-length and segmental heterotopic rat SBT was performed between PVG donor and DA recipients. To transplant reduced length small bowel grafts but to exclude immunologic differences between jejunum and ileum, equal lengths of bowel were resected from proximal and distal ends in the donor. A proportional amount of MLN was carefully dissected using a microvascular technique and then excised. Serial serum samples from the transplant recipients were tested for anti-PVG (rejection) and anti-DA (graft-versus-host) antibodies using a two-color flow cytometric technique, described previously, with the aim of looking for differences in immunologic responses to full and segmental grafts. RESULTS: We have established a model of segmental SBT that includes a proportional amount of MLN and is free from differences between jejunum and ileum. Preliminary data have demonstrated the development of circulating anti-host and anti-graft antibodies with time for both full-length and segmental SBT.

Perioperative analgesia in experimental small bowel transplantation.

BACKGROUND: Despite numerous studies in experimental rat small bowel transplantation (SBT), few authors make reference to perioperative analgesia. Recent changes to the Animals (Scientific Procedures) Act 1986 in the United Kingdom have made the use of analgesia in laboratory animals compulsory because pain is unnecessary in the majority of scientific procedures. METHODS: Heterotopic SBT (PVG-->DA) was performed on male rat recipients weighing 220 to 250 mg under isoflurane with a mean anesthetic time of 100 minutes. Recovery from anesthesia was usually within 15 minutes. Analgesia regimens were based on those in common use for other procedures. All drugs were administered in the 30 minutes prior to recovery from anesthesia. Group A received carprofen (2 mg/kg IM or SC). Group B was given buprenorphine (0.05 mg/kg either IM or SC). Group C received paracetamol (10- 30 mg) rectally. An early postoperative scoring system of four criteria was used, giving a maximum (least desirable) score of 16. Sixty transplants were performed, divided between the three groups. RESULTS: In group A animals scored a median of 1 of 16 but all except three recipients died within 3 hours. Those in group B scored a median of 8 of 16, but all animals except one died between 4 to 16 hours after surgery. Group C had a median score of 11 of 16, but there was no early mortality. Postmortem examination excluded technical failures in all but three animals. CONCLUSION: We recommend the use of paracetamol for perioperative analgesia in SBT because of the high mortality associated with other drugs when used in this procedure.

The pre-operative rate of growth of colorectal metastases in patients selected for liver resection does not influence post-operative disease-free survival.

AIMS: To assess the potential association between the change in diameter of colorectal liver metastases between pre-operative imaging and liver resection and disease-free survival in patients who do not receive pre-operative liver-directed chemotherapy. MATERIALS AND METHODS: Analysis of a prospectively maintained database of patients undergoing liver resection for colorectal liver metastases between 2005 and 2012 was undertaken. Change in tumour size was assessed by comparing the maximum tumour diameter at radiological diagnosis determined by imaging and the maximum tumour diameter measured at examination of the resected specimen in 157 patients. RESULTS: The median interval from first scan to surgery was 99 days and the median increase in tumour diameter in this interval was 38%, equivalent to a tumour doubling time (DT) of 47 days. Tumour DT prior to liver resection was longer in patients with T1 primary tumours (119 days) than T2-4 tumours (44 days) and shorter in patients undergoing repeat surgery for intra-hepatic recurrence (33 days) than before primary resection (49 days). The median disease-free survival of the whole cohort was 1.57 years (0.2-7.3) and multivariate analysis revealed no association between tumour DT prior to surgery and disease-free survival. CONCLUSIONS: The rate of growth of colorectal liver metastases prior to surgery should not be used as a prognostic factor when considering the role of resection.

Short- and long-term efficacy of nicardipine, assessed by placebo-controlled single- and double-blind crossover trials in patients with chronic stable angina.

The efficacy of nicardipine, a new calcium ion antagonist, was studied in 39 patients aged 42 to 70 years with chronic stable angina in two different placebo-controlled single- and double-blind crossover trials and with long-term follow-up, using serial quantitated exercise testing and ambulatory ST segment monitoring. In the first study the minimal effective dose was determined, and in the repeat study the effects of three different dose levels were evaluated. Treadmill exercise testing was performed at the end of each 2 week treatment period with on-line computer analysis of the electrocardiogram. The mean (+/- standard error of the mean) exercise time was 6.8 +/- 0.7 minutes on placebo and 7.0 +/- 0.8 minutes during treatment with nicardipine, 60 mg/day (p = NS). This increased to 8.7 +/- 0.8 (p less than 0.001) and 9.2 +/- 0.9 minutes (p less than 0.001) with 90 and 120 mg/day, respectively. The mean heart rate at rest during placebo administration was 75 +/- 2 beats/min and increased to 85 +/- 3, 84 +/- 2 and 88 +/- 3 beats/min (p less than 0.02, p less than 0.01, p less than 0.01, respectively) at each dose level. The time taken to develop 1 mm of ST segment depression was prolonged from 4.8 +/- 0.6 minutes during placebo administration to 5.3 +/- 0.7 (p = NS), 6.4 +/- 0.7 (p less than 0.01) and 6.7 +/- 0.8 minutes (p less than 0.001), respectively, at each dose level. The improvement achieved after 2 weeks of nicardipine, 120 mg daily, was maintained over a period of 6 months of follow-up. Three patients were withdrawn, one taking 60 mg of nicardipine, one taking 90 mg of nicardipine and one taking placebo, but the overall incidence of side effects was low. Nicardipine is an effective antianginal agent with an optimal dose of 90 to 120 mg/day.

Objective evaluation of three dose levels of diltiazem in patients with chronic stable angina.

Twenty-one patients with chronic stable angina were treated with the calcium antagonist diltiazem. Dose titration studies involving 180, 270 and 360 mg/day were conducted using a blinded objective protocol. Improvement in exercise tolerance was observed at all dose levels, but the best reduction of anginal attacks and glyceryl trinitrate consumption, enhancement of exercise capacity and improvement of objective ischemic variables were observed with the 360 mg/day dose. The mean exercise time to produce grade II angina on treadmill walking increased from 5.6 +/- 0.7 minutes on placebo to 7.9 +/- 0.8 minutes on diltiazem 180 mg/day (probability [p] less than 0.001), 8.0 +/- 0.8 minutes on 270 mg/day and 9.5 +/- 0.9 minutes on 360 mg/day (p less than 0.001 as compared with 270 mg/day). One patient was withdrawn at the 360 mg/day dosage because of pedal edema. The 24 hour Holter monitoring data confirmed the findings on exercise testing, and left ventricular function was not altered with any dose level. Diltiazem in doses ranging from 180 to 360 mg/day is another powerful antianginal agent in the calcium antagonist group producing excellent therapeutic benefit in chronic stable angina with no adverse effects on left ventricular function.

Anti-interleukin 2 receptor antibodies and mycophenolate mofetil for treatment of steroid-resistant rejection in adult liver transplantation.

BACKGROUND: Steroid-resistant rejection (SRR) results in significant morbidity and mortality from the adverse effects of rescue therapy and in graft loss from chronic rejection. In our knowledge, the efficacy and safety of anti-interleukin (IL) 2r antibodies (daclizumab and basiliximab) for the treatment of SRR in adult liver transplantation has not previously been evaluated. METHODS: Twenty-five patients received either daclizumab or basiliximab as rescue therapy for SRR. Outcome and biochemical parameters were recorded before and after treatment with an anti-IL-2r antibody. RESULTS: The median time from transplantation to SRR was 25 days. Secondary immunosuppression included mycophenolate mofetil in 18 patients. Twelve patients (48%) had complete resolution of SRR. Aspartate transaminase levels normalized at a median of 37 days (range, 1-168 days). In 13 patients (52%) progressive hepatic dysfunction developed. Four of these patients received another transplant, and 6 patients had chronic rejection. Three patients died with graft failure. Of 16 patients with acute cellular rejection, 12 (75%) had resolution, 2 had chronic rejection, 1 required a repeat transplantation, and 1 died with graft failure. In contrast, all 9 patients with established chronic rejection in their pretreatment biopsy continued to have significant graft dysfunction, with 4 having persistent chronic graft dysfunction, 3 requiring repeat transplantation, and 2 dying with graft failure. CONCLUSION: Twelve (48%) of 25 patients who received an anti-IL-2r antibody because of SRR were successfully treated. All successfully treated patients had ongoing acute cellular rejection at liver biopsy (75%), whereas patients with histologic evidence of chronic rejection responded poorly.

Development of an enzyme immunoassay for rat soluble interleukin-2 receptors.

This study describes the development of a sandwich enzyme immunoassay (ELISA) for rat soluble IL-2 receptors (sIL-2R) using a combination of monoclonal antibodies reactive with different epitopes on the rat IL-2R. Coating plates with NDS61 and NDS64 monoclonal antibodies produced similar dose-response curves when incubated with a standard sIL-2R preparation followed by biotinylated OX39, streptavidin-alkaline phosphatase and the substrate. Although normal rat serum inhibited the assay, the effects were more profound when NDS64 was used as the capture antibody and subsequent development of the assay was performed using NDS61. The intra- and interassay variations were typically less than 5%. This assay will be valuable for monitoring immune activation status in a variety of experimental models.

Induction of antigraft and antirecipient antibody responses after fully allogeneic and semiallogeneic rat small bowel transplantation.

BACKGROUND: Given the potential influence of alloantibodies on organ graft outcome, this study investigated the induction of antigraft and antirecipient antibodies after allogeneic and semiallogeneic rat small bowel transplantation. METHODS: Fully allogeneic, unidirectional rejection and unidirectional graft-versus-host disease (GvHD) heterotopic small bowel transplantation was performed using DA, PVG, and (PVGxDA)F1 donor-recipient combinations. Serum was obtained before and at time points after transplantation and incubated with blood from untransplanted DA and PVG rats. Antibody binding to T cells was detected by whole blood flow cytometry using FITC-conjugated anti-rat IgM murine monoclonal antibody. Antibody levels were determined by reference to a standard curve of fluorescent intensity generated using a serum sample with known anti-target cell IgM activity. Data are presented as arbitrary units/ml (AU/ml). RESULTS: In the PVG-->DA combination, five of six DA recipients had detectable anti-graft (PVG) antibodies by day 4 after transplantation (mean 72 AU/ml) and all animals were positive by day 6 (976 AU/ml). Antirecipient (DA) antibodies were also induced, however, they were only apparent after 6 days in five of eight animals (90 AU/ml). Antigraft (DA) antibody responses were also induced in the DA-->PVG combination (day 6-218 AU/ml), however no antirecipient (PVG) response was apparent. Transplantation induced antirecipient (DA) antibodies in the unidirectional GvHD model (day 6-90 AU/ml) and an anti-graft (PVG) response in the unidirectional rejection model (day 6-60 AU/ml). However, the latter was quantitatively lower than that generated in the PVG-->DA combination (day 6-976 AU/ml). CONCLUSIONS: Antigraft and antirecipient antibody responses are simultaneously induced after fully allogeneic small bowel transplantation, despite rejection being the predominant clinical feature. Further studies are required to elucidate their influence on graft outcome.

Antimurine immunoglobulin antibody responses after the administration of murine monoclonal antibodies to rats are altered by small bowel allograft rejection.

BACKGROUND: This study monitored the induction of antimurine immunoglobulin antibody responses after the administration of anti-CD4 (OX38) and anti-LFA-1 (WT.1) monoclonal antibodies to DA rats. METHODS: Monoclonal antibody was administered i.v. on 3 consecutive days to untransplanted DA rats, and DA recipients of PVG small bowel allografts. Control animals received no monoclonal antibody. Antimurine immunoglobulin antibody levels in serum samples were determined by enzyme immunoassay. RESULTS: No antimurine immunoglobulin antibody was detected in untransplanted animals receiving OX38 alone. Reactivity was apparent in WT.1-treated animals, but this response was totally abrogated by the co-administration of OX38. A combination of OX38 and WT.1 had no effect on allograft recipient survival and antimurine immunoglobulin antibody responses were detected in all allograft recipients, irrespective of the treatment regimen. CONCLUSIONS: Although OX38 inhibited the antibody response both to itself and to WT.1 in untransplanted animals, the immune reaction induced by small bowel allograft rejection overcame this inhibitory capacity.

Activation antigen expression on peripheral blood neutrophils following rat small bowel transplantation. NKR-P1 is a novel antigen preferentially expressed during allograft rejection.

This study used flow cytometric analyses to monitor activation antigen expression (MHC class II; interleukin-2 receptor, p55IL-2R and 3.2.3/NKR-P1 antigen) on peripheral blood neutrophils following rat small bowel transplantation. The rat 3.2.3 antigen is a member of the NKR-P1 family of natural killer (NK) cell-associated molecules, which are expressed at high levels on NK cells and lymphokine-activated killer cells, and low levels on at least one T cell subset. Peripheral blood neutrophils in normal animals express very low or undetectable levels of NKR-P1. Detectable levels of NKR-P1 were induced as early as day 1 following small bowel transplantation in all allografted animals, whereas expression was only rarely detected in isografted animals. In addition, NKR-P1 density was significantly higher in allografted animals and was maintained as rejection developed. MHC class II and p55IL-2R expression was also induced following transplantation. The mechanisms of induction and functional relevance of NKR-P1 expression on neutrophils remain to be defined. However, the concomitant increased expression of MHC class II and p55IL-2R suggest NKR-P1 to be a neutrophil activation marker and implicate a potential role for NKR-P1+ neutrophils in small bowel allograft rejection. This hypothesis is further supported by the loss of detectable peripheral blood neutrophils only with developing rejection. Flow cytometric analysis of neutrophil activation antigen expression may be useful for monitoring human small bowel transplant recipients.

Combined therapy with verapamil and propranolol in chronic stable angina.

The comparative efficacy of verapamil (360 mg daily) and propranolol (240 mg daily) was evaluated with computerized treadmill exercise in 22 patients with chronic stable angina in a placebo-controlled double-blind crossover study with 4 weeks on each active phase. Fourteen of these patients still had angina despite active drug therapy and they were further treated with a combination of verapamil (360 mg) and propranolol (120 mg) for 4 weeks. The mean exercise time for these patients taking placebo was 4.8 +/- 0.22 minutes (mean +/- standard error of the mean) and this increased to 6.8 +/- 0.64 minutes with propranolol and 8.0 +/- 0.5 minutes with verapamil. A further increase to 10.1 +/- 0.88 minutes was observed with the combination of both drugs and seven patients became symptom-free. S-T segment criteria improved with both drugs, and combination therapy produced a further reduction in peak S-T depression. Electrocardiographic ambulatory monitoring showed no evidence of conduction defects and mean hourly heart rates were similar to those seen with propranolol alone. Left ventricular function indexes were not significantly different from those obtained with propranolol. Combination therapy with verapamil and propranolol appears to be efficacious in the treatment of selected patients with severe chronic stable angina. The patients need to be carefully monitored for adverse effects.

Does placebo improve indexes of effort-induced myocardial ischemia? An objective study in 150 patients with chronic stable angina pectoris.

The effects of placebo were studied in 150 patients (135 men, 15 women) aged 42 to 75 years with stable exertional angina pectoris, using multistage graded exercise testing. Treadmill exercise, using on-line computer analysis of the electrocardiogram, was performed after a basal period, during which time the patients had no treatment for 2 weeks, and after 2 weeks of placebo therapy. Mean exercise time during no treatment was 6.0 +/- 0.2 minutes and during placebo was 6.1 +/- 0.2 minutes (difference not significant). Similarly, time to development of 1 mm of ST-segment depression of 4.0 +/- 0.2 minutes without treatment was 4.1 +/- 0.2 minutes after 2 weeks of placebo therapy (difference not significant). Placebo failed to show any effect on rest or maximal heart rate or on maximal ST-segment depression. It also failed to increase exercise tolerance or to improve other objective indexes of effort-induced myocardial ischemia in both single-and double-blind protocols in patients with stable exertional angina pectoris. Therefore, placebo control of antianginal drug trials that use exercise testing for evaluation of effect is unnecessary and can be omitted.

Usefulness of bevantolol for chronic, stable angina pectoris.

An objective assessment of the efficacy of bevantolol was performed in 21 patients with chronic, stable angina using computer-assisted exercise testing and ambulatory ST-segment monitoring. Given once daily, 200 mg of bevantolol was compared with 200 mg of bevantolol given twice daily and with placebo, using a double-blind crossover technique. The mean exercise time with placebo was 7.4 +/- 0.6 minutes; this increased to 10.6 +/- 0.9 minutes (p less than 0.001) with once-daily bevantolol and to 9.4 +/- 0.9 minutes (p less than 0.001) with twice-daily bevantolol. The mean heart rate at rest was 80 +/- 3 beats/min with placebo; it decreased to 63 +/- 2 beats/min (p less than 0.001) with once-daily bevantolol and to 66 +/- 2 beats/min (p less than 0.001) with twice-daily bevantolol. The maximum exercise heart rate of 118 +/- 6 beats/min with placebo was reduced to 99 +/- 4 beats/min (p less than 0.001) on once-daily and 101 +/- 4 beats/min (p less than 0.001) on twice-daily bevantolol. There was a corresponding decrease in the rate-pressure product. The corrected maximum ST-segment depression was reduced from 0.3 +/- 0.06 mm min-1 with placebo to 0.2 +/- 0.03 mm min-1 (p less than 0.02) with once-daily and 0.2 +/- 0.04 mm min-1 (p less than 0.05) with twice-daily bevantolol. The mean hourly ambulatory heart rate was significantly reduced for 21 hours with once-daily and 22 hours with twice-daily bevantolol. The lowest mean minimum heart rate was 55 beats/min during twice-daily treatment. The mean number of episodes of ST depression over 24 hours in lead CM5 was decreased from 6.89 +/- 1.7 with placebo to 2.50 +/- 0.6 (p less than 0.001) with once-daily and to 3.72 +/- 1.3 (p less than 0.001) with twice-daily bevantolol. Three patients were withdrawn during the once-daily bevantolol regimen due to adverse experiences, and another patient was admitted for coronary artery bypass surgery after 25 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized double-blind comparison of gallopamil and propranolol in stable angina pectoris.

A new calcium ion antagonist, gallopamil, 150 mg/day, was compared with propranolol, 240 mg/day, in 20 patients with stable chronic angina. The patients were studied in a randomized, placebo-controlled, double-blind, crossover trial. Multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and at the end of each 4-week active treatment period. The mean (+/- standard error of the mean) exercise time to development of angina was 5.4 +/- 0.3 minutes with placebo; this increased to 9.4 +/- 0.7 minutes with propranolol (p less than 0.001) and 10.1 +/- 0.7 minutes with gallopamil (p less than 0.001 vs placebo; difference not significant vs propranolol). Both drugs significantly prolonged the time to development of 1 mm of ST depression. Five patients became free of angina during treadmill testing with gallopamil therapy and 2 with propranolol. Both drugs decreased the heart rate at rest; propranolol also decreased the maximal exercise heart rate, which was slightly increased with gallopamil. With the exception of 1 patient in whom raised liver enzymes developed, gallopamil was well tolerated. Thus, gallopamil is an effective antianginal agent that has few of the unwanted effects associated with other calcium channel-blocking drugs.

Long-term efficacy of diltiazem assessed with multistage graded exercise tests in patients with chronic stable angina pectoris.

The long-term efficacy of diltiazem, 360 mg/day, in patients with grade II or III stable exertional angina pectoris (Canadian Cardiovascular Society criteria) was assessed by multistage graded exercise tests. Seventeen patients undertook a placebo-controlled, double-blind, dose-titration protocol and all received long-term therapy. Exercise tests were performed at the end of 2 weeks of placebo treatment and after 6, 18, 26, 40 and 52 weeks of diltiazem, 360 mg/day. All patients had angina during treadmill testing with placebo and the mean (+/- standard error of the mean) exercise time was 5.8 +/- 0.7 minutes. This increased to 10.8 +/- 1.0 minutes after 6 weeks, 11.3 +/- 1.1 minutes after 18 weeks, 11.4 +/- 1.1 minutes after 26 weeks, 12.9 +/- 1.2 minutes after 40 weeks and 11.6 +/- 1.3 minutes after 52 weeks of continuous diltiazem therapy (p less than 0.001 vs placebo at all stages). Four patients were withdrawn after 26 weeks of treatment; one patient underwent coronary artery bypass surgery and 3 patients required the addition of beta-adrenoreceptor blocking agents. In 1 patient an irritant rash developed on the torso, legs and arms after 39 weeks of diltiazem and disappeared after discontinuing the drug. One patient complained of swelling and stiffness of the fingers and 3 patients complained of shoulder and elbow pain. Another patient had a myocardial infarction after 8 weeks of diltiazem treatment and died. No other adverse effects were observed during this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized double-blind comparison of verapamil and nifedipine in chronic stable angina.

A randomized double-blind crossover trial was performed in 32 patients with chronic stable angina to compare the antianginal actions of verapamil (120 mg 3 times daily) and nifedipine (20 mg 3 times daily). Efficacy was assessed using objective end points obtained by computer-assisted exercise testing and 24 hour ambulatory monitoring for S-T segment shift. Twenty-eight patients completed the trial. The mean exercise time to produce angina improved from 5.7 +/- 0.3 minutes (mean +/- standard error of the mean) in patients on placebo, to 7.9 +/- 0.5 minutes in those on nifedipine and 10.0 +/- 0.7 minutes in those on verapamil. Similar improvement was seen in all other objective variables. Generally verapamil produced mild bradycardia and nifedipine mild tachycardia. Four patients complained of palpitations and angina after ingestion of nifedipine and were identified by ambulatory monitoring to have tachycardia and persistent S-T depression. These opposite effects on heart rate may explain the differences in efficacy between these 2 potent calcium ion antagonists.

Rationale for the choice of calcium antagonists in chronic stable angina. An objective double-blind placebo-controlled comparison of nifedipine and verapamil.

The effectiveness and safety of verapamil, nifedipine, and placebo in patients with chronic stable angina pectoris were evaluated and compared in two double-blind randomized crossover trials. In the first study, nifedipine (10 mg 3 times daily) was compared with placebo in 24 patients with chronic effort-related angina pectoris; no significant differences in exercise performance were observed with nifedipine compared with placebo. In the second study, the effects of verapamil (120 mg 3 times daily), nifedipine (20 mg 3 times daily), and placebo were compared in 32 patients with chronic stable angina using a double-blind crossover study design. Compared with placebo, both nifedipine and verapamil prolonged exercise duration (5.7 +/- 0.3 minutes with placebo, 7.9 +/- 0.5 minutes with nifedipine [p less than 0.001], and 10.0 +/- 0.7 minutes with verapamil [p less than 0.001]), but the improvement with verapamil was greater than that seen with nifedipine (p less than 0.01). Seven patients had increasing angina with nifedipine, none did with verapamil; the exacerbation of angina during nifedipine therapy appeared related to our observation that, compared with placebo, patients receiving nifedipine had higher heart rates, while patients receiving verapamil had slower heart rates. This study indicates that, at the doses used, verapamil was more effective and better tolerated than nifedipine in patients with chronic stable angina pectoris.

Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind placebo-controlled comparison of verapamil and propranolol.

The effectiveness and safety of the beta-adrenergic blocking agent propranolol and the calcium channel antagonist verapamil were compared in 22 patients with chronic stable angina pectoris using a double-blind randomized placebo-controlled crossover protocol. The double-blind phase was preceded by a 2 week single-blind placebo period, followed by randomization to either 4 weeks' therapy with verapamil, 360 mg/day, or propranolol, 240 mg/day, followed by crossover to the other drug. Both verapamil and propranolol increased exercise tolerance (5.5 +/- 0.4 minutes with placebo, 7.8 +/- 0.5 minutes with propranolol [p less than 0.001], and 9.1 +/- 0.5 minutes with verapamil [p less than 0.001]), but the increase with verapamil was significantly greater (p less than 0.01). Both drugs prolonged the exercise duration to 1 mm S-T depression (3.3 +/- 0.4 minutes with placebo, 5.7 +/- 0.5 minutes with propranolol [p less than 0.001] and 5.5 +/- 0.6 minutes with verapamil [p less than 0.001]); the degree of improvement was similar with both active drugs. Both drugs decreased the resting heart rate (76 +/- 3 beats/min with placebo, 56 +/- 2 beats/min with propranolol [p less than 0.001], and 71 +/- 3 beats/min with verapamil [p less than 0.01]), but the heart rate decreased more with propranolol than with verapamil (p less than 0.001). Neither drug produced significant adverse reactions. This study, along with 8 similar double-blind placebo-controlled randomized investigations which have compared verapamil with propranolol, indicate that verapamil is as effective and safe as propranolol in relieving symptoms and improving exercise tolerance in patients with chronic stable angina pectoris and may be considered a first-line therapeutic agent in patients with ischemic heart disease.