Open-label Randomized Trial Research Articles

An open-label randomized trial comparing addition of olanzapine 5 mg versus olanzapine 10 mg as anti-emetic to standard anti-emetic regime for doxorubicin or epirubicin and cyclophosphamide in breast cancer.

e12531 Background: Chemotherapy-induced nausea and vomiting (CINV) is an important therapy related side effects in the treatment of malignancies. Breast cancer patients receive a highly-emetogenic chemotherapy with Doxorubicin or Epirubicin and Cyclophosphamide. The addition of Olanzapine 10 mg is known to reduce acute and delayed CINV, however, Olanzapine 10 mg is associated with somnolence and fatigue. In this study, the proportion of complete response of CINV to Olanzapine 5 mg was compared to Olanzapine 10 mg that was added to standard antiemetic regime. Methods: This was an open-label randomized clinical trial comparing the effectiveness of Olanzapine 5 mg against Olanzapine 10 mg in preventing acute and delayed phases of CINV. This study was conducted at a tertiary care cancer centre in India between 2020 – 2021. The sample size was calculated 118 subjects that were allocated with simple randomization method. The primary outcome of CINV in acute and delayed phase were collected using the Multinational Association for Supportive Care in Cancer (MASCC) Antiemesis Tool; the intensity of symptoms of nausea, retching and vomiting were assessed using the Rhodes index; the overall patient experience was assessed using the Edmonton Symptom Assessment Scale. The comparison of proportions of CINV in the two groups were compared using Chi-square test while intensity scores were compared using Wilcoxon rank-sum test. All p values <0.05 were considered significant. Ethics approval was obtained from the Institutional Review Board. The trial was registered at the Clinical Trials Registry of India. Results: Of the118 patients randomized, 57 received Olanzapine 5 mg and 61 received Olanzapine 10 mg in addition to standard antiemetic regime. The overall complete response rate was 54.2% in acute phase and 72.0% in delayed phase. The complete response rate of Olanzapine 5 mg was 57.9% in acute phase and 91.2% in delayed phase. The complete response rate of Olanzapine 10 mg was 50.9% in acute phase and 54.1% in delayed phase. The nausea intensity score on day 5 after chemotherapy was significantly lower among those receiving Olanzapine 10 mg. However, there were no difference in the reduction retching and overall symptoms between the groups. In terms of side effect profile, those receiving Olanzapine 10 mg reported significantly higher grades of somnolence and fatigue. There was no difference in the occurrence of pain, depression, anxiety, shortness of beath, appetite and wellbeing. Conclusions: There was no difference in the effectiveness of Olanzapine 5 mg compared to Olanzapine 10 mg in the prevention of CINV. However, Olanzapine 10 mg was associated with higher proportions of somnolence and fatigue. Therefore, it is recommended that Olanzapine 5 mg may replace current antiemetic regimes that contain Olanzapine 10 mg. Clinical trial information: CTRI/2020/01/023076.

Additional Bicarbonate Infusion Complements WHO Rehydration Therapy in Children with Acute Diarrhea and Severe Dehydration Presenting with Severe Non-anion Gap Metabolic Acidemia: An Open Label Randomized Trial.

To assess the efficacy and safety of bicarbonate infusion in children with Acute Diarrhea and Severe Dehydration (ADSD) having severe Non-Anion Gap Metabolic Acidemia (sNAGMA). Children (aged 1-144 mo) with ADSD and sNAGMA (pH ≤7.2 and/or serum bicarbonate ≤15mEq/L) were enrolled in an open-label randomized design. Controls (n = 25) received WHO-recommended rehydration therapy with Ringer Lactate, while intervention group (n = 25) received additional bicarbonate deficit correction. Primary outcome was time taken to resolve metabolic acidemia (pH >7.30 and/or bicarbonate >15mEq/L). Secondary outcome measures were adverse outcome [composite of pediatric intensive care unit (PICU) transfer and deaths], acute care area free days in 5 d (ACAFD5), hospital stay, and adverse effects. Time taken to resolve metabolic acidemia was significantly lesser with intervention [median (IQR); 8h (4, 12) vs. 12h (8, 24); p = 0.0067]. Intervention led to acidemia resolution in significantly more children by 8h and 16h (17/25 vs. 9/25, p = 0.035 and 23/25 vs. 17/24, p = 0.018, respectively). Patients with fluid refractory shock needed lesser inotropes in intervention group [median Vasoactive Inotrope Score (VIS), 10.5 vs. 34]. Intervention led to significantly lesser adverse outcome (0/25 vs. 5/25, p = 0.049), and noticeably more ACAFD5 [median (IQR); 2 (1, 2) vs. 1 (1, 2); p = 0.12]. Two patients died in the control group while none in the intervention group. No adverse effect was documented. Additional calculated dose of bicarbonate infusion led to significantly early resolution of metabolic acidemia, lesser utilization of critical care facilities, and lesser adverse outcome in children with ADSD and sNAGMA, compared to standard therapy, with no adverse effect.

Simulation Based vs Conventional Training for Initial Steps in Delivery Room Care of Preterm Neonates: An Open Label Randomized Trial

To assess whether simulation based education (SBE) improves the practices and knowledge of junior residents for stabilization of a preterm neonate in delivery room as compared to conventional education (CE). This trial randomized 24 pediatric residents to either SBE (n=12) or CE (n=12) groups. One-time SBE was imparted to the SBE group. Both the groups had similar facilitator participant ratio and equally timed sessions. The individual skills scores and performance by preterm stabilization performance evaluation (PSPE) score in real time were recorded using a validated tool within 8 weeks of the training. Knowledge gain was evaluated using pre and post-test scores. The mean (SD) skill and PSPE scores were comparable between the two groups (skill score 51.1 (8.1), 46.5 (7.8), respectively mean difference 4.6; 95% CI -2.1 to 11.3; PSPE-score 80.2 (14.2) vs. 82.9 (10.3); mean difference -2.68; 95% CI -8.35 to 13.71). The mean (SD) knowledge gain was similar in the groups [4.4 (1.9), 5.3 (4.1); mean difference 0.91; 95% CI, -1.81 to 3.64. In junior residents, a one-time SBE session, when compared to conventional task training, did not lead to improvement in the performance of the initial steps of neonatal resuscitation.

Twice Weekly Vs. Thrice Weekly Low-Dose Prophylactic Factor VIII Therapy in Children with Hemophilia A: An Open Label Randomized Trial

Low dose factor VIII prophylactic therapy in hemophilia has not been well established till date. This randomized controlled trial compared the efficacy of twice vs. thrice weekly schedule of low dose prophylactic factor VIII in children with hemophilia A as evaluated by the bleeding rate and clinico-radiological evaluation. Thirty-three children with severe hemophilia A (≤18 years) were randomized into two groups. Baseline evaluation included detailed history, clinical (HJHS 2.1 score and FISH score) and radiological examination (Pettersson score and ultrasound score). Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose being 10 U/kg in both groups. All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at the end of follow up were recorded. We analyzed 14 children in twice weekly prophylaxis group and 16 children in thrice weekly prophylaxis group. Statistically insignificant difference was found between the bleeding rates in both the groups after prophylaxis with the median values of monthly bleeding rate being 0.17 and p-value of 0.79. The differences between the initial and final clinical and radiological scores within each group were found to be statistically significant. There was no significant difference in the clinical and radiological scores in between the groups. Twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A. Lay summaryHemophilia A is one of the most common congenital coagulation factor deficiencies. Low dose factor VIII prophylaxis is recommended for hemophilia in resource-poor settings to reduce the bleeding episodes and improve the quality of life, although the optimal schedule for the same has not been well established. A randomized controlled trial on 33 children with hemophilia A (≤18 years) was done to compare the efficacy of twice versus thrice weekly schedule of prophylactic factor VIII. Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose in both groups being 10 U/kg. They were evaluated by the bleeding rate and clinical (HJHS 2.1 score and FISH score) and radiological scores (Pettersson score and ultrasound score). All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at end of follow up were recorded. When analyzed, statistically insignificant difference was found between the bleeding rates after the two prophylaxis regimes. There was a significant improvement between initial and final clinical and radiological scores in both the groups and no difference was recorded in between the groups. To conclude, twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A.

Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial

SummaryBackgroundThe ALLR3 trial investigated outcomes of children with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. We analysed long-term follow-up outcomes of these patients.MethodsALLR3 was an open-label randomised clinical trial that recruited children aged 1–18 years with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. Eligible patients were recruited from centres in Australia, Ireland, the Netherlands, New Zealand, and the UK. Patients were randomly assigned from Jan 31, 2003, to Dec 31, 2007, and the trial closed to recruitment on Oct 31, 2013. Randomly assigned patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation; after randomisation stopped in Dec 31, 2007, all patients were allocated to receive mitoxantrone. After three blocks of therapy, patients with high minimal residual disease (≥10−4 cells) at the end of induction were allocated to undergo allogeneic stem-cell transplantation and those with low minimal residual disease (<10−4 cells) at the end of induction were allocated to receive chemotherapy. Minimal residual disease level was measured by real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements. The primary endpoint of the original ALLR3 clinical trial was progression-free survival of randomly assigned patients. The primary endpoint of this long-term follow-up analysis was progression-free survival of patients with late bone marrow relapses stratified by minimal residual disease level. Outcomes were correlated with age, site, time to recurrence, and genetic subtypes, and analysed by both intention to treat and actual treatment received. This trial is registered on the ISRCTN registry, number ISRCTN45724312, and on ClinicalTrials.gov, number NCT00967057.FindingsBetween Feb 2, 2003, and Oct 28, 2013, 228 patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses were treated. After a median follow-up of 84 months (IQR 48–109), progression-free survival of all randomly assigned patients was 60% (95% CI 54–70). 220 patients achieved second complete remission, and minimal residual disease was evaluable in 192 (87%). 110 patients with late bone marrow relapses and high minimal residual disease at the end of induction were allocated to undergo stem-cell transplantation, and 82 patients with low minimal residual disease at the end of induction were allocated to receive chemotherapy. In the patients allocated to undergo stem-cell transplantation, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted. Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell transplantation. In patients allocated to receive chemotherapy, one early treatment-related death was reported and 11 patients were transplanted. Of the 70 patients who continued on chemotherapy, 49 (70%) remained in second complete remission, two (3%) died of complications, and 19 (27%) relapsed. Progression-free survival at 5 years was 56% (95% CI 46–65) in those with high minimal residual disease and 72% (60–81) in patients with low minimal residual disease (p=0·0078). Treatment-related serious adverse events were not analysed in the long-term follow-up.InterpretationPatients with B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses and low minimal residual disease at end of induction had favourable outcomes with chemotherapy without undergoing stem-cell transplantation. Patients with high minimal residual disease benefited from stem-cell transplantation, and targeted therapies might offer further improvements in outcomes for these patients.FundingBloodwise (Formerly Leukaemia and Lymphoma Research) UK, Cancer Research UK, Sporting Chance Cancer Foundation, National Health and Medical Research Council Australia, KindreneKankervrij Netherlands, European Union Seventh Framework Programme, India Alliance Wellcome DBT Margdarshi Fellowship.

Comparison of Local Infiltration with Modified Pectoralis Block for Post-operative Analgesia after Modified Radical Mastectomy: An Open Label Randomized Trial

Comparison of Local Infiltration with Modified Pectoralis Block for Post-operative Analgesia after Modified Radical Mastectomy: An Open Label Randomized Trial

Tinzaparin for the treatment of foetal growth retardation: An open-labelled randomized clinical trial

ObjectiveFoetal growth retardation (FGR) is a leading cause of perinatal death and long-term harms at survivors. Placental infarction plays a role in FGR, yet, no trials have evaluated whether low molecular weight heparins increase birth weight in ongoing FGR pregnancies. MethodsAn open-labelled randomized trial in Denmark during 2011–2016, including singleton pregnant women with FGR (estimated foetal weight < 2.3 percentile) diagnosed before gestational weeks 32. Participants were randomly assigned using sealed, blinded envelopes 1:1 to tinzaparin (4500 IU daily until 37 gestational weeks) or no tinzaparin. The primary outcomes were the observed birthweight relative to the expected for gestational age and gender, and foetal growth rates in the two trial groups evaluated by an intention to treat analysis. ResultsWe enrolled 53 women. The mean gestational age was 261 days in the tinzaparin group and 246 days in the no treatment group. The mean birth weight was 2229 g in the tinzaparin group compared to 1968 g in the no treatment group. However, the birth weight relative to the expected from gestational age and gender was only 2.5 percentage points higher in the tinzaparin group [−5.1 to 10.0] (p = 0.51). The foetal growth rate during follow-up was 124 g/week in the tinzaparin group and 119 g/week in the no treatment group, a difference of 5 g/week [−19 to 29] (p = 0.67). Two perinatal deaths both occurred in the no treatment group. ConclusionWe found no evidence of a tinzaparin effect on the foetal growth rate or the birth weight after adjustment for gestational age.

Adjuvant androgen-deprivation therapy following prostate total cryoablation in high-risk localized prostate cancer patients — Open-labeled randomized clinical trial

PurposeTo investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). Materials and MethodsThis open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. ResultsThe adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non-adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. ConclusionsAdjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort.

Effects of low calcium dialysate on the progression of coronary artery calcification in hemodialysis patients: An open-label 12-month randomized clinical trial

BackgroundThe association between the dialysate calcium level and coronary artery calcification (CAC) has not yet been evaluated in hemodialysis patients. The objective of this study was to determine whether lowering the dialysate calcium levels would decrease the progression of coronary artery calcification (CAC) compared to using standard calcium dialysate. MethodsWe conducted an open-label randomized trial with parallel groups. The patients were randomly assigned to either 12-month treatment with low calcium dialysate (LCD; 1.25mmol/L, n=36) or standard calcium dialysate (SCD; 1.5mmol/L, n=40). The primary outcome was the change in the CAC scores assessed by 64-slice multidetector computed tomography after 12months. ResultsDuring the treatment period, CAC scores increased in both groups, especially significant in LCD group (402.5±776.8, 580.5±1011.9, P=0.004). When we defined progressors as patients at second and third tertiles of CAC changes, progressor group had a higher proportion of LCD-treated patients than SCD-treated patients (P=0.0229). In multivariate analysis, LCD treatment is a significant risk factor for increase in CAC scores (odds ratio=5.720, 95% CI: 1.219–26.843, P=0.027). ConclusionsUse of LCD may accelerate the progression of CAC in patients with chronic hemodialysis over a 12-month period. Trial registrationClinical Research Information Service [Internet]; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea), 2010: KCT0000942.Available from: https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=3572&sLeft=2&type=my

To Compare Endoscopic Variceal Ligation + Carvedilol Versus Endoscopic Variceal Ligation + Propranolol on Hepatic Vein Pressure Gradient Reduction at 1 Month in Patients with First Episode of Esophageal Varix Bleed: Open Label Randomized Trial

and 0.041% (n = 17) were positive for HIV. Since the number of female donors was very less, overall prevalence was calculated and no comparison among sexes was made. HBV and HCV positive cases were seen to have an increased trend while HIV showed a decreased trend towards the end. Conclusion: Seroprevalence of HBV, HCV and HIV though is low in our setup compared to other states, but still they are a potential threat to the recipients of the blood and thus stringent measures need to be taken to screen the blood to avoid the transmission of these infections to the recipients which would in turn decrease the burden of these transmissible diseases among blood recipients. As replacement donors are not professional blood donors and grossly represent the community, this study as suchmay give us an idea about the real prevalence of these diseases in our community in the absence of community-based epidemiological studies.

Oral Paricalcitol Reduces the Prevalence of Posttransplant Hyperparathyroidism: Results of an Open Label Randomized Trial

Postkidney transplant hyperparathyroidism is a significant problem. Vitamin D receptor agonists are known to suppress parathyroid hormone (PTH) secretion. We examined the effect of oral paricalcitol on posttransplant secondary hyperparathyroidism by conducting an open label randomized trial in which 100 incident kidney transplant recipients were randomized 1:1 to receive oral paricalcitol, 2 μg per day, for the first year posttransplant or no additional therapy. Serial measurements of serum PTH, calcium and bone alkaline phosphatase, 24-h urine calcium and bone density were performed. The primary endpoint was the frequency of hyperparathyroidism 1-year posttransplant. Eighty-seven patients completed the trial. One-year posttransplant, 29% of paricalcitol-treated subjects had hyperparathyroidism compared with 63% of untreated patients (p = 0.0005). Calcium supplementation was discontinued in two control and 15 treatment patients due to mild hypercalcemia or hypercalcuria. Paricalcitol was discontinued in four patients due to hypercalcuria/hypercalcemia and in one for preference. Two subjects required decreasing the dose of paricalcitol to 1 μg daily. Hypercalcemia was asymptomatic and reversible. Incidence of acute rejection, BK nephropathy and renal function at 1 year were similar between groups. Moderate renal allograft fibrosis was reduced in treated patients. Oral paricalcitol is effective in decreasing posttransplant hyperparathyroidism and may have beneficial effects on renal allograft histology.

Su1631 Are There Any Differences Among Predictive Response Factors for a Proton Pump Inhibitor and Prokinetics? Sub-Analysis of a Multicenter Open-Label Randomized Trial Comparing Rabeprazole Versus Itopride in Japanese Functional Dyspepsia: the NAGOYA Study

Su1631 Are There Any Differences Among Predictive Response Factors for a Proton Pump Inhibitor and Prokinetics? Sub-Analysis of a Multicenter Open-Label Randomized Trial Comparing Rabeprazole Versus Itopride in Japanese Functional Dyspepsia: the NAGOYA Study

Results of a Multicenter Open-Label Randomized Trial Evaluating Infusion Duration of Zoledronic Acid in Multiple Myeloma Patients (the ZMAX Trial)

Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid-induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level < 3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3-4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.

TCT-430: Clinical and Angiographic Outcomes in Patients with Acute Myocardial Infarction from the RESOLUTE All Comers Open Label Randomized Trial - RESOLUTE-AMI

TCT-430: Clinical and Angiographic Outcomes in Patients with Acute Myocardial Infarction from the RESOLUTE All Comers Open Label Randomized Trial - RESOLUTE-AMI

TCT-34: Multivessel Stenting from the RESOLUTE All Comers Open Label Randomized Trial: 12-Month Clinical Outcomes

TCT-34: Multivessel Stenting from the RESOLUTE All Comers Open Label Randomized Trial: 12-Month Clinical Outcomes

Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial

Percutaneous vertebroplasty is increasingly used for treatment of pain in patients with osteoporotic vertebral compression fractures, but the efficacy, cost-effectiveness, and safety of the procedure remain uncertain. We aimed to clarify whether vertebroplasty has additional value compared with optimum pain treatment in patients with acute vertebral fractures. Patients were recruited to this open-label prospective randomised trial from the radiology departments of six hospitals in the Netherlands and Belgium. Patients were aged 50 years or older, had vertebral compression fractures on spine radiograph (minimum 15% height loss; level of fracture at Th5 or lower; bone oedema on MRI), with back pain for 6 weeks or less, and a visual analogue scale (VAS) score of 5 or more. Patients were randomly allocated to percutaneous vertebroplasty or conservative treatment by computer-generated randomisation codes with a block size of six. Masking was not possible for participants, physicians, and outcome assessors. The primary outcome was pain relief at 1 month and 1 year as measured by VAS score. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00232466. Between Oct 1, 2005, and June 30, 2008, we identified 431 patients who were eligible for randomisation. 229 (53%) patients had spontaneous pain relief during assessment, and 202 patients with persistent pain were randomly allocated to treatment (101 vertebroplasty, 101 conservative treatment). Vertebroplasty resulted in greater pain relief than did conservative treatment; difference in mean VAS score between baseline and 1 month was -5·2 (95% CI -5·88 to -4·72) after vertebroplasty and -2·7 (-3·22 to -1·98) after conservative treatment, and between baseline and 1 year was -5·7 (-6·22 to -4·98) after vertebroplasty and -3·7 (-4·35 to -3·05) after conservative treatment. The difference between groups in reduction of mean VAS score from baseline was 2·6 (95% CI 1·74-3·37, p<0·0001) at 1 month and 2·0 (1·13-2·80, p<0·0001) at 1 year. No serious complications or adverse events were reported. In a subgroup of patients with acute osteoporotic vertebral compression fractures and persistent pain, percutaneous vertebroplasty is effective and safe. Pain relief after vertebroplasty is immediate, is sustained for at least a year, and is significantly greater than that achieved with conservative treatment, at an acceptable cost. ZonMw; COOK Medical.