Glyceryl trinitrate to reduce the need for manual removal of retained placenta following vaginal delivery: the GOT-IT RCT.

BACKGROUND: Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management. DESIGN: A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis. SETTING: There were 29 obstetric units in the UK involved in the study. PARTICIPANTS: There were 1107 women (glyceryl trinitrate group, n = 543; placebo group, n = 564) randomised between October 2014 and July 2017. INTERVENTIONS: Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group. MAIN OUTCOME MEASURES: Four primary outcomes were defined: (1) clinical - the need for manual removal of placenta, (2) safety - measured blood loss, (3) patient sided - satisfaction with treatment and side effects and (4) economic - cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics. RESULTS: No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval -£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p < 0.001). The need for a blood transfusion was also more common in the glyceryl trinitrate group than in the control group (odds ratio 1.53, 95% confidence interval 1.04 to 2.25; p = 0.033). CONCLUSIONS: Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88609453. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 70. See the NIHR Journals Library website for further project information.

A retained placenta is diagnosed when, following the birth of a baby, the placenta is not delivered. When this situation occurs, women are at risk of bleeding heavily. The only way to treat a retained placenta is for a trained doctor to remove it by an operation in theatre. This procedure can be painful and upsetting. Furthermore, the timing of the operation can interrupt mother­baby bonding immediately after giving birth. The study tested if the use of glyceryl trinitrate spray, given as two puffs under the woman's tongue following the diagnosis of retained placenta, may help the placenta to deliver without an operation. The study also tested if glyceryl trinitrate was safe, assessed what women thought about the treatment and compared the costs of glyceryl trinitrate with those of current operative management. This study included 1107 women diagnosed with retained placenta following the birth of their baby. Half of the women were treated with glyceryl trinitrate spray and the other half were treated with a dummy spray, which looked identical but did not contain the active treatment. If the placenta delivered within 15 minutes of the study treatment being taken, this was considered a success. However, if the placenta did not deliver within 15 minutes and the woman had to have her placenta removed by an operation, then this was viewed as unsuccessful. Neither the woman nor the clinical staff knew if the treatment given was the glyceryl trinitrate spray or the dummy spray. The results indicate that, although women were happy to be involved in the trial and the treatment was safe, the use of glyceryl trinitrate spray did not reduce the need for the placenta to be manually removed by an operation in theatre. Furthermore, glyceryl trinitrate spray was not cost-effective.

A pragmatic group sequential, placebo-controlled, randomised trial to determine the effectiveness of glyceryl trinitrate for retained placenta (GOT-IT): a study protocol.

INTRODUCTION: A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP). METHODS AND ANALYSIS: The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North-East Newcastle & North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISCRTN88609453; Pre-results.

A cost analysis of the impact of a new intravenous antihypertensive in managing perioperative blood pressure during cardiac surgery.

OBJECTIVE: To examine the impact of intravenous antihypertensive selection on hospital health resource utilization using data from the Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) trials. METHODS: Analysis of ECLIPSE trial data comparing clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine and unit costs based on the Premier Hospital database to assess surgery duration, time to extubation, and length of stay (LOS) with the associated cost. RESULTS: A total of 1414 patients from the ECLIPSE trials and the Premier hospital database were included for analysis. The duration of surgery and postoperative LOS were similar across groups. The time from chest closure to extubation was shorter in patients receiving clevidipine group compared with the pooled comparator group (median 7.0 vs 7.6 hours, P = 0.04). There was shorter intensive care unit (ICU) LOS in the clevidipine group versus the nitroglycerin group (median 27.2 vs 33.0 hours, P = 0.03). A trend toward reduced ICU LOS was also seen in the clevidipine compared with the pooled comparator group (median 32.3 vs 43.5 hours, P = 0.06). The costs for ICU LOS and time to extubation were lower with clevidipine than with the comparators, with median cost savings of $887 and $34, respectively, compared with the pooled comparator group, for a median cost savings of $921 per patient. CONCLUSIONS: Health resource utilization across therapeutic alternatives can be derived from an analysis of standard costs from hospital financial data to matched utilization metrics as part of a randomized controlled trial. In cardiac surgical patients, intravenous antihypertensive selection was associated with a shorter time to extubation in the ICU and a shorter ICU stay compared with pooled comparators, which in turn may decrease total costs.

Cost-effectiveness of transdermal nitroglycerin use for preterm labor.

OBJECTIVE: The objective of this study was to determine the cost-effectiveness of using transdermal nitroglycerin (GTN) for cases of preterm labor. METHODS: The study included 153 women with clinical preterm labor, who were randomly allocated to either a GTN or placebo arm. All randomized cases were included in the final economic analysis. Differences between the two arms in gestational age at delivery, neonatal intensive care unit (NICU) admission, length of NICU stay, and NICU cost were assessed. Costs for non-NICU cases were calculated using Ottawa Hospital data through the Ontario Case Costing Initiative (OCCI). Cost-effectiveness and sensitivity analyses using a hospital perspective were both conducted. RESULTS: In the 153 randomized cases, 55 babies were admitted to NICU (GTN = 24; placebo = 31). We found no significant differences between the two arms in gestational age at delivery, NICU admission rate (32.4% vs. 39.2%), NICU length of stay (42.7 days vs. 52.8 days), or NICU cost (CAN $34,306 vs. CAN $44,326). Overall, (based on all randomized cases) the cost-effectiveness analyses showed that the GTN arm was the dominant strategy, with both lower cost (CAN $13,397 vs. CAN $18,427) and higher NICU admission avoided rate (67.6% vs. 60.8%) compared to the placebo arm. This dominance persisted in all sensitivity analyses. CONCLUSION: The use of GTN patch for preterm labor could reduce NICU costs, while improving important neonatal outcomes.

Science or fiction: use of nesiritide as a first-line agent?

Nesiritide is an effective agent for the treatment of decompensated CHF. However, the VMAC trial shows that the agent's efficacy and safety are actually more similar than dissimilar to those of nitroglycerin. Indeed, objective reviews have placed nesiritide as a second-line agent behind current standard drug therapy. Finally, nesiritide is approximately 40 times the purchase price of standard agents such as nitroglycerin. For these reasons, we feel that nesiritide should not be considered as first-line therapy. Reflecting this notion, one institution has implemented a protocol that recommends administration of nitroglycerin and intravenous diuretics (using > or = 2 times the usual daily diuretic dose) before using nesiritide. In light of the existing data, we feel that this approach appears to be an appropriate and prudent one for nesiritide's place in therapy.

Modelling the economic impact of managing a chronic anal fissure with a proprietary formulation of nitroglycerin (Rectogesic) compared to lateral internal sphincterotomy in the United Kingdom.

BACKGROUND AND AIMS: This study estimated the economic impact of using a proprietary formulation of 0.2% nitroglycerin (GTN) ointment (Rectogesic) compared with lateral internal sphincterotomy in the treatment of a chronic anal fissure in the United Kingdom (UK), from the perspective of the National Health Service (NHS). PATIENTS AND METHODS: Clinical and surgical outcomes attributable to managing a chronic anal fissure were obtained from published literature, supplemented with information about resource utilisation derived from interviews with a panel of colorectal surgeons and general practitioners. Using this information, a decision tree modelling the management of a chronic anal fissure by a colorectal surgeon was constructed. Unit resource costs at 1999/2000 prices were applied to the resource utilisation estimates in the model to estimate the expected NHS cost of managing a chronic anal fissure. Consensus on the information contained within the model was reached at a meeting with an expert panel comprising five of the interviewees and one other colorectal surgeon. RESULTS: The expected NHS cost of a colorectal surgeon initially managing a chronic anal fissure with GTN was estimated to be pound616, compared to pound840 when a lateral internal sphincterotomy is the first-line treatment. Moreover, the expected probability of successful healing following initial treatment with either intervention is 99-100%, taking into account all subsequent treatments. CONCLUSION: The initial use of GTN compared to lateral internal sphincterotomy to treat a chronic anal fissure affords a potential cost reduction to the NHS of pound224 per patient without any loss in effectiveness. Hence, GTN is potentially a cost-effective first-line treatment strategy for the management of a chronic anal fissure.

Impact of reference-based pricing of nitrates on the use and costs of anti-anginal drugs.

BACKGROUND: Reference-based pricing limits reimbursement for a group of drugs that are deemed therapeutically equivalent to the cost of the lowest-priced product within that group. We estimated the effect of reference-based pricing of nitrate drugs used for long-term prophylaxis on prescribing of and expenditures on nitrates and other anti-anginal drugs dispensed to senior citizens in British Columbia. METHODS: We assessed trends in the monthly volume of prescriptions of anti-anginal drugs and the associated drug ingredient cost paid by the province's publicly funded drug subsidy program, Pharmacare, and by the patients themselves for the period April 1994 to May 1999. Trends in monthly rates of nitrate expenditures per 100,000 senior citizens before the introduction of reference-based pricing were extrapolated to infer what expenditures would have been without the policy. RESULTS: During the 3 1/2 years after reference-based pricing was introduced, Pharmacare expenditures on nitrates prescribed to senior citizens declined by $14.9 million (95% confidence interval $10.7 to $19.1 million). Most of these savings were due to the lower prices that Pharmacare paid for sustained-release nitroglycerin tablets and the nitroglycerin patch, which were the 2 most frequently prescribed nitrates before the introduction of reference-based pricing; $1.2 million (8%) of the savings represented expenditures by senior citizens who purchased drugs that were only partially reimbursed. There were no compensatory increases in expenditures for other anti-anginal drugs. Use of sublingual nitroglycerin--a marker for deteriorating health in patients with angina--did not increase after the introduction of reference-based pricing. The nitroglycerin patch is now the most frequently prescribed nitrate, owing to the fact that Pharmacare resumed the provision of full subsidies for the drug after its manufacturers voluntarily reduced retail prices. INTERPRETATION: Evidence to date suggests that reference-based pricing of nitrates has achieved its primary goal of reducing drug expenditures. The effects of this policy on patient health, associated health care costs and administrative costs remain to be investigated.

Transdermal nitroglycerin for the prevention of intravenous infusion failure due to phlebitis and extravasation.

OBJECTIVE: To evaluate the clinical use of transdermal nitroglycerin for the prevention of intravenous infusion failures due to phlebitis or extravasation. DATA SOURCES: Clinical literature was accessed through a MEDLINE search (1966-May 2000). Key search terms included nitroglycerin, transdermal, phlebitis, extravasation, intravenous, and infusion. DATA SYNTHESIS: Common and serious consequences of intravenous therapy include the occurrence of postinfusion phlebitis and failure to maintain intravenous therapy due to intravenous fluid extravasation. Transdermal application of nitroglycerin has been evaluated as a treatment and preventive method for intravenous infusion failures related to phlebitis or extravasation. An evaluation of studies focusing on transdermal nitroglycerin in the prevention of infusion failures due to phlebitis or extravasation was conducted. CONCLUSIONS: Use of transdermal nitroglycerin as a prophylactic measure for intravenous infusion failures is a therapeutic option for patients requiring long-term intravenous therapy (i.e., > 50 h).

A study of drug utilisation and cost of treatment in patients hospitalised with unstable angina.

OBJECTIVE: The current study was designed to investigate drug utilisation in the management of unstable angina in India and to calculate the costs incurred by patients in the treatment of a single episode of unstable angina. METHODS: We conducted a prescription survey to examine the use of antianginal drugs in patients with unstable angina in a tertiary care Indian hospital. The use of concurrent medications such as antidiabetic, antihypertensive and lipid-lowering agents was also examined. Data on the cost of treatment, investigations, income, and family size were collected from the case histories or direct interviews with the patients/relatives. RESULTS: A total of 336 consecutive prescriptions were evaluated. Aspirin was the most frequently prescribed drug (98%) followed by nitroglycerin infusion (90%) and enoxaparin (52%). One of the heparins was used by 89% of all patients and beta-blockers by up to 62% of the patients. Besides antianginals, antihypertensive (49%) and antidiabetic (16%) drugs were commonly coadministered. The mean (+/- SD) cost of treatment of a single episode of unstable angina in the hospital was US $494 (+/- 271) against an annual per capita income of US $245. The mean (+/- SD) cost incurred by the patients due to drugs alone during the hospital stay was US $70 (+/- 18) and enoxaparin accounted for 60% of the expenditure due to drugs. CONCLUSIONS: The results of our study show that low-molecular-weight heparin, enoxaparin, is replacing unfractionated heparin in the treatment of unstable angina. In view of the use of costly new drugs, there is an urgent need for carrying out pharmacoeconomic analysis in developing countries as the treatment of a single episode of unstable angina imparts a considerable economic burden on the patient.

Cost-effectiveness analysis of the terlipressin-glycerin trinitrate combination in the pre-hospital management of acute gastro-intestinal haemorrhage in cirrhotic patients.

OBJECTIVES: To assess the cost-effectiveness of an early treatment of upper gastro-intestinal haemorrages in cirrhotic patients. DESIGN: Utilization data linked to the results of a double-blind, placebo-controlled trial demonstrating the efficacy of the terlipressin-glycerin trinitrate combination (TER-GTN) in the reduction of mortality at day 42 for haemorragic patients due to rupture of oesophageal varices. SETTING: Hôpital Jean Verdier, Bondy, Assistance Publique-Hôpitaux de Paris, France. SUBJECTS: Eighty-four patients included over 2 years by emergency services and hospitalized in an intensive care unit (ICU) for haemorrage, 41 in the "treated" group and 43 in the "placebo" group. MAIN OUTCOME MEASURES: Mortality at day 42, cost per death avoided. RESULTS: The mortality rate in the placebo group was 46.5% versus 27.5% in the treated group. The mean length of stay was 5 days longer in the treatment group. The excess cost per death avoided was 25,849 FF. Of this extra cost 27% was due to treatment and 24% was due to increased length of stay. The excess cost per case treated was FF 5,097, 10% of the total cost per stay for rupture of oesophageal varices (ROV). CONCLUSIONS: Our results are of the same magnitude as those published by Mac Cormick et al. in the United Kingdom for similar treatment. The extra cost appears to be moderate, and much lower than monoclonal antibody therapy for sepsis. The impact on the study hospital budget did not exceed 1.7 10(-4).

Vasoconstrictors in the management of bleeding from oesophageal varices. A clinico-economic appraisal in the UK.

BACKGROUND: Bleeding from oesophageal varices is an uncommon but potentially fatal condition that often leads to expensive hospitalizations in intensive care or high-dependency units. METHODS: To assess the clinical and economic impact of this condition, we have devised a management plan illustrating current clinical practice in the UK. RESULTS: Approximately 6.1 million pounds of NHS resources are devoted to the treatment of 3000 acute hospital admissions for variceal bleeding every year. Vasoconstrictors like vasopressin may save approximately 36 lives per annum for an additional 145 thousand pounds. However, current clinical practice requires vasopressin to be concurrently administered with intravenous glyceryl trinitrate, increasing overall costs by 582 thousand pounds to a total of 6.7 million pounds. The additional cost for each extra life saved is estimated at 16,180 pounds. CONCLUSION: The efficacy of current vasoconstrictors requires further confirmation. In particular, new agents like octreotide (Sandostatin) should be carefully assessed to determine their potential clinical and economic benefits.