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Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Objectives: Postoperative hypertension frequently occurs after surgery for congenital heart disease. Given safety concerns when using calcium channel blockers in infants along with the cost and side-effect profile of nitroprusside, we retrospectively assessed our experience of using nicardipine and nitroprusside for postoperative blood pressure control in infants who underwent surgery for congenital heart disease. We also investigated the cost difference between the medications., Design: This study was a single-center retrospective, pre-post chart review of patients who had surgery for congenital heart disease between 2016 and 2020. The primary aim was a noninferiority comparison of achievement of blood pressure goal at 1-hour post-initiation of an antihypertensive agent. Secondary comparisons included achievement of blood pressure goal at 2 hours after medication initiation, Vasoactive-Inotropic Score (VIS), and blood transfusion, crystalloid volume, and calcium needs., Setting: Academic quaternary-care center., Patients: Infants under 1 year old who required treatment for hypertension with nitroprusside ( n = 71) or nicardipine ( n = 52) within 24 hours of surgery for congenital heart disease., Interventions: None., Measurements and Main Results: We failed to identify any difference in proportion of patients that achieved blood pressure control at 1-hour after medication initiation (nitroprusside 52% vs. nicardipine 54%; p = 0.86), with nicardipine noninferior to nitroprusside within a 15% margin. Of patients who did not achieve control at 1-hour post-medication initiation, receiving nicardipine was associated with blood pressure control at 2 hours post-medication initiation (79% vs. 38%; p = 0.003). We also failed to identify an association between antihypertensive types and mean VIS scores, blood transfusion volumes, crystalloid volumes, and quantities of calcium administered. Index cost of using nitroprusside was 16 times higher than using nicardipine, primarily due to difference in wholesale cost., Conclusions: In our experience of achieving blood pressure control in infants after surgery for congenital heart disease (2016-2020), antihypertensive treatment with nicardipine was noninferior to nitroprusside. Furthermore, nicardipine use was significantly less expensive than nitroprusside. Our contemporary practice is therefore to use nicardipine in preference to nitroprusside., Competing Interests: Dr. Mirea disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: While advanced therapies for severe persistent pulmonary hypertension of the newborn (PPHN) such as inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are standard treatments in high-income countries, these therapies are often unavailable in resource-limited settings such as middle-income countries. However, there are small clinical trials illustrating the efficacy of sildenafil at reducing mortality in PPHN. This analysis sought to determine the cost-utility of enteral sildenafil for the treatment of severe PPHN., Study Design: A Markov-state transition model was constructed for the two clinical approaches to compare costs, clinical outcomes, and quality of life: (1) "conventional," (2) "sildenafil." The impact of sildenafil was modeled as a relative risk modifier of the conventional strategy's mortality risk. Transitional probabilities, costs, and utility metrics were extracted from the literature. Sensitivity analyses for each model input as well as 100-patient Monte Carlo simulations were used to test the durability of the model conclusion., Results: The sildenafil strategy was cost-effective for upper but not lower middle-income countries with an incremental cost-effectiveness ratio of $2,339 per quality-adjusted life year. This conclusion was durable across a wide-range of model assumptions; the sildenafil strategy only failed to meet criteria for cost-effectiveness when sildenafil therapy had a mortality relative risk efficacy of >0.89, if life expectancy in that country is <40 years, or if the lifetime forecasted costs of a survivor's life was quite high., Conclusion: Enteral sildenafil is a cost-effective intervention for severe PPHN for upper middle-income countries where ECMO and iNO are not available., Key Points: · PPHN is a common life-threatening condition in newborns.. · Sildenafil improves survival of PPHN.. · Sildenafil is cost-effective for upper-middle income countries.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background To evaluate the cost-effectiveness of combination pulmonary arterial hypertension specific therapy in systemic sclerosis-related PAH. Methods and Results Health outcomes and costs were captured through data linkage. Health utility was derived from Medical Outcomes Study Short Form-36 scores. A probabilistic discrete-time model was developed to simulate lifetime changes in costs and health utility. Mortality was predicted using a Gompertz parametric survival model. For both treatment arms, the simulations were started using the same cohort of 10 000 patients. Probabilistic sensitivity analysis was performed using the Monte Carlo simulation with 1000 sets of sampled parameter values. Of 143 patients with systemic sclerosis-related pulmonary arterial hypertension, 89 were on monotherapy and 54 on combination therapy. Mean simulated costs per patient per year in monotherapy and combination therapy groups were AU$23 411 (US$16 080) and AU$29 129 (US$19 982), respectively. Mean life years and quality-adjusted life years from pulmonary arterial hypertension diagnosis to death of patients receiving monotherapy were 7.1 and 3.0, respectively, and of those receiving combination therapy were 9.2 and 3.9, respectively. Incremental costs per life year and quality-adjusted life year gained of combination therapy compared with monotherapy were AU$47 989 (US$32 920) and AU$113 823 (US$78 082), respectively. At a willingness-to-pay threshold of AU$102 000 (US$69 972) per life year gained, and of AU$177 222 (US$121 574) per quality-adjusted life year gained, the probability of combination therapy being cost-effective was 0.95. Conclusions The incremental cost per quality-adjusted life year gained of combination therapy compared with monotherapy was substantial in the base case analysis. Given the fatal prognosis of systemic sclerosis-related pulmonary arterial hypertension and the incremental cost per life year of AU$47 989 (US$32 920), combination therapy could be considered cost-effective in systemic sclerosis-related pulmonary arterial hypertension.

Aim: The cost-effectiveness of isosorbide-5-mononitrate (5-ISMN) and isosorbide dinitrate (ISDN) in real-world use in patients with coronary heart disease (CHD; either angina pectoris or myocardial infarction) was retrospectively compared. Method: In this retrospective real-world evaluation, patients with established CHD satisfying the following criteria were selected from information system of two tertiary hospitals in China: with pharmacy claiming for at least one injection of 5-ISMN or ISDN between July 2008 and May 2017; and, CHD patients. By using propensity score matching (PSM), we compared clinical aspects of efficacy, safety, length of hospital stay and cost during hospitalization between 5-ISMN and ISDN group. All data were processed by R statistical package v.2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Result: Of 5609 patients selected, 4047 received 5-ISMN and 1562 received ISDN. After PSM, we acquired 1555 pairs based on balancing of age, sex, insurance and comorbidities on admission. The frequency (4.2 ± 6.6-times vs 6.5 ± 9.5-times; p < 0.05) and total dosage (47.5 ± 153.4 vs 136.4 ± 261.0 mg; p < 0.05) of sublingual nitroglycerin use decreased and hypotension incidence lowered (8.0 vs 13.0%; p < 0.05) in 5-ISMN group compared with ISDN group. Hospital stay (16.0 ± 11.3 days vs 17.7 ± 13.2; p < 0.05) and hospitalization expenditure ([the ratio of cost in the study to the average hospitalization cost in the city] [odds ratio: 2.5 vs 2.6; p < 0.05]) were reduced in 5-ISMN group as with that of ISDN group. Moreover, the main component of hospitalization cost was medical consumables and medications in both the groups. Conclusion: In the present retrospective real-world evaluation, by using PSM analysis, we found that newer injection agent of 5-ISMN was associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization expenditure related to its comparator ISDN in patients with established CHD. Further evaluation and clinical experience are need in different circumference for the usage of ISDN.

In heart transplantation, pulmonary hypertension and increased pulmonary vascular resistance followed by donor right ventricular dysfunction remain a major cause of perioperative morbidity and mortality. In lung transplantation, primary graft dysfunction remains a major obstacle because it can cause bronchiolitis obliterans and mortality. Pulmonary vasodilators have been used as an adjunct therapy for heart or lung transplantation, mainly to treat pulmonary hypertension, right ventricular failure, and associated refractory hypoxemia. Among pulmonary vasodilators, inhaled nitric oxide is unique in that it is selective in pulmonary circulation and causes fewer systemic complications such as hypotension, flushing, or coagulopathy. Nitric oxide is expected to prevent or attenuate primary graft dysfunction by decreasing ischemia-reperfusion injury in lung transplantation. However, when considering the long-term benefit of these medications, little evidence supports their use in heart or lung transplantation. Current guidelines endorse inhaled vasodilators for managing immediate postoperative right ventricular failure in lung or heart transplantation, but no guidance is offered regarding agent selection, dosing, or administration. This review presents the current evidence of inhaled nitric oxide in lung or heart transplantation as well as comparisons with other pulmonary vasodilators including cost differences in consideration of economic pressures to contain rising pharmacy costs.

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., Competing Interests: Fiona C Denison has received funding from Dilafor AB (Solna, Sweden) outside the submitted work. Jane E Norman has received funding from Dilafor AB and GlaxoSmithKline plc (Middlesex, UK) outside the submitted work and declares membership of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Maternal Newborn and Child Health Panel. Jane Norman was a member of the HTA and Efficacy and Mechanism Evaluation (EME) Editorial Board. John Norrie declares grants from the University of Aberdeen and the University of Edinburgh during the conduct of the study and membership of the following NIHR boards: Cardiopulmonary Resuscitation Decision-making Committee, HTA Commissioning Board, HTA Commissioning Sub-Board (Expression of Interest), HTA Funding Boards Policy Group, HTA General Board, HTA post-board funding teleconference, NIHR Clinical Trials Unit Standing Advisory Committee, NIHR HTA and EME Editorial Board and Pre-exposure Prophylaxis Impact Review Panel. Julia Lawton declares membership of the HTA General Board.

Background: This study aims to assess the cost-effectiveness and budget impact of adopting sildenafil to the benefits package for the indication of pulmonary arterial hypertension (PAH), compared to beraprost., Methods: Based on a societal perspective, a model-based economic evaluation was performed using local and international data to quantify the potential costs and health-related outcomes in terms of life years (LYs) and quality-adjusted life years (QALYs)., Results: The economic model calculated the incremental cost-effectiveness ratio (ICER) per QALY gained for using sildenafil as first-line therapy compared to beraprost for the patient in functional class (FC) II and III, i.e. USD 3098 and USD 2827, respectively. The results indicated that in spite of sildenafil being more expensive than beraprost, generic sildenafil could potentially be a good value for money since ICER per QALY is below one times gross domestic product (GDP) per capita in Indonesia. Furthermore, budget impact analysis estimated that the incremental budget needed within 5 years for including sildenafil compared to beraprost for PAH patients starting in FC II and FC III was USD 436,775 and USD 3.6 million, respectively., Conclusions: Compared to beraprost, sildenafil would be preferable for the treatment of PAH patients in FC II and FC III in Indonesia. The additional budget for adopting sildenafil compared to beraprost as the treatment of PAH in the benefits package was estimated at around USD 4.0 million.

Objectives: In the follow-up of patients in a trial of intracoronary sodium nitrite given during primary percutaneous coronary intervention (PCI) after acute myocardial infarction (AMI), we found a reduction in the incidence of major adverse cardiac events (MACEs). Specifically, MACE rates were 5.2% versus 25.0% with placebo at 3 years ( P = .013). Such MACE reductions should also be associated with economic benefit. Thus, we assessed the cost utility of sodium nitrite therapy versus standard primary PCI only., Methods and Results: We developed a model to simulate costs and quality-adjusted life years (QALYs) over the first 36 months after ST-Segment Elevation Myocardial Infarction (STEMI). Decision tree analysis was used to assess different potential cardiovascular outcomes after STEMI for patients in both treatment groups. Model inputs were derived from the NITRITE-AMI study. Cost of comparative treatments and follow-up in relation to cardiovascular events was calculated from the United Kingdom National Health Service perspective. Higher procedural costs for nitrite treatment were offset by lower costs for repeat revascularization, myocardial infarction, and hospitalization for heart failure compared to primary PCI plus placebo. Nitrite treatment was associated with higher utility values (0.91 ± 0.19 vs 0.82 ± 0.30, P = .041). The calculated incremental cost-effectiveness ratio of £2177 per QALY indicates a cost-effective strategy. Furthermore, positive results were maintained when input parameters varied, indicating the robustness of our model. In fact, based on the difference in utility values, the cost of nitrite could increase by 4-fold (£2006 per vial) and remain cost-effective., Conclusion: This first analysis of sodium nitrite as a cardioprotective treatment demonstrates cost-effectiveness. Although more comparative analysis and assessment of longer follow-up times are required, our data indicate the considerable potential of nitrite-mediated cardioprotection.

Right ventricular (RV) failure is a potentially fatal complication following heart transplantation (HTx). Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that is used to decrease pulmonary vascular resistance immediately post-HTx to reduce the risk of RV failure. The aim of this study was to describe utilization patterns, costs, and outcomes associated with post-transplant iNO use in children. All pediatric HTx recipients (2002-2016) were identified from a unique linked PHIS/SRTR dataset. Post-HTx iNO use was determined based on hospital billing data. Utilization patterns and associated costs were described. The association of iNO support with post-HTx survival was assessed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to adjust for risk factors. A total of 2833 pediatric HTx recipients from 28 centers were identified with 1057 (36.5%) receiving iNO post-HTx. Post-HTx iNO use showed significant increase overall (17.2-54.7%, p < 0.001) and wide variation among centers (9-100%, p < 0.001). Patients with congenital heart disease (aOR 1.4, 95% CI 1.2, 1.6), requiring mechanical ventilation at HTx (aOR 1.3, 95% CI 1.1, 1.6), and pre-transplant iNO (aOR 9.3, 95% CI 5.4, 16) were more likely to receive iNO post-HTx. The median daily cost of iNO was $2617 (IQR $1843-$3646). Patients who required > 5 days of iNO post-HTx demonstrated inferior 1-year post-HTx survival (p < 0.001) and iNO use > 5 days was independently associated with worse post-HTx survival (AHR 1.6, 95% CI 1.2, 2.1; p < 0.001). There is wide variation in iNO use among centers following pediatric HTx with use increasing over time despite significant incremental cost. Prolonged iNO use post-HTx is associated with worse survival, likely serving as a marker of residual illness severity. Further research is needed to define the populations that derive the greatest benefit from this costly therapy.

Objectives: Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication., Methods: Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments., Results: A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain., Conclusions: Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Study Objective: To compare the frequency of adverse events in patients undergoing myocardial perfusion imaging (MPI) with either regadenoson or dipyridamole., Design: Single-center, retrospective cohort study., Setting: Large community teaching hospital., Patients: A total of 568 adults who underwent single-photon emission tomography MPI with either regadenoson (284 patients) or dipyridamole (284 patients) as a vasodilator agent, following an institution conversion from regadenoson to dipyridamole in the MPI protocol on July 15, 2013, for cost-saving purposes., Measurements and Main Results: Data were collected from the patients' electronic medical records. The primary endpoint was the composite occurrence of any documented adverse event in each group. Secondary endpoints were individual components of the primary endpoint, reason for termination of the MPI examination (protocol completion or premature end due to an adverse event), use of an interventional agent to an treat adverse event, and cost-related outcomes. A higher proportion of patients in the regadenoson group experienced an adverse event than those who received dipyridamole (84.9% vs 56.7%, p<0.0001). None of the patients in either group required early MPI study termination due to an adverse event. No significant differences were noted between groups regarding use of aminophylline or other interventions to treat adverse events. The overall drug cost savings in the postconversion dipyridamole group was $51,526., Conclusion: Dipyridamole was associated with fewer adverse events than regadenoson in patients undergoing MPI. Dipyridamole offers a safe and cost-effective alternative to regadenoson for cardiac imaging studies., (© 2017 Pharmacotherapy Publications, Inc.)

Pharmaceutical costs for patients in the intensive care unit (ICU) constitute a large portion of hospital drug budgets. Unfortunately, prices for medications commonly used in the ICU are on the rise for a variety of reasons. In particular, the U.S. Food and Drug Administration's Unapproved Drugs Initiative, generic manufacturers cornering the marketplace, drug shortages, and regulatory device changes are major drivers of pharmaceutical price escalation affecting costs in the ICU. Furthermore, traditional high acquisition cost items still pose challenges to controlling costs. To offer strategies to mitigate the rising costs of pharmaceuticals in the ICU setting, we searched the PubMed/Medline and International Pharmaceutical Abstracts databases and other related sources to identify published cost-saving protocols concerning specific medications that are affected by rising prices or have traditional high acquisition costs. In the absence of specific protocols, we offer possible cost-saving initiatives based on published literature regarding specific agents or based on our own diverse set of experiences. Finally, we review suggested clinical and operational activities at an institutional level to address these rising drug costs in the ICU setting., (© 2016 Pharmacotherapy Publications, Inc.)

An adult diabetic male with three toes amputated on his right foot presented with an ulcer infection on his left foot, unresponsive to conventional antifungal oral medication for over two months. The ulcerated foot wound had a large impairment on the patient's quality of life, as determined by the Wound-QoL questionnaire. The compounding pharmacist recommended and the physician prescribed two topical compounded medicines, which were applied twice a day, free of charge at the compounding pharmacy. The foot ulcer infection was completely resolved following 13 days of treatment, with no longer any impairment on the patient's quality of life. This scientific case study highlights the value of pharmaceutical compounding in current therapeutics, the importance of the triad relationship, and the key role of the compounding pharmacist in diabetes care., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Background: Computed tomography coronary angiography (cTCA) and stress cardiac magnetic resonance (stress-CMR) are suitable tools for diagnosing obstructive coronary artery disease in symptomatic patients with previous history of revascularization. However, performance appraisal of noninvasive tests must take in account the consequent diagnostic testing, invasive procedures, clinical outcomes, radiation exposure, and cumulative costs rather than their diagnostic accuracy only. We aimed to compare an anatomic (cTCA) versus a functional (stress-CMR) strategy in symptomatic patients with previous myocardial revascularization procedures., Methods and Results: Six hundred patients with chest pain and previous revascularization included in a prospective observational registry and evaluated by clinically indicated cTCA (n=300, mean age 68.2±9.7 years, male 255) or stress-CMR (n=300, mean age 67.6±9.7 years, male 263) were enrolled and followed-up in terms of subsequent noninvasive tests, invasive coronary angiography, revascularization procedures, cumulative effective radiation dose, major adverse cardiac events, defined as a composite end point of nonfatal myocardial infarction and cardiac death, and medical costs. The mean follow-up for cTCA and stress-CMR groups was similar (773.6±345 versus 752.8±291 days; P=0.21). Compared with stress-CMR, cTCA was associated with a higher rate of subsequent noninvasive tests (28% versus 17%; P=0.0009), invasive coronary angiography (31% versus 20%; P=0.0009), and revascularization procedures (24% versus 16%; P=0.007). Stress-CMR strategy was associated with a significant reduction of radiation exposure and cumulative costs (59% and 24%, respectively; P<0.001). Finally, patients undergoing stress-CMR showed a lower rate of major adverse cardiac events (5% versus 10%; P<0.010) and cost-effectiveness ratio (119.98±250.92 versus 218.12±298.45 Euro/y; P<0.001)., Conclusions: Compared with cTCA, stress-CMR is more cost-effective in symptomatic revascularized patients., (© 2016 American Heart Association, Inc.)

Background: The mainstay of acute management of intracerebral hemorrhage (ICH) is blood pressure reduction. Intravenous (IV) nicardipine is an effective but costly intervention for blood pressure reduction in the intensive care unit (ICU). Earlier transition to oral (PO) antihypertensive agents may reduce ICU length of stay (LOS) and associated costs. We sought to study the effectiveness of an interdisciplinary intervention to start earlier transition to PO antihypertensives., Methods: From July 2011 to July 2012, patients with ICH who received IV nicardipine were reviewed and screened for eligibility by an interdisciplinary team including physicians and pharmacists. These patients were compared to a control group 1 year prior to this intervention. The duration of nicardipine treatment (median hours), estimated costs, and ICU LOS were measured., Results: A total of 35 patients and 44 controls were studied. The median hours of IV nicardipine use were significantly decreased from a baseline mean of 118 to 30 hours (P < .001); total cost savings per year was $433,566 ($18,475 per patient). The average LOS remained similar (8.4 versus 8.9 days, P < .990). In a follow-up study 1 year later, after the intervention was no longer used, a sample of 21 consecutive patients was reviewed and the duration of IV nicardipine treatment had increased to a mean of 96 hours., Conclusion: A physician and pharmacist-led project to initiate oral antihyperintensive medications earlier was successful in reducing the duration of IV nicardipine treatment in patients with ICH while leading to substantial cost savings., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Direct comparisons of inhaled nitric oxide (iNO) to inhaled epoprostenol (iEPO) in patients with acute pulmonary hypertension (PHT) following cardiac surgery are lacking., Objective: To compare the relative efficacy, safety, and cost of iNO versus iEPO in patients with acute PHT following cardiac surgery., Methods: This is a single-center, retrospective, observational, cohort study comparing iNO to iEPO for acute postoperative PHT following cardiac surgery. The primary outcome was reduction of mean pulmonary artery pressure (mPAP) to < 30 mm Hg, 6 hours after ICU admission from the operating room. Secondary outcomes, included ICU and hospital length of stay, duration of mechanical ventilation, bleeding complications, hypotension, in-hospital mortality, and cost., Results: A total of 98 patients met inclusion criteria (iNO, n = 49; iEPO, n = 49). There was no difference in the primary outcome of reduction of mPAP to < 30 mm Hg 6 hours after ICU admission (iNO, 33 [67%] vs iEPO, 35 [71%]; P = 0.83) or in the incidence of adverse events collected (iNO, 10 [20%] vs iEPO, 11 [22%]; P = 1.00). Based on cost estimates, the median cost of iEPO per patient was $363.53 ($226-$864.60) versus $2562.50 ($1875-$8625) for iNO (P < 0.01)., Conclusions: The relative efficacy of iEPO appeared to be similar to that of iNO in reducing mPAP following cardiac surgery, in this retrospective review. Significant cost savings were associated with the use of iEPO., (© The Author(s) 2015.)

Acute respiratory distress syndrome (ARDS) is a syndrome of acute lung injury that is characterized by noncardiogenic pulmonary edema and severe hypoxemia second to a pathogenic impairment of gas exchange. Despite significant advances in the area, mortality remains high among ARDS patients. High mortality and a limited spectrum of therapeutic options have left clinicians searching for alternatives, spiking interest in selective pulmonary vasodilators (SPVs). Despite the lack of robust evidence, SPVs are commonly employed for their therapeutic role in improving oxygenation in patients who have developed refractory hypoxemia in ARDS. While inhaled epoprostenol (iEPO) also impacts arterial oxygenation by decreasing ventilation-perfusion (V/Q) mismatching and pulmonary shunt flow, this effect is not different from inhaled nitric oxide (iNO). The most effective and safest dose for yielding a clinically significant increase in PaO2 and reduction in pulmonary artery pressure (PAP) appears to be 20-30 ng/kg/min in adults and 30 ng/kg/min in pediatric patients. iEPO appears to have a ceiling effect above these doses in which no additional benefit may be derived. iNO and iEPO have shown similar efficacy profiles; however, they differ with respect to cost and ease of therapeutic administration. The most beneficial effects of iEPO have been seen in adult patients with secondary ARDS as compared with primary ARDS, most likely due to the difference in etiology of the two disease states, and in patients suffering from baseline right ventricular heart failure. Although iEPO has demonstrated improvements in hemodynamic parameters and oxygenation in ARDS patients, due to the limited number of randomized clinical trials and the lack of studies investigating mortality, the use of iEPO cannot be recommended as standard of care in ARDS. iEPO should be reserved for those refractory to traditional therapies., (© The Author(s), 2015.)

Background: Proven strategies to reduce right ventricular (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation are lacking. We sought to evaluate the tolerability, feasibility, efficacy, and pharmacokinetics of inhaled milrinone (iMil) delivery after CF-LVAD implantation., Methods and Results: We prospectively evaluated fixed-dose nebulized iMil delivered into a ventilator circuit for 24 hours in 10 postoperative CF-LVAD (Heartmate-II) patients. Tolerability (arrhythmias, hypotension, and hypersensitivity reaction), efficacy (hemodynamics), pharmacokinetics (plasma milrinone levels), and cost data were collected.Mean age was 56 ± 9 years, 90% were male, and mean INTERMACS profile was 2.5 ± 0.8. No new atrial arrhythmia events occurred, although 3 (30%) ventricular tachycardia (1 nonsustained, 2 sustained) events occurred. Sustained hypotension, drug hypersensitivity, death, or need for right ventricular assist device were not observed. Invasive mean pulmonary arterial pressure from baseline to during iMil therapy was improved (P = .017). Mean plasma milrinone levels (ng/mL) at baseline, and 1, 4, 8, 12, and 24 hours were 74.2 ± 35.4, 111.3 ± 70.9, 135.9 ± 41.5, 205.0 ± 86.7, 176.8 ± 61.3 187.6 ± 105.5, respectively. Reduced institutional cost was observed when iMil was compared with nitric oxide therapy over 24 hours ($165.29 vs $1,944.00, respectively)., Conclusions: iMil delivery after CF-LVAD implantation was well tolerated, feasible, and demonstrated favorable hemodynamic, pharmacokinetic, and cost profiles. iMil therapy warrants further study in larger clinical trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Nebivolol is a highly selective β1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via β1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via β3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory β-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While β-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other β-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other β-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.

Purpose: Pentaerythrityl tetranitrate (PETN) was the most commonly prescribed long-acting nitrate in Germany. We aimed to assess whether the discontinuation of PETN reimbursability in 2011 resulted in alternative prescriptions of anti-anginal medications or in a discontinuation of anti-anginal therapy., Methods: This is an observational study using health claims data from one German federal state analysing all patients discontinuing a PETN treatment. Patients starting a new alternative anti-anginal treatment (long-acting nitrates, molsidome, ivabradine and ranolazine) were compared with patients without a new anti-anginal treatment with respect to use of short-acting nitrates, beta blockers (BBs) and calcium channel blockers (CCBs)., Results: Out of 12,909 patients, 12,763 (99%) discontinued PETN until 12/2012. Of these, 52% started an alternative anti-anginal treatment, 43% did not receive any alternative treatment and 5% were excluded from analysis. Before termination of PETN reimbursability, 65% of patients received BBs, 29% CCBs and 10% short-acting nitrates. In patients started on alternative anti-anginal treatment, prescription rates for short-acting nitrates, BBs and CCBs remained constant after discontinuing PETN. In patients without any alternative anti-anginal treatment, prescription rates for BBs and CCBs did not change meaningfully (<3%), and prescription rates for short-acting nitrates decreased from 9% to 6%., Conclusions: Half of the patients discontinued PETN without alternative. This did not lead to increased prescription rates of standard IHD medications or total medication number indicating that there might still be a high percentage of ischaemic heart disease patients treated unnecessarily with long-acting nitrates. The undertreatment with prognostically relevant first-line medications indicates a need for better guideline implementation activities., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: We reported recently that early use of inhaled nitric oxide therapy (iNO) for term and late preterm infants with hypoxic respiratory failure (HRF) at an oxygenation index (OI) of ≥15 and <20 is associated with earlier discharge from the hospital, relative to babies treated at OI ≥25. The objective of the present analysis is to determine whether earlier use of iNO in this cohort leads to lower cost of medical care., Methods: We used a decision-analytic model, which was developed to compare hospital resource use and costs associated with early versus standard use of iNO in HRF. The model population included infants with moderate HRF caused by primary pulmonary hypertension with an OI ≥15 and <20. A hypothetical case population of 1000 patients was assumed and probabilistic sensitivity analyses were completed where all the clinical inputs into the model were varied. Two deterministic sensitivity analyses were also completed, one surrounding the hospital cost inputs and another surrounding the cost of iNO., Results: Early iNO was associated with fewer hospital days, fewer days of ventilation and fewer hours on extracorporeal membrane oxygenation (ECMO). In probabilistic sensitivity analyses, total costs per patient were $88,518 ± $7574 and $92,581 ± $9664 for early iNO and standard iNO, respectively. The probability of early iNO being cost-effective was approximately 72%, based on a willingness to pay $100,000 or less to prevent ECMO therapy and/or death. In both deterministic sensitivity analyses, early iNO was cost-saving., Conclusion: Our analysis shows that early use of iNO at an OI of ≥15 and <20 may be associated with shorter hospitalizations and a decreased cost of care for term/late preterm infants with HRF associated with pulmonary hypertension. Our results are based on clinical data from a single trial; future research using data from real-world practice is warranted.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Background: Little is known concerning the degree to which initiation of sildenafil for pulmonary arterial hypertension (PAH) impacts patterns of healthcare utilization and costs., Methods: Using a large US health insurance claims database, we identified all patients with evidence of PAH (ICD-9-CM diagnosis codes 416.0, 416.8) who received sildenafil between 1/1/2005 and 9/30/2008. Date of the first-noted prescription for sildenafil was designated the "index date," and claims data were compiled for all study subjects for 6 months prior to their index date ("pretreatment") and 6 months thereafter ("follow-up"); patients with incomplete data during either of these periods were excluded. Healthcare utilization and costs were then compared between pretreatment and follow-up for all study subjects., Results: A total of 567 PAH patients were identified who began therapy with sildenafil and met all other study entry criteria. Mean (SD) age was 52 (10) years; 73% were women. Healthcare utilization was largely unchanged between pretreatment and follow-up, the only exceptions being decreases in the mean number of emergency department visits (from 0.7 to 0.5 per patient; p<0.01) and the percentage of patients hospitalized (from 35% to 29%; p=0.01). The mean cost of all PAH-related medication was $7139 during pretreatment and $14,095 during follow-up (sildenafil cost during follow-up= $5236); exclusive of PAH-related medications, however, total healthcare costs decreased modestly (from $30,104 to $27,605) (p<0.01 for all comparisons)., Conclusions: The cost of sildenafil therapy may be partially offset by reductions in other healthcare costs.

Background: Pulmonary arterial hypertension (PAH) is considered an orphan disease. Prostacyclins are the keystone for PAH treatment. Choosing between the three available prostacyclin therapies could be complicated because there are no comparison studies, so the final decision must be driven by factors such as efficacy, administration route, safety profile and economic aspects., Objective: This study provides a cost-effectiveness and cost-utility comparison of initiating prostacyclin therapy with three different treatment alternatives (inhaled iloprost [ILO], intravenous epoprostenol [EPO] and subcutaneous treprostinil [TRE]) for patients with PAH. The goal of this work is to help physicians with their therapeutic decision-making., Methods: A Markov model was built to simulate a patient cohort with class III PAH according to the classification of the New York Heart Association (NYHA). Four health states corresponding with the NYHA classes plus death were allowed for patients in the model. Changing the treatment was possible when patients worsened from functional class III to IV. The time horizon was 3 years, allowing patients to transition between health states on a 12-week cycle basis. The study perspective was that of the National Health System (NHS) [only direct medical costs were included]. Unitary costs were obtained from the Drug Catalogue and e-Salud Database in 2009 and are given in euros (€). Data on health resources and treatment pathways were informed by a four-member expert panel. Efficacy was obtained from pivotal clinical trials of ILO, EPO and TRE, the latter used in Spain as a foreign medication. Utilities for each health state were obtained from the literature. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). Costs and effects were discounted at a 3% rate. To check for the robustness of the results, sensitivity analyses were performed., Results: At the end of the 3 years, in the base case of the deterministic analysis, initiating prostacyclin therapy with iloprost was the less costly strategy (€132,840), followed by treprostinil (€359,869) and epoprostenol (€429,775). Epoprostenol has shown the best efficacy results with 2.73 LYG and 1.78 QALY, followed by iloprost (2.69 LYG and 1.74 QALY) and treprostinil (2.69 LYG and 1.73 QALY). Incremental cost-effectiveness ratios (ICER) and cost-utility ratios (ICUR) of epoprostenol versus iloprost and treprostinil were much above the €30,000 per LYG or QALY threshold commonly used in Spain. Iloprost was dominant compared with treprostinil. In the probabilistic analysis, epoprostenol, when compared with iloprost, was a dominant strategy in 15% of the simulations, but it was not a cost-effective option in 83% of the cases. When compared with treprostinil, epoprostenol was dominant in 43% of the simulations. Iloprost was dominant compared with treprostinil in 45% of the cases and it was a cost-effective alternative in 39% of the simulations., Conclusions: Initiating prostacyclin treatment with iloprost in patients with PAH, functional class III of the NYHA, is the less costly alternative for the NHS in Spain, with a good efficacy profile when compared with the other alternatives.

Background: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest., Objective: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management., Data Source: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews)., Review Methods: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%., Results: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs)., Conclusions: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

The health and economic implications of new imaging technologies are increasingly relevant policy issues. Cardiac magnetic resonance imaging (CMR) is currently not or not sufficiently reimbursed in a number of countries including Germany, presumably because of a limited evidence base. It is unknown, however, whether it can be effectively used to facilitate medical decision-making and reduce costs by serving as a gatekeeper to invasive coronary angiography. We investigated whether the application of CMR in patients suspected of having coronary artery disease (CAD) reduces costs by averting referrals to cardiac catheterization. We used propensity score methods to match 218 patients from a CMR registry to a previously studied cohort in which CMR was demonstrated to reliably identify patients who were low-risk for major cardiac events. Covariates over which patients were matched included comorbidity profiles, demographics, CAD-related symptoms, and CAD risk as measured by Morise scores. We determined the proportion of patients for whom cardiac catheterization was deferred based upon CMR findings. We then calculated the economic effects of practice pattern changes using data on cardiac catheterization and CMR costs. CMR reduced the utilization of cardiac catheterization by 62.4%. Based on estimated catheterization costs of € 619, the utilization of CMR as a gatekeeper reduced per-patient costs by a mean of € 90. Savings were realized until CMR costs exceeded € 386. Cost savings were greatest for patients at low-risk for CAD, as measured by baseline Morise scores, but were present for all Morise subgroups with the exception of patients at the highest risk of CAD. CMR significantly reduces the utilization of cardiac catheterization in patients suspected of having CAD. Per-patient savings range from € 323 in patients at lowest risk of CAD to € 58 in patients at high-risk but not in the highest risk stratum. Because a negative CMR evaluation has high negative predictive value, its application as a gatekeeper to cardiac catheterization should be further explored as a treatment option.

Objectives: to categorise online suppliers of Viagra based on their legal status, and to quantify the suppliers within each category., Methods: Google was used to search for websites offering to sell or supply either proprietary Viagra tablets or generic versions containing sildenafil citrate. Relevant websites were classified as falling into one of three categories, which were further subclassified. Simple descriptive statistics were calculated., Key Findings:  the number of relevant sites found within the first 100 Google hits, following the removal of mirror and affiliate sites, was 44. Only 6.8% of sites identified were legitimate online pharmacies. Some 34.1% of sites offered to sell Viagra to patients in the UK without any form of medical consultation. Whether or not the online consultation offered by 59.1% of sites had to be completed in order to make a purchase could not be confirmed. The location of only three pharmacies could be ascertained; the remainder made various claims as to their location, which could not be verified., Conclusions: we have been unable to verify that the questionnaires used for online consultations are scrutinised by any healthcare practitioners to determine the appropriateness of the treatment sought. This represents a serious safety concern for UK residents who procure drugs for erectile dysfunction on the internet.

Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition that is characterized by supra-systemic pulmonary vascular resistance causing right-to-left shunting through the ductus arteriosus and/or foramen ovale, leading to a vicious cycle of hypoxemia, acidosis and further pulmonary vasoconstriction. Advances in neonatology including surfactant instillation, high-frequency ventilation, extracorporeal membrane oxygenation and, most importantly, inhaled nitric oxide (INO), have revolutionized the management of PPHN. However, given that INO does not improve oxygenation in a significant proportion (30-40%) of cases, there is an urgent need to consider other therapeutic options for PPHN. The issue is more important for developing nations with a higher PPHN-related health burden and limited resources. This article discusses the evidence about INO in term and preterm neonates in brief, and focuses mainly on the potential alternative drugs in the management of PPHN.

Sildenafil is an orally administered phosphodiesterase type 5 inhibitor that is approved for the treatment of pulmonary arterial hypertension (PAH). The hemodynamic effects of sildenafil are mitigated primarily via potentiating the effects of endogenous nitric oxide, leading to smooth muscle cell relaxation and reductions in pulmonary arterial pressures and pulmonary vascular resistance. When added to standard background therapy in patients with idiopathic or associated PAH from congenital heart disease, anorexigen use, or connective tissue disease, sildenafil treatment results in improved exercise capacity as measured by 6 minute walk distance, improved hemodynamics, and favorable changes in quality of life. Sildenafil use is contraindicated with concomitant nitrate administration, and caution should be exercised when used in combination with antihypertensive agents due to risks of precipitating hypotension. Side effects are generally mild, and include flushing, headaches, and epistaxis. The combination of sildenafil with intravenous epoprostenol is safe and well tolerated, and further improves exercise capacity. Sildenafil is approved only for treatment of PAH, and although emerging data suggest a potential role in treating other types of pulmonary hypertension, larger trials are required to confirm these findings.

Objective: To explore treatment patterns and resource utilization and cost for subjects with pulmonary arterial hypertension (PAH)., Research Design: Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization., Results: In the final sample of PAH patients treated with bosentan (n=251) or sildenafil (n=455), average age was 57 years, 86% of patients were commercially insured, and 52% of patients were male. Gender distribution varied significantly across subgroups, with a lower proportion of males in the bosentan (30%) subgroup compared with the sildenafil group (64%) (p<0.001). Average baseline Charlson comorbidity score was 2.4. Average numbers of fills per month were 0.8 and 0.4 for bosentan and sildenafil patients, respectively (p<0.001). Over 80% of patients received only one PAH treatment in the first 90 days following the index date, with 28% of bosentan and 13% of sildenafil patients receiving combination therapy (p<0.001). Over one-third of bosentan patients and one-quarter of sildenafil patients experienced a dose increase in the follow-up period (p=0.009). Sixteen percent of sildenafil patients experienced a dose decrease in the follow-up period, while a smaller proportion of patients receiving bosentan (4%) experienced a dose decrease (p<0.001). On average, number of PAH-related per subject per month (PSPM) inpatient stays and emergency department visits and PSPM length of inpatient stays were statistically similar between the subgroups. PAH-related PSPM healthcare costs were high for both subgroups, with average monthly costs of $5,332 and $3,632 among bosentan and sildenafil patients, respectively (p=0.003). Differences in total costs were driven mainly by differences in pharmacy expenditures., Conclusions: Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, such as the potential for coding errors and lack of information on whether a drug was taken as prescribed. Furthermore, PAH severity (WHO functional class) was not assessed.

Objective(s): To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications., Data Sources: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies., Review Methods: The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out., Results: In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results., Conclusion(s): All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

The aim of this study was to evaluate clinical and pharmacoeconomic effects of long-term use of trimetazidine MR in patients with ischemic heart disease (IHD) undergoing coronary artery bypass grafting (CABG). Patients with IHD (n=306) were included in open, prospective, randomized clinical trial. One group (group 1, n=153) was pretreated with trimetazidine MR two weeks prior to CABG and continued to take trimetazidine MR for 3 years after the procedure. The other group without of trimetazidine MR (group 2, n=153) was the group of comparison. All patients received conventional therapy of IHD. Six hours after CABG serum creatinine kinase and creatinine-kinase MB were significantly lower in group 1 than in group 2. Rate of ischemic events was also lower in patients treated with trimetazidine MR. Long-term use of trimetazidine MR was characterized by improvement of left ventricular systolic function and exercise tolerance and associated with lower expenses for treatment. We concluded that trimetazidine MR appeared to reduce myocardial reperfusion injury after CABG in patients with IHD.

Acute decompensated heart failure (ADHF) is a growing public health problem with high mortality and costs. ADHF often, if not usually, occurs in the setting of cardiovascular and noncardiovascular comorbidities as well as advanced age. New insights provide support for the concept of heart failure as a state of deficiency of and/or resistance to endogenous B-type natriuretic peptide. The primary goals of ADHF therapy are to relieve symptoms and optimize volume status with minimal side effects. Few therapies are proven to effectively do so. Nesiritide is a balanced vasodilator with favorable neurohumoral effects and is superior to placebo in providing rapid symptom relief and to nitroglycerin in reducing filling pressures. Recent trials confirm a lack of renal toxicity at recommended doses. An adequately powered multinational mortality trial is underway. Nesiritide represents a proven therapy for normotensive/hypertensive ADHF patients with severe symptoms at rest.

Introduction: Both pentaerythrithyltetranitrate (Pentalong, PETN) and isosorbide dinitrate (ISDN) are commonly used in the therapy of ischemic heart disease (IHD). However, little is known about the therapeutic patterns in diabetic patients and no comparative data are available regarding the prescription costs of these two substances. Thus, the aim of this investigation was to compare the costs for PETN and ISDN therapy in diabetic patients in primary care., Material and Methods: All continuously treated patients aged > or = 40 years with diabetes (anti-diabetic agents) and IHD or angina pectoris (ICD codes) and newly started on PETN or ISDN therapy (index date) in the period 2000-2005 were selected from a database containing data from 400 practices throughout Germany (Disease Analyzer, IMS Health). Prescriptions costs for PETN and ISDN, as well as costs for cardiovascular comedication, were determined for the period 183 days before and after the index date, and that changes in costs after the index date were calculated. Differences in costs between the two groups were evaluated using multivariate regression, adjusting for age, sex and comorbidity. Patients in Eastern (n = 137, age 71 +/- 10 years, 55% male) and Western Germany (n = 212, age 73 +/- 9 years, 50% male) were analyzed separately since there is a longer history of PETN use in Eastern Germany., Results: Significantly more patients were treated with PETN in Eastern Germany (61 vs. 11%, p < 0.05). The patient groups treated with PETN and ISDN differed with respect to sex and comorbidity. PETN therapy was more expensive than ISDN therapy in both German regions (adjusted cost differences were 10 and 17 Euro). However, when comedication was taken into account, a smaller cost increase after the index date was observed in the PETN group than in the ISDN group (non-significant cost savings of 43 and 52 Euro after adjustment for Western and Eastern Germany, respectively)., Conclusion: PETN therapy tends to produce a saving in costs compared to ISDN therapy in diabetic patients when costs for comedication are taken into account and after adjustment for age and comorbidity. The prescription patterns in Eastern and Western Germany and the patient characteristics of those receiving PETN and ISDN differed, indicating differences in patients selection and prescribing by physicians in the two regions.

Introduction: Pulmonary arterial hypertension, both primary and secondary, continues to pose a therapeutic problem. In this study, we evaluate the efficacy and safety of a low-dose of oral sildenafil in 10 patients with pulmonary arterial hypertension., Methods: We administered a single daily dose of 0.5 milligrams per kilogram of sildenafil for 3 months to 10 patients with pulmonary arterial hypertension. Their average age was 26.8 years. Diagnoses were primary pulmonary arterial hypertension in 3 patients, and secondary pulmonary arterial hypertension due to congenital cardiac disease in the remaining 7 patients. Outcome measures included the clinical state, the mean pulmonary arterial pressure, and the indexed pulmonary vascular resistance; the latter two assessed at the beginning and at the end of the treatment period by cardiac catheterization. We also analysed the cost of the treatment., Results: Oral treatment was well tolerated, and resulted in an improvement of the functional capacity in 9 of the 10 patients. Pulmonary arterial pressure decreased from 70 to 60 millimetres of mercury (p equal to 0.05), and indexed pulmonary vascular resistance decreased from 21.8 to 15.8 Wood units per square metre (p equal to 0.006). The mean cost per patient for 3 months on oral treatment with sildenafil was 120.99 American dollars., Conclusions: A low dose of 0.5 milligrams per kilogram per day of oral sildenafil, instead of 1 to 4 milligrams per kilogram per day, provided early clinical and haemodynamic improvements, and proved less expensive. Additional experience is now required to define more reliably the true long-term benefits of this therapy.

Background: Coronary saphenous vein bypass graft (SVG) stenting has been associated with up to a 30% rate of no-reflow or myocardial infarction (MI) when performed without distal protection., Methods: We evaluated the technique using prophylactic pharmacologic arteriolar vasodilatation with intracoronary nicardipine followed by immediate direct stenting for the treatment of degenerated coronary SVGs without mechanical distal protection. Data were collected from 83 consecutive elective SVG interventions in 68 patients. Quantitative coronary angiographic measurements were performed by the Borgess angiographic core lab. Electrocardiograms (ECGs), CPKs, and CPK-MBs were obtained preprocedure and at 12 to 18 hours after the intervention. Follow-up data at 30 days were obtained in 67/68 (98%) patients., Results: The average graft age was 11.9 +/- 6.6 years with thrombus in 26/83 vessels (31%). The primary adverse endpoint of total CPK >3 times the upper limit of normal (ULN), or CPK-MB >3 times the ULN were seen in 1/68 (1.5%) and 3/68 (4.4%) patients, respectively. No-/slow-reflow was observed transiently in 2/83 SVG interventions (2.4%). Of the patients, 1/68 had persistent, minor ECG changes after stenting (1.4%). No patient had a Q-wave MI. Inhospital major adverse cardiac events (MACE) (death, MI, repeat TLR) were observed in only 3/68 patients (CPK-MB elevation). There were no additional MACE events (0/68) from hospital discharge to 30 days., Conclusions: (1) Prophylactic vasodilatation with intragraft nicardipine followed by direct stenting appears to be a safe and effective means of performing elective SVG revascularization; (2) this approach may provide a simple and time- and cost-effective alternative or adjunct to mechanical distal protection for elective SVG interventions.

Background: Inhaled nitric oxide (iNO) use is widespread, but the long-term outcomes after therapy in adult patients remain unknown., Methods: All 376 patients receiving perioperative iNO (excluding pediatric and interventional cardiology procedures) at Columbia University Medical Center were prospectively followed from 2000 to 2003. Survival data were collected from chart review., Results: Inhaled nitric oxide was used to treat pulmonary and right ventricular failure in patients undergoing orthotopic heart transplantation (OHT, n = 67), orthotopic lung transplantation (n = 45), cardiac surgery (n = 105), and ventricular assist device placement (n = 66), and for hypoxemia in other surgery (n = 34) and medical patients (n = 59). Average follow-up was 2.9 +/- 1.0 years. Overall mortality was lowest when iNO was used after OHT (25.4%) and orthotopic lung transplantation (37.8%), intermediately after cardiac surgery (61%), ventricular assist device (62%), and other surgery patients (75%), and highest among medical patients (90%; all p < 0.005). The cost of iNO therapy was lower in transplantation versus medical patients, with a trend toward shorter duration of use. In multivariate analysis, respiratory failure and use in non-OHT were independent predictors of mortality (both p = 0.001). A risk score greater than 1 (score = non-OHT use 1, plus right ventricular failure 1) predicted a mortality of 76.5% versus 37.2% (p < 0.001)., Conclusions: Use of iNO for pulmonary hypertension in patients undergoing OHT and orthotopic lung transplantation was associated with a significantly lower overall mortality rate compared with its use after cardiac surgery or for hypoxemia in medical patients. Inhaled nitric oxide does not appear to be cost effective when treating hypoxemia in medical patients with high-risk scores and irreversible disease.

Background: Heparin remains the drug most commonly used for anticoagulation in continuous renal replacement therapies (CRRTs). However, in patients with hypercoagulability, heparin is insufficient or, in cases with an increased risk of bleeding or thrombocytopenia, it may be contraindicated. Epoprostenol, a potent vasodilator, antithrombotic and antiplatelet agent, could be an alternative., Patients and Methods: We studied the records of patients treated under continuous venovenous hemodiafiltration in an academic tertiary hospital of 900 beds, between January 2000 and June 2003. Epoprostenol was prescribed to patients with (i) filter hypercoagulability, defined as consumption of 2 or more filters in the last 24 hours; (ii) low platelet count; or (iii) recent severe hemorrhage., Results: Thirty-eight out of 248 (15%) patients who were under CRRT received epoprostenol for more than 72 hours. Epoprostenol was indicated due to filter hypercoagulability in 48%, thrombocytopenia in 68% (7 patients both) and hemorrhage in 3% of cases. The overall time for epoprostenol therapy was 9,749 hours. The mean filter duration previous to epoprostenol was 23 +/- 12 hours and after administering this drug 38.2 +/- 11.9 hours (p = 0.0001). In 6 patients, heparin and epoprostenol were simultaneously administered. The adverse effects were hemorrhage, which presented in 7 patients (18%) and a fall in blood pressure in another 7 (18%), which recovered in the next 24 hour after starting treatment. Cost analysis demonstrates some advantage with epoprostenol in patients with increased tendency to clotting., Conclusions: Epoprostenol may be safely used to prevent clotting of the extracorporeal circuits, either alone in patients with thrombocytopenia and/or increased risk of bleeding, or in combination with heparin in states of hypercoagulability.

Aim: This study was conducted to evaluate the health-related quality of life (HRQOL) and cost-effectiveness of LipoPGE(1) when added to the conventional treatment of arteriosclerosis obliterans (ASO) patients. The research design consisted of a before and after-treatment study without comparison groups. We collected data from May 1999 through July 2001 at 473 institutions located throughout Japan. The subjects were ASO patients who experienced pain at rest or had ulcers of the extremities., Methods: The observation period was a 2-month period that commenced with the start of administration of LipoPGE1. The HRQOL score (utility value) was obtained from the EQ-5D instrument, and the incremental cost-effectiveness ratio was calculated on the basis of quality-adjusted life years (QALYs)., Results: The mean utility value for the 2 months after the start of the administration of LipoPGE(1) was 0.672, and it was a significantly higher (P<0.0001) than the 0.616 before administration of LipoPGE(1). The incremental cost-effectiveness ratio was 18,807 US dollar/QALY assuming that drug efficacy persisted for 1 year after the end of LipoPGE1 therapy, and 75,227 dollar/QALY assuming a duration of just 3 months., Conclusions: We concluded that when LipoPGE1 is added to the conventional treatment of ASO patients, the HRQOL of the patient improves, and it is highly cost-effective.

Objective: To estimate the net cost of adding nicorandil to usual treatment for patients with angina and to compare this with indicators of health benefit., Design: Cost effectiveness analysis., Setting: Based on results of the IONA (impact of nicorandil on angina) trial., Patients: Patients with angina fulfilling the entry criteria for the IONA trial., Interventions: In one arm of the trial nicorandil was added to existing antianginal treatment and compared with existing treatment alone., Main Outcome Measures: Costs were for use of hospital resources (for cardiovascular, cerebrovascular, and gastrointestinal reasons), nicorandil, and care after hospital discharge. Benefits were assessed in three ways: (1) IONA trial primary outcome (coronary heart disease (CHD) death, non-fatal myocardial infarction, or hospital admission for cardiac chest pain); (2) acute coronary syndrome (CHD death, non-fatal myocardial infarction, or unstable angina); and (3) event-free survivors at the end of the trial., Results: The net cost for each additional IONA trial end point averted was -5 pounds sterling (-7 euros). The net cost for each case of acute coronary syndrome averted was -8 pounds sterling (-12 euros). The net cost for each event-free survivor was -5 pounds sterling (-7 euros). These figures are based on gastrointestinal events that were judged definitely or probably related to nicorandil. When all gastrointestinal events were included these three ratios rose to 567 pounds sterling (835 euros), 886 pounds sterling (1305 euros), and 516 pounds sterling (760 euros), respectively., Conclusions: A substantial amount of the additional cost of nicorandil is offset by reduced use of hospital services. The limited comparisons possible with other CHD interventions suggest that nicorandil compares favourably.