Clinical and economic impact of surgery for treating infantile hemangiomas in the era of propranolol: overview of single-center experience from La Paz Hospital, Madrid.

Propranolol has changed the management of infantile hemangiomas (IHs). We summarize the evolution of surgical treatment for IH at La Paz Children's Hospital (Madrid) in the era of propranolol, with a focus on hepatic IHs.Retrospectively, we compared surgical treatment of IHs in children referred during the periods 2004-2009 and 2009-2014. Hepatic IH mortality rates before and after the introduction of propranolol therapy were evaluated specifically.The majority of hemangiomas needing surgical excision were located on the head/face/scalp of female patients. Since the introduction of propranolol therapy, surgery for IH has decreased from about 60 to 6 procedures/year at our institution and no transplants for hepatic IH have been registered.Conclusions: Surgical procedures for IH have decreased by about 90% at our institution since the introduction of propranolol treatment and hepatic IH have not needed liver transplantation. Referrals for surgery for IH are generally the consequence of absent or delayed propranolol treatment. Given the significant reduction in the number of surgical procedures, propranolol can be considered as having a strong economic and social impact. What is Known: • The use of oral propranolol solution is currently considered as the treatment of choice in the management of infantile hemangiomas. • Propranolol treatment achieves better outcomes and less side effects than systemic corticosteroids. What is New: • Social and financial impact of the significant reduction in the number of reconstructive surgical procedures and liver transplants due to the use of propranolol in tertiary health institutions remains to be analyzed.

Repurposing existing medications as cancer therapy: design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation.

BACKGROUND: Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. METHODS: We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18-75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. RESULTS: One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. CONCLUSIONS: Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. TRIAL REGISTRATION: This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

Cost-effectiveness analysis of interventions for migraine in four low- and middle-income countries.

BACKGROUND: Evidence of the cost and effects of interventions for reducing the global burden of migraine remains scarce. Our objective was to estimate the population-level cost-effectiveness of evidence-based migraine interventions and their contributions towards reducing current burden in low- and middle-income countries. METHODS: Using a standard WHO approach to cost-effectiveness analysis (CHOICE), we modelled core set intervention strategies for migraine, taking account of coverage and efficacy as well as non-adherence. The setting was primary health care including pharmacies. We modelled 26 intervention strategies implemented during 10 years. These included first-line acute and prophylactic drugs, and the expected consequences of adding consumer-education and provider-training. Total population-level costs and effectiveness (healthy life years [HLY] gained) were combined to form average and incremental cost-effectiveness ratios. We executed runs of the model for the general populations of China, India, Russia and Zambia. RESULTS: Of the strategies considered, acute treatment of attacks with acetylsalicylic acid (ASA) was by far the most cost-effective and generated a HLY for less than US$ 100. Adding educational actions increased annual costs by 1-2 US cents per capita of the population. Cost-effectiveness ratios then became slightly less favourable but still less than US$ 100 per HLY gained for ASA. An incremental cost of > US$ 10,000 would have to be paid per extra HLY by adding a triptan in a stepped-care treatment paradigm. For prophylaxis, amitriptyline was more cost-effective than propranolol or topiramate. CONCLUSIONS: Self-management with simple analgesics was by far the most cost-effective strategy for migraine treatment in low- and middle-income countries and represents a highly efficient use of health resources. Consumer education and provider training are expected to accelerate progress towards desired levels of coverage and adherence, cost relatively little to implement, and can therefore be considered also economically attractive. Evidence-based interventions for migraine should have as much a claim on scarce health resources as those for other chronic, non-communicable conditions that impose a significant burden on societies.

Topiramate: new indication. Migraine prevention: best avoided.

(1) The first-line drug for prevention of migraines is propranolol: it is the most thoroughly evaluated treatment, and thus far no other drug has been found to be more effective. (2) Topiramate, an antiepileptic drug, is now also approved for migraine prevention. Only 3 out of 4 double-blind placebo-controlled trials showed that topiramate 100 mg/day was effective: on average, 46% of patients had a reduction of at least 50% in the frequency of migraines, compared to 23% of patients on placebo. Increasing the dose to 200 mg did not lead to better efficacy. (3) A double-blind trial versus propranolol failed to show that topiramate was as effective or better than propranolol. (4) Topiramate has numerous, frequent and sometimes serious adverse effects, mainly including neurosensory disorders (paraesthesias, language disorders, confusion) and gastrointestinal disturbances. (5) Topiramate treatment costs nearly 5 times more than propranolol. (6) In practice, the adverse effects of topiramate outweigh its efficacy in the prevention of migraine attacks.

Propranolol vs corticosteroids for infantile hemangiomas: a multicenter retrospective analysis.

OBJECTIVE: To determine whether propranolol therapy is safe and effective and superior to oral corticosteroids for treating infantile hemangiomas (IHs). DESIGN: Multicenter retrospective chart review. SETTING: University of Miami and Miami Children's Hospital, Miami, Florida. Patients  The study included 110 patients with IHs. MAIN OUTCOME MEASURES: The percentage of clearance was quantified by documented serial global photography and clinical examinations (length, height, and width) to segregate patients into 2 groups: patients who had clearance of 75% or more and patients who had less than 75% clearance. RESULTS: The mean duration of treatment was 7.9 months for propranolol and 5.2 months for oral corticosteroids. Fifty-six of 68 patients (82%) who were receiving propranolol achieved clearance of 75% or more compared with 12 of 42 patients (29%) who were receiving oral corticosteroids (P < .01). Adverse effects were minimal in the propranolol group: 1 patient had hypoglycemia and 2 patients had a nonspecifice skin eruption that was not associated with propranolol therapy. All 42 patients in the corticosteroid group had 1 or more adverse effects (P < .01). Relapse after discontinuation of propranolol therapy occurred in 2 of the 68 patients; however, both patients responded to propranolol therapy on reinitiation of treatment. Surgical referrals after treatment were required in 8 patients (12%) in the propranolol group and 12 patients (29%) in the oral corticosteroid group (P < .01). CONCLUSIONS: Propranolol therapy was more clinically effective and more cost-effective than oral corticosteroids in treating IHs. It also resulted in fewer surgical interventions and demonstrated better tolerance, with minimal adverse effects, compared with oral corticosteroids. Therefore, propranolol should be considered a first-line agent given its safety and efficacy in the treatment of IHs.

P3MC: a double blind parallel group randomised placebo controlled trial of Propranolol and Pizotifen in preventing migraine in children.

BACKGROUND: A recent Cochrane Review demonstrated the remarkable lack of reliable clinical trials of migraine treatments for children, especially for the two most prescribed preventative treatments in the UK, Propranolol and Pizotifen.Migraine trials in both children and adults have high placebo responder rates, e.g. of 23%, but for a trial's results to be generalisable "placebo responders" should not be excluded and for a drug to be worthwhile it should be clearly superior, both clinically and statistically, to placebo. METHODS/DESIGN: Two multicentre, two arm double blind parallel group randomised controlled trials, with allocation ratio of 2:1 for each comparison, Propranolol versus placebo and Pizotifen versus placebo. The trial is designed to test whether Propranolol is superior to placebo and whether Pizotifen is superior to placebo for the prevention of migraine attacks in children aged 5-16 years referred to secondary care out-patient settings with frequent migraine (2-6/4 weeks). The primary outcome measure is the number of migraine attacks during trial weeks 11 to 14. DISCUSSION: A strength of this trial is the participation of clinically well defined migraine patients who will also be approached to help with future longer-term follow-up studies. TRIAL REGISTRATION: ISRCTN97360154.

Migraine prophylactic drugs: proof of efficacy, utilization and cost.

OBJECTIVES: In order to understand the pattern of utilization of migraine prophylactic drugs by US physicians, we reviewed the scientific rigor of published trials of anti-migraine medications, assessed their cost, and tested the correlation, if any, between utilization, scientific rigor and cost. MATERIALS AND METHODS: Scientific rigor of published reports. We identified all placebo-controlled, randomized, double-blind trials of migraine prophylactic agents through Medline search, major Headache textbooks and proceedings of major scientific meetings where headache-related topics are discussed. We excluded trials that did not include placebo treatment during the active phase of the study. The trials were reviewed and rated for scientific rigor using a 5-point scale (scientific score [ss]; 1 = low, 5 = good), blinded to the physicians' utilization data and cost of the drugs. Studies that did not show benefit of the active drug over placebo were scored -1 to -5, thus allowing for the reverse logic of negative studies. US physicians utilization. Neurologists and primary care physicians (PCP) completed phone-mail-phone questionnaires which inquired about first and second choices of migraine prophylaxis. These choices were averaged to obtain a weighted average percent usage of each drug. Cost. The average wholesale price (AWP) of each drug was obtained from data published by Adelman and Von Seggern, and from the Amerisource (7/9/96) catalog. STATISTICAL ANALYSIS: Spearman's correlation coefficient was used to assess the relationship between the average ss, physician use, and cost of each drug. RESULTS: Propranolol (ss = 1.44), amitriptyline (ss = 2.33) and verapamil (ss = 1.00) were the three preferred migraine prophylactic drugs by both neurologists and PCPs. Approximately 10% of neurologists said that divalproex (ss = 3.75) would be their first or second choice. The selective serotonin reuptake blockers were favored by 13.21% of PCPs. All other prophylactic drugs were felt to be first or second line of treatment by less than 10% of either neurologists or PCPs. Except for one study (ss = 1) that showed that propranolol reduced the migraine frequency by 76% over placebo, trials of the three most preferred medications failed to demonstrate that the active drug is > 50% better than placebo, i.e. the difference in headache frequency when on placebo vs active drug is > 50%. Of the drugs available in the United States, flurbiprofen and metoprolol achieved the best ss (5.00 and 4.33, respectively) but their efficacy over placebo (23% and 14-33%, respectively) and cost ($67.2 and $65.6) were unfavorable. Neurologists and PCPs chose migraine prophylaxis on the basis of scientific merit (r = 0.644, p = 0.018; r = 0.576, p = 0.05, respectively) but not cost (r = -0.254, p = 0.45; r = -0.255, p = 0.455). CONCLUSION: The three most commonly chosen migraine prophylactic agents have not been shown irrefutably to prevent migraine. Furthermore, their benefit, if any, does not exceed 50% over placebo. The well-conducted recent trials that demonstrated the efficacy of divalproex in migraine prevention are steps in the right direction of finding the "ideal migraine preventative agent". Until that drug is discovered, it is difficult to argue that one migraine prophylactic medication is superior to another and accordingly should be used as a first line of treatment.