Follow-up of sickle cell disease patients with priapism treated by hydroxyurea

Hydroxyurea is one of the most successfully used therapies for sickle cell disease. Results of many clinical trials point to hydroxyurea administration for patients with frequent painful crises and acute chest syndrome. Priapism is one of the complications that could be prevented by hydroxyurea, but there are few reports demonstrating the results. Since November 1993, hydroxyurea has been used in our clinic for preventing priapism in patients with stuttering or major attacks who are still capable of achieving intercourse on demand. Five patients were enrolled in the study, and 4 cases benefited by this treatment. After the initial treatment for the acute attack, all five patients developed stuttering priapism. Hydroxyurea was then introduced at the initial dose of 10 mg/kg, and as the hydroxyurea dosage increased, the number or length of priapism episodes decreased. One to two months after the maximal dose (20-35 mg/kg) was introduced, the episodes disappeared. In two patients, we were forced to administer over 30 mg hydroxyurea/kg to abort the episodes, and, in another patient, 25 mg/kg was necessary. All patients present normal sexual activity. Hydroxyurea was discontinued in two patients, but stuttering priapism reappeared. Hydroxyurea was then re-introduced, and priapism disappeared. One patient, using 20 mg hydroxyurea/kg, had a 6-year remission of priapism after hydroxyurea administration; however, he experienced stuttering priapism, 1 month before a major attack, that progressed to impotence. During that month, he did not seek medical attention. In conclusion, the data here presented suggests that hydroxyurea may prevent priapism attacks in sickle cell disease, probably at higher doses than usually prescribed for painful crisis prevention.     

Value of prophylaxis vs on‐demand treatment: Application of a value framework in hemophilia

Introduction

Therapeutic advances over the past 30 years have led to longer life expectancy and improved quality of life (QOL) for persons with hemophilia. Access to innovative therapy may be compromised if treatment decisions are driven solely by cost. New strategies are needed to assess true therapeutic values, along with financial cost, as physicians, policymakers, payers and manufacturers work together to improve patient care.

Aim

To provide an evidence‐based assessment of the value of prophylaxis vs on‐demand therapy for hemophilia, based on a widely recognized three‐tiered value framework approach for assessing a range of therapeutic interventions.

Methods

Data from six randomized clinical trials (ESPRIT, Joint Outcomes Study, SPINART, LEOPOLD II, ADVATE and POTTER) and four observational studies comparing primary and secondary prophylaxis vs on‐demand therapy were applied to a hemophilia value framework.

Results

Both primary and secondary prophylaxis showed advantages in Tier 1 “Degree of health/recovery” outcomes, including measures of bleeding, musculoskeletal complications, pain, function/activity and QOL. Tier 2 “Process of Recovery” outcomes, also favoured prophylaxis, including measures of recovery time, return to normal activities, orthopaedic intervention and venous access. In Tier 3 “Sustainability of Health Recovery,” measures of breakthrough bleeds, joint preservation, sustained productivity and QOL showed significant improvement with prophylaxis.

Conclusion

The hemophilia value framework affirmed value of primary and secondary prophylaxis vs on‐demand therapy, with clinical benefit demonstrated in all three tiers. This analysis also demonstrates clinical utility of the value framework process in the determination of optimal and cost‐effective hemophilia care for all stakeholders.     

Akutversorgung des isch?mischen Schlaganfalls

New diagnostic and therapeutic developments have led to an innovative approach to stroke therapy. The slogan “time is brain” emphasizes that stroke is a medical emergency comparable to myocardial infarction. The stroke unit conception is an evidence based therapy for all stroke patients and improves outcome significantly. The monitoring of vitals signs and the management of stroke specific complications are highly effective. Early secondary prophylaxis reduces the risk of recurrence. The effect of CT based thrombolysis within the time window of 4,5 h has been substantiated by current data. Stroke MRI holds the promise for an improved therapy by patient stratification and by opening the time window. Interventional recanalisation, vascular interventions and hemicraniectomy complement the therapeutic options in the acute phase of stroke.     

The use of GLP‐1 receptor agonists in hospitalised patients: An untapped potential

In the outpatient setting, glucagon‐like peptide‐1 (GLP‐1) receptor agonists have proved to be highly efficacious drugs that provide glycaemic control with a low risk of hypoglycaemia. These characteristics make GLP‐1 receptor agonists attractive agents to treat dysglycaemia in perioperative or high‐dependency hospital settings, where glycaemic variability and hyperglycaemia are associated with poor prognosis. GLP‐1 also has a direct action on the myocardium and vasculature—which may be advantageous in the immediate aftermath of a vascular insult. This is a narrative review of the work in this area. The aim was to determine the populations of hospitalised patients being evaluated and the clinical and mechanistic end‐points tested, with the institution of GLP‐1 therapy in hospital. We searched the PubMed, Embase, and Google scholar databases, combining the term “glucagon‐like peptide 1” OR “GLP‐1” OR “incretin” OR “liraglutide” OR “exenatide” OR “lixisenatide” OR “dulaglutide” OR “albiglutide” AND “inpatient” OR “hospital” OR “perioperative” OR “postoperative” OR “surgery” OR “myocardial infarction” OR “stroke” OR “cerebrovascular disease” OR “transient ischaemic attack” OR “ICU” OR “critical care” OR “critical illness” OR “CCU” OR “coronary care unit.” Pilot studies were reported in the fields of acute stroke, cardiac resuscitation, coronary care, and perioperative care that showed advantages for GLP‐1 therapy, with normalisation of glucose, lower glucose variability, and lower risk of hypoglycaemia. Animal and human studies have reported improvements in myocardial performance when given acutely after vascular insult or surgery, but these have yet to be translated into randomised clinical trials.     

Do Automated Red Cell Exchanges Relieve Priapism In Patients with Sickle Cell Anemia?

Abstract: Priapism is a dramatic, painful complication for some men afflicted by sickle cell anemia. Although the natural history remains unclear, many believe replacing the patient's abnormal red blood cells (RBCs) with normal RBCs by apheresis is effective. However, no controlled trials have demonstrated its effectiveness. We exchanged 7 men after medical management failed. All procedures reduced sickle hemoglobin levels to < 30%. Two patients underwent emergency automated red cell exchanges without any detumescence or reduction of pain. The remaining 5 patients were exchanged non‐emergently; 4 experienced no detumescence or relief of pain. One adult experienced resolution 8 h postexchange. However, he had a history of “stuttering” priapism. All required decompression procedures. Automated RBC exchanges were not effective in achieving detumescence or reducing pain.     

Tertiary prophylaxis in adults: is there a rationale?

There is lack of evidence‐based recommendations or clear‐cut consensus regarding the clinical and economic utility of regular prophylaxis started in adulthood, with the aim of keeping the clinical situation from getting worse by prevention of further bleeds contributing to increasing musculo‐skeletal or other morbidity in haemophilia. Such a prophylaxis program has been shown in relatively small cohorts to be effective in reducing bleeding occurrence, with a variable effect on the joint status, but with significantly higher factor consumption and consequently higher costs than on‐demand therapy. There has been no attempt to identify subsets of patients who may benefit from “tertiary” prophylaxis more than others, for example, due to their bleeding phenotype and/or requirements for product issued on‐demand or to identify the dosage that provides the optimal balance of clinical benefit and cost effectiveness. This article reviews the published literature on prophylaxis started beyond the age of 18 years, the barriers to the uptake of prophylaxis programs particularly in adults and highlights areas in need of further research.     

Simple office‐based behavioral approach to patients with chronic belching

Chronic belching can be a difficult and socially disabling symptom often attributed to reflux with poor response to therapy. In patients where aerophagia is identified as a clear cause, treatment with baclofen may not be tolerated, and biofeedback therapy is time‐intensive and may still not be effective. In this pilot study, an office‐based easy‐to‐perform method based on sustained glottal opening was used in five patients with chronic belching, in whom reflux and other causes had been excluded. Treatment consisted of having the patient breathe slowly and diaphragmatically with his or her mouth open during supine, then sitting periods to prevent belching. When this was successful, patients were then counseled on continuing this breathing with mouth slightly ajar as an outpatient using this persistently. Wide mouth opening was used for rescue therapy of belching attacks. All five patients responded to the office‐based therapy with complete cessation of belching during the visit. At 1‐month follow up, four patients remained asymptomatic. One patient was asymptomatic but for two breakthrough attacks easily managed with the protocol. A simple office‐based procedure based on complete glottal opening can be curative for a subset of patients with chronic eructation secondary to repetitive air swallowing.     

Peyronie's disease: state of the art and future perspectives

Peyronie's disease (PD) is characterized by the onset of a fibrous plaque within the tunica albuginea of the penile corpora cavernosa, resulting in pain and bending during the erection, which can make the intercourse difficult or impossible. Evidence from literature supports the autoimmune etiology of PD, and suggests genetic and familiar conditions, penile traumatisms and history of genital tract diseases as risk factors, even though no definitive conclusions arise about the pathogenesis of the disease. Few randomized trials demonstrated that medical therapies, such as Vitamin E, Colchicine, Potassium amminobenzoate, Tamoxifen and injection therapy with Verapamil are effective in stabilizing the acute phase of the disease. Extracorporeal shock wave therapy (ESWT) and ionophoresis cannot be considered as first line or gold standard therapies. Satisfactory results have been published about Nesbit operation in large number of cases with low-stage disease, whereas plication procedures have shown significant rates of relapse. High incidence of long-term penile retraction have been reported in high-stage disease treated with plaque incision and simple graft insertion. Malleable, soft or inflatable prostheses combined with graft implant have given the best results in terms of penile straightening and lengthening and patients' satisfaction. In conclusion, the PD etiopathogenesis hasn't been clearly understood-yet, no medical therapy is fully effective; surgery remains therefore the gold standard in case of severe deformity and/or erectile dysfunction.     

Diabetes mellitus and male sexual function: a controlled study

Summary There is an extensive clinical literature on the erectile disorders of diabetic men but a paucity of controlled studies that have taken into account the effects of age, concurrent illnesses and medication on sexual function. This investigation was carried out on 40 diabetic men free from other illness or drugs that could affect sexual capacity and 40 age-matched healthy control subjects. Each subject and his female partner underwent semistructured interviews and the men had comprehensive medical evaluations and polygraphic assessment of sleep and nocturnal penile tumescence in the sleep laboratory during three nights. In comparison to control subjects, diabetic patients reported significant decreases in sexual desire, subjective arousal, erectile capacity, coital frequency and sexual satisfaction. The diabetic group also had significant decrements in duration of rapid eye movement sleep and in frequency, duration and degree of nocturnal penile tumescent episodes. There were no differences between Type 1 (insulin-dependent) and Type 2 (non-insulin dependent) diabetic patients in prevalence of sexual problems or in nocturnal tumescent measures. Significant relations were observed between lack of metabolic control, diabetic complications and impaired nocturnal tumescence. Sexually non-dysfunctional diabetic men had significant nocturnal penile tumescence abnormalities. Diabetic men without coital failures may have a subclinical impairment in erectile function which, although of not significant magnitude to interfere with penetration, is reflected in nocturnal penile tumescent measures. This result raises a note of caution in the interpretation of the nocturnal penile tumescence test for the differential diagnosis of diabetic erectile impotence.     

Current options for prophylactic treatment of hereditary angioedema in the United States: patient-based considerations

Hereditary angioedema (HAE) results from mutations in the C1-esterase inhibitor (C1 INH) gene that decrease production of C1 INH or render it dysfunctional. HAE is characterized by recurrent, unpredictable, bradykinin-mediated edema of the extremities, face, genitalia, trunk, gastrointestinal tract, or upper airway. Attacks causing laryngeal edema can be fatal. Patients with HAE need medications for acute attacks; some also require prophylaxis. Management requires consideration of the patient's disease burden and effect on the patient's quality of life. This review examines an individualized approach to identifying HAE patients who may benefit from prophylaxis. A literature search was performed for HAE and prophylaxis. HAE guidelines, case reports, safety studies, and randomized, controlled clinical prophylaxis trials were selected. Authors provided cases demonstrating individualized prophylaxis. U.S. Food and Drug Administration-approved options for prophylaxis of HAE include attenuated androgens and nanofiltered C1 INH (C1 INH-nf). In other countries, pasteurized C1 INH and purified C1 INH are also available. Alternative therapies include fresh frozen plasma for preprocedural prophylaxis and antifibrinolytics for long-term prophylaxis. Attenuated androgens reduce attack frequency in many patients. Adverse effects include weight gain, virilization, increased hair growth, hypercholesterolemia, depression, and liver adenomas. C1 INH-nf reduces frequency of attacks and is well tolerated. Each patient with HAE has unique needs, based on the nature and frequency of past attacks, proximity to a medical center, occupation, and the patient's wishes. These factors should be used to create a patient-centered approach to management of HAE.     

The prevalence of underpowered randomized clinical trials in rheumatology

OBJECTIVE: The conduct of underpowered randomized controlled trials (RCT) has recently been criticized in medical journals. We investigated the current prevalence of underpowered RCT in rheumatology. METHODS: We searched to identify randomized, prospective RCT assessing clinical efficacy of treatments for adult rheumatic diseases published in English in 2001 and 2002. RCT were assessed as positive or negative based on the result of the primary outcome measure. For phase III RCT with negative results without power analysis, we calculated adequate sample size using beta = 0.20 and alpha = 0.05. We also examined trial quality by assessing the adequacy of reported random sequence generation, allocation concealment, and analysis, and compared the quality of reporting of RCT with adequate and inadequate sample size. RESULTS: A total of 228 RCT met inclusion criteria; of the 205 phase III trials, 119 were positive, 81 were negative. The remaining 5 trials made no statistical comparison between interventions, and did not supply enough information for a result to be calculated. Of the 86 negative or indeterminate RCT, 37 reported sample size calculations (all but 4 had adequate power). Of the 49 remaining phase III trials that did not report power calculations, we conducted sample size calculations; only 10 were adequately powered. Few of the underpowered RCT studied rare rheumatic diseases. Negative RCT with inadequate sample size were less likely to describe adequate random sequence generation or allocation concealment than positive RCT or negative RCT with adequate sample size. CONCLUSION: The conduct of underpowered trials is not an infrequent occurrence in rheumatology, with only 50% of negative or indeterminate phase III rheumatology RCT in 2001-2002 having adequate sample size.     

Is prophylaxis required for delivery in women with factor VII deficiency?

Factor VII (fVII) deficiency is a rare congenital bleeding disorder in which fVII activity level and bleeding tendency do not completely correlate. Pregnancy and delivery present a significant haemostatic challenge to women with fVII deficiency. Treatment with recombinant factor VIIa (rfVIIa) carries a thrombotic risk and the literature is not clear whether prophylaxis is necessary prior to delivery. The aim of this study was to define management, haemorrhagic and thrombotic complications of pregnant women with fVII deficiency through a systematic review. Medical databases (PubMed, MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, Web of Science and Scopus) were searched using “factor VII deficiency” and “pregnancy” or “surgery.” Overall 34 articles, four abstracts, and three institutional cases were reviewed. Literature from 1953 to 2011 reported 94 live births from 62 women with fVII deficiency. The median fVII activity was 5.5%. Haemostatic prophylaxis was used in 32% of deliveries. Without prophylaxis, 40 vaginal deliveries and 16 caesarean sections were completed. The odds of receiving prophylaxis were 2.9 times higher in women undergoing caesarean section compared to vaginal delivery. Post‐partum haemorrhage occurred in 10% of deliveries with prophylaxis and 13% of deliveries without prophylaxis. The fVII level did not significantly differ between women who did and did not receive prophylaxis. We present the only systematic review of the management of pregnancy in fVII deficient women. No difference in post‐partum haemorrhage was seen in deliveries with and without prophylaxis. Therefore, we recommend that rfVIIa be available in the case of haemorrhage or surgical intervention, but not as mandatory prophylaxis.     

Dronedarone: Current Evidence and Future Questions

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting more than 2.2 million Americans. ACC/AHA/ESC guidelines for the management of patients with AF recommend amiodarone for maintaining sinus rhythm. Dronedarone is a derivative of amiodarone indicated for the treatment of AF. To provide an overview of dronedarone with a focus on the phase III trials and discuss unresolved questions of dronedarone. A literature search was conducted via the PubMed database using the keyword “dronedarone.” Search was limited to human trials in english. The FDA website was searched for briefing documents and subcommittee meetings on dronedarone. Clinicaltrials.gov was searched with the keyword dronedarone for upcoming or unpublished clinical trials. Five phase III trials are available for dronedarone: ANDROMEDA, EURIDIS/ADONIS, ATHENA, ERATO, and DIONYSIS. EURIDIS/ADONIS and ATHENA demonstrated a reduction AF recurrence with dronedarone compared to placebo. The ANDROMEDA trial recruited patients with recent hospitalization for heart failure and was terminated due to an excess of deaths in the dronedarone group. The DIONYSIS trial was a comparative effectiveness trial that demonstrated less efficacy for dronedarone but improved tolerability compared to amiodarone. Dronedarone represents an option in the management of AF in select patients. Dronedarone is not appropriate in patients with recently decompensated heart failure or those treated with strong CYP3A4 inhibitors or medications prolonging the QT interval. Dronedarone appears to have improved tolerability at the expense of decreased efficacy when compared to amiodarone. Questions remain on the long‐term safety, use in patients with heart failure, retreatment after dronedarone or amiodarone failure, and comparative efficacy with a rate control strategy.     

Venous thromboembolism prophylaxis in medically ill patients and the development of strategies to improve prophylaxis rates

Venous thromboembolism (VTE) is common but often unrecognized in medically ill patients. Over the past 5 years, three large-scale placebo-controlled trials enrolling a total of 5500 medically ill patients have highlighted the risk of VTE in this group. These trials have helped to define a specific at-risk patient profile, including those admitted to the hospital with severe congestive heart failure, respiratory illness, acute infection, and inflammatory bowel disease. We performed a retrospective review of patients admitted to the medical service at our tertiary care center to define how common the at-risk medical patient is and to evaluate and improve prophylaxis rates in this patient group. The study was conducted in two phases. Based on admission characteristics, patients were stratified into high-risk or low-risk groups for the development of VTE. During the pre-intervention phase, 75% of patients admitted to the medical service were characterized as increased risk for VTE, yet only 43% of these high-risk patients received prophylaxis of any sort. After interventions designed to increase awareness of VTE, we conducted a second review period. In this post-intervention phase, where 79% of patients were at risk for VTE, prophylaxis rates improved to 72%. Based on these results, we conclude that the majority of patients admitted to the medical service at our tertiary care center constitute a high-risk population that warrants consideration for VTE prophylaxis. Implementation of strategies to improve prophylaxis rates, including educational sessions and risk stratification guidelines, can be successful and improve identification and prophylaxis of this population.     

New treatment options for erectile dysfunction. Pharmacologic and nonpharmacologic options

Erectile dysfunction is a medical condition that influences the sexual life of millions of men and women worldwide. Due to a large number of currently available drugs, the therapy of erectile dysfunction has changed profoundly during the last decades. The pharmacologic options are divided into initiators versus conditioners and central- or peripheral-acting drugs. Besides intraurethral and intracavernous application of prostaglandin E(1) (PGE(1), peripheral initiator)--a transdermal application is still in clinical testing--there are drugs for oral application. PGE(1), the vasoactive drug mainly used, was replaced by sildenafil in first-line-therapy. PGE(1), administered intracavernosally or intraurethrally, is highly effective with success rates up to 90%, but the attrition rate due to personal inconvenience remains significant. Yohimbine is known as a central amplifier of erection and is useful in psychogenic and mild organic erectile dysfunction. Apomorphine, a central initiator of erection, amplifies erectile response as a central dopamine agonist in mild and moderate erectile dysfunction and starts acting 15-20 min after sublingual application. The phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil, and taldalafil are peripheral conditioners. Sildenafil, the most distributed oral agent worldwide, should be taken orally 60 min before sexual intercourse in combination with sexual stimulation. Sildenafil shows a high efficacy-safety profile with success rates for all etiologies between 50-80%. Paralleling nitrate-containing medication is an absolute contraindication. Vardenafil, another selective PDE-5 inhibitor with potentially higher selectivity and efficacy compared to sildenafil was just approved. The data from the clinical trials show the same adverse events and success rates as sildenafil. Tadalafil, just launched as well, amplifies erectile function for up to 24 h, allowing the patient to engage in sexual activity for this period. Adverse events and success rates resemble those of the other two substances. If medical treatment fails, there are nonpharmacologic options such as the vacuum constriction device and penile implants. The vacuum device is a safe and effective option for well-selected patients. Penile implants, especially the inflatable ones, completely imitate the physiologic erection. Due to recent research, infection rates and mechanical failures were minimized. Therefore penile implant surgery is well accepted by the patients and their partners. Despite this wide variety of options, therapy of erectile dysfunction should be performed in an individually adapted way. The patient's exact history, physical examination, collaboration of medical disciplines and choice of therapy will offer all patients the possibility to achieve or regain a satisfying sexual life.     

Influence of medical insurance schemes and charity assistance projects on regular prophylaxis treatment of the boys with severe haemophilia A in China

Objective

To explore the influence of medical insurance policy and charity assistance projects on the uptake and discontinuation of regular prophylaxis treatment in Chinese severe haemophilia A children.

Methodology

This retrospective study was conducted on children with severe haemophilia A, who received FVIII prophylaxis treatment at 12 haemophilia centres in China from 1 November 2007 to 31 May 2013.

Results

The average duration of prophylaxis treatment received by haemophilia children significantly increased from 16.7 weeks in 2008 to 32.8 weeks in 2012 (P < .001). The main reason for prophylaxis acceptance included dissatisfaction with previous “on‐demand” regimens, availability of improved local medical insurance policies and patient/family awareness of haemophilia. The main reason for subsequent discontinuation of prophylaxis was economic instability. The upper limit of insurance was up to RMB 150 000/y (~USD: 22 000/y) for 80.1% of the insured patients and would be sufficient to cover the continuous low‐dose prophylaxis regimen. However, for many patients the burden of out‐of‐pocket copayment cost represented a risk for poor adherence to regular prophylaxis. In about two third of the patients, the annual out‐of‐pocket copayment cost amounted to >50% of their average annual disposable income. Many patients therefore required assistance from the charity assistance projects, but nonadherence remained prevalent.

Conclusion

Medical insurance policy and charity assistance projects helped haemophilia children to accept and continue prophylaxis regimens. It was the proportion of the out‐of‐pocket copayment cost rather than the upper limit of insurance reimbursement that restricted long‐term regular low‐dose prophylaxis in China.