As-needed Therapy Research Articles

Action-plan and as-needed therapy in allergic rhinitis.

Action-plan is a written set of instructions that helps patient manage their symptoms and respond to worsening of their condition. The action-plan usually includes information on how to recognize, treat, and prevent worsening of symptoms. The plan also helps patient understand when to use their medications, how much to use, and how often to use them as-needed. An action-plan should be developed through a discussion between the patient and the physician, reflecting the patient's severity, preferences, and values and should be regularly updated to reflect changes in the person's condition. In asthma, action-plans and as-needed therapy are already well utilized. Unlike asthma, the importance of an action-plan has been overlooked in allergic rhinitis (AR), but its importance has recently been recognized. AR is a chronic condition that affects people differently, and can cause a range of symptoms, including nasal congestion, runny nose, sneezing, itching, and watery eyes. Therefore, an action-plan and as-needed therapy can help patients manage these symptoms more effectively, reducing the impact on their daily activities and quality of life. Furthermore, it can be tailored to meet the personal needs of each patient, based on the severity of their symptoms, their triggers, and their overall health. Because action-plan can help patients adhere to their treatment regimen by providing clear instructions on when and how to take medication, it can help patients stay on track with their treatment, reducing the likelihood of missed doses and treatment failures. Overall, an action-plan and as-needed therapy are important components of a comprehensive treatment plan for patients with AR. They can help to improve symptom control, prevent complications, and promote adherence to treatment, leading to better outcomes and a higher quality of life.

Budesonide Attains Its Wide Clinical Profile by Alternative Kinetics.

The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines.

Radiomics-Based Prediction of Anti-VEGF Treatment Response in Neovascular Age-Related Macular Degeneration With Pigment Epithelial Detachment.

Machine learning models based on radiomic feature extraction from clinical imaging data provide effective and interpretable means for clinical decision making. This pilot study evaluated whether radiomics features in baseline optical coherence tomography (OCT) images of eyes with pigment epithelial detachment (PED) associated with neovascular age-related macular degeneration (nAMD) can predict treatment response to as-needed anti-vascular endothelial growth factor (VEGF) therapy. Thirty-nine eyes of patients with PED undergoing anti-VEGF therapy were included. All eyes underwent a loading dose followed by as-needed therapy. OCT images at baseline, month 3, and month 6 were analyzed. Images were manually separated into non-responding, recurring, and responding eyes based on the presence or absence of subretinal fluid at month 6. PED radiomics features were then extracted from each image and images were classified as responding or recurring using a machine learning classifier applied to the radiomics features. Linear discriminant analysis classification of baseline features as responsive versus recurring resulted in classification performance of 64.0% (95% confidence interval [CI] = 0.63-0.65), area under the curve (AUC = 0.78, 95% CI = 0.72-0.82), sensitivity 0.79 (95% CI = 0.63-0.87), and specificity 0.58 (95% CI = 0.50-0.67). Further analysis of features in recurring eyes identified a significant shift toward non-responding mean feature values over 6 months. Our results demonstrate the use of radiomics features as predictors for treatment response to as-needed anti-VEGF therapy. Our study demonstrates the potential for radiomics feature in clinical decision support for personalizing anti-VEGF therapy. The ability to use PED texture features to predict treatment response facilitates personalized clinical decision making.

The role of modeling studies in asthma management and clinical decision-making: a Delphi survey of physician knowledge and perceptions

Objective To investigate the knowledge and perceptions of physicians on the role of modeling studies in asthma, using a modified Delphi procedure. Methods Group opinions among a panel of respiratory experts were obtained using two online questionnaires and a virtual scientific workshop. A consensus was pre-defined as agreement by >75% of participants. Results From 26 experts who agreed to participate, 22 completed both surveys. At the end of the process, the panel rated their own understanding of modeling as good (77%) but that among physicians in general as poor (77%). Participants agreed that data from modeling studies should be used, at least sometimes, to inform treatment guidelines (91%) and could be useful for guiding clinical decisions (100%). Perceived barriers to using modeling studies were ‘A lack of understanding’ (81%) and ‘A lack of standardized methodology’ (82%). Based on data from two modeling studies, no consensus was reached on physicians recommending regular inhaled corticosteroids (ICS) versus as-needed therapy for patients with mild asthma, whereas 77% agreed that they would recommend regular ICS over maintenance and reliever therapy for ≥80% of their patients with moderate asthma. No consensus was reached on the value of modeling data in relation to empirical data. Conclusion There is overall support among respiratory experts for the usefulness of modeling data to guide asthma treatment guidelines and clinical decision making. More publications on modeling data using robust models and accessible terminology will aid the understanding of physicians in general and help clarify the evidence-based value of modeling studies.

Biological Therapy Interruption and Re-Treatment in Chronic Plaque Psoriasis.

While biological treatments for chronic plaque psoriasis should be administered continuously to maximize and maintain efficacy, interruptions in therapy may be necessary for a number of reasons. We reviewed the evidence from clinical trials on efficacy, safety and immunogenicity in clinical trials for approved biologic agents for chronic plaque psoriasis. A systematic search of three major medical databases was performed and a total of 35 articles were included into the analysis, including 13 controlled trials. Trials assessing continuous therapy against dosing as-needed therapy (including infliximab, etanercept and secukinumab) have demonstrated superior efficacy for continuous regimes. However, randomized withdrawal trials for etanercept, adalimumab, ixekizumab, brodalumab, guselkumab, risankizumab and tildrakizumab, showed no significant impact on skin clearance rates in patients who are interrupted once and then re-treated. With the possible exception of infliximab, temporary interruption in biologic therapy appears to be safe and most agents will regain efficacy after re-introduction. J Drugs Dermatol. 2021;20(10):1063-1071. doi:10.36849/JDD.5716.

Stepping down for mild asthma and disadvantages of the ‘as‐needed’ strategy—Perspectives from a developing country

Stepping down for well-controlled asthma is crucial to achieve the lowest effective inhaled corticosteroid (ICS) dose. However, recommendations for stepping down are still ambiguous, particularly regarding the step-down strategy in patients with well-controlled asthma treated with once-daily low-dose ICS/long-acting beta2-agonist (LABA) combination. The 2021 Global Initiative for Asthma (GINA) guideline recommended ‘as-needed’ low-dose ICS-formoterol (ICS-FOR) as a therapeutic option for Step 2 asthmatics among adolescents and adults.1 Whether patients whose asthma is well controlled with once-daily low-dose ICS/LABA could be stepped down to ICS-FOR as needed is still an open question because: (1) as-needed therapy is inconsistent with the previous preventive purpose of GINA guidelines and (2) it has the potential risk of poor outcomes if not enough ICS are taken. To circumvent disadvantages of the as-needed strategy, we have suggested the scheduled University Medical Center (UMC) step-down strategy for well-controlled mild asthma with daily low-dose ICS or once-daily low-dose ICS/LABA (one inhalation every other day → two inhalations a week → one inhalation a week).3 Each step of the step-down process will be applied as a trial if an asthma patient achieves well-controlled, stabilized pulmonary function for at least 3 months.3 The pre-existing dose would be prescribed if loss of asthma control appeared to be induced by insufficient ICS dosing. A randomized controlled trial to compare the UMC strategy and the as-needed strategy has been planned. In conclusion, the as-needed ICS-FOR strategy could be helpful to avoid treatment with short-acting beta2-agonist only in mild asthma, but its indication should be considered carefully and balanced against characteristics of individual patients and their country setting. The recommendation of as-needed ICS-FOR as an option for stepping down requires more evidence. We thank Dove Medical Press Ltd. (the original publisher of figure 1) for granting permission to re-publish this figure. None declared.

Patient Preferences for Symptom-Driven or Regular Preventer Treatment in Mild to Moderate Asthma: Findings From the PRACTICAL Study, a Randomised Clinical Trial

C Baggott, HK Reddel, J Hardy. Eur Respir J. 2020;55(4):1902073 Symptom-driven low-dose inhaled corticosteroid–formoterol use is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma (GINA). However, there are no data on patient preferences for this regimen. The purpose of this study was to investigate patient preferences between two regimens: symptom-driven budesonide-formoterol versus maintenance inhaled corticosteroid (ICS) with a separate as-needed reliever inhaler. This study …

SAFETY AND PHARMACOKINETICS OF VARDENAFIL INHALATION POWDER (RT234) FOLLOWING ORAL INHALATION IN HEALTHY ADULT VOLUNTEERS

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Vardenafil Inhalation Powder (RT234) is being developed for use as an as-needed treatment of episodic symptoms of Pulmonary Arterial Hypertension (PAH), to acutely improve exercise capacity, performance, and disease-associated symptom impacts. To evaluate the pharmacokinetics (PK) and safety of RT234, a Phase 1 single-center, open label, randomized clinical study in healthy human adult subjects was performed in two parts, a crossover single ascending dose (SAD), followed by a multiple ascending dose (MAD) study. METHODS: SAD: Single ascending doses of 0.2, 0.6, 1.2, and 2.4 mg of vardenafil hydrochloride were administered via oral inhalation with the RS01 monodose dry powder inhaler (Plastiape, Osnago, Italy) (N=6/group). The 0.6 mg dose group was compared to a 20 mg oral tablet of Levitra in a crossover design. Safety, tolerability and pharmacokinetics were assessed. MAD: The 2.4 mg dose was then administered for up to four times daily over a period of 9 days (N=8). SAD: Single ascending doses of 0.2, 0.6, 1.2, and 2.4 mg of vardenafil hydrochloride were administered via oral inhalation with the RS01 monodose dry powder inhaler (Plastiape, Osnago, Italy) (N=6/group). The 0.6 mg dose group was compared to a 20 mg oral tablet of Levitra in a crossover design. Safety, tolerability and pharmacokinetics were assessed. MAD: The 2.4 mg dose was then administered for up to four times daily over a period of 9 days (N=8). RESULTS: SAD: RT234 was well tolerated with all treatment emergent adverse events (TEAEs) mild to moderate in intensity. Headache and dizziness the most commonly reported TEAEs. Brief, asymptomatic decreases in systolic, diastolic, and mean arterial pressure were noted. These changes were not associated with reflex tachycardia or AEs of dizziness, and were not considered clinically significant. Vardenafil was rapidly absorbed in a dose proportional manner, with a Tmax at the first timepoint, 5 minutes post-administration. After Cmax, the plasma concentration declined rapidly in an exponential fashion. MAD: Treatment-related TEAEs were similar in the SAD and MAD cohorts. No clinically significant accumulation was observed in the MAD study. Mean half-life values were comparable to that measured in the SAD portion of the study. CONCLUSIONS: Vardenafil Inhalation Powder (RT234), was found to be safe and well tolerated when orally inhaled in normal human volunteers. This study indicates that vardenafil, administered via oral inhalation, is rapidly absorbed into the bloodstream, and when combined with vardenafil’s known long binding time at the catalytic receptor on the phosphodiesterase-5 enzyme, is well-suited for further clinical development as an as-needed therapeutic in PAH. CLINICAL IMPLICATIONS: Safety and Pharmacokinetics of Vardenafil Inhalation Powder (RT234) are ideal for further development as an as-needed therapy for PAH. A Phase 2a clinical study is underway. DISCLOSURES: No relevant relationships by Michael Eldon, source=Web Response Employee relationship with Respira Therapeutics, Inc. Please note: >$100000 Added 03/23/2020 by Mari Maurer, source=Web Response, value=Salary Consultant relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/26/2020 by Ed Parsley, source=Web Response, value=Consulting fee Employee relationship with Respira Therapeutics Please note: >$100000 Added 03/22/2020 by Jeffry Weers, source=Web Response, value=Salary

Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

In the present study, we investigated the association between susceptible genetic variants to age-related macular degeneration (AMD) and response to as-needed intravitreal aflibercept injection (IAI) therapy for exudative AMD including both typical neovascular AMD and polypoidal choroidal vasculopathy (PCV) over 12-months. A total of 234 patients with exudative AMD were initially treated with 3 monthly IAI and thereafter as-needed IAI over 12 months. Seven variants of 6 genes including ARMS2 A69S (rs10490924), CFH (I62V:rs800292 and rs1329428), C2-CFB-SKIV2L(rs429608), C3 (rs2241394), CETP (rs3764261) and ADAMTS-9 (rs6795735) were genotyped for all participants using TaqMan technology. After adjusting for age, gender, baseline BCVA and AMD subtype, A (protective) allele of C2-CFB-SKIV2L rs429608 was associated with visual improvement at 12-month (P = 0.003). Retreatment was associated with T(risk) allele of ARMS2 A69S (P = 2.0 × 10−4; hazard ratio: 2.18:95%CI: 1.47-3.24) and C(risk) allele of CFH rs1329428 (P = 2.0 × 10−3; hazard ratio: 1.74:95%CI: 1.16–2.59) after adjusting for the baseline confounders. The need for additional injections was also associated with T allele of ARMS2 A69S (P = 1.0 × 10−5) and C allele of CFH rs1329428 (P = 3.0 × 10−3) after adjusting for the baseline confounders. The variants of ARMS2 and CFH are informative for both physicians and patients to predict recurrence and to quantify the need for additional injections.

Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma: findings from the PRACTICAL study, a randomised clinical trial.

Symptom-driven low-dose inhaled corticosteroid-formoterol is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma. However, there are no data on patient preferences for this regimen.A subgroup of participants in the PRACTICAL study (ACTRN12616000377437), a randomised controlled trial comparing symptom-driven budesonide-formoterol with maintenance budesonide plus as-needed terbutaline completed a survey on treatment preferences, satisfaction, beliefs and experience at their final study visit.306 (75%) out of 407 eligible participants completed the survey. Regimen preference was strongly associated with randomised treatment, as were preferences for and beliefs about preventer inhaler use. Combination preventer and reliever as-needed therapy was preferred by 135 (90%, 95% CI 85.2-94.8%) out of 150 who were randomised to as-needed budesonide-formoterol, and by 63 (40%, 95% CI 32.7-48.1%) out of 156 who were randomised to maintenance budesonide. By contrast, twice-daily preventer inhaler with a reliever inhaler as required was preferred by 15 (10%) out of 150 of those randomised to as-needed budesonide-formoterol and 93 (60%) out of 156 of those randomised to maintenance budesonide. Satisfaction with all study inhalers was high. Of patients randomised to as-needed budesonide-formoterol 92% (n=138) were confident using it as a reliever at the end of the study.Although most participants preferred the regimen to which they had been randomised, this association was much stronger for those randomised to budesonide-formoterol as needed, indicating that most patients preferred as-needed corticosteroid-formoterol therapy if they had experienced it.

Can Mild Asthma Be Managed with Only As-Needed Inhaled Steroids Plus a Bronchodilator?

Several trials have shown that as-needed therapy with an inhaled corticosteroid (ICS) plus a bronchodilator is at least as effective as daily ICS

Comparison of Intravitreal Aflibercept and Ranibizumab following Initial Treatment with Ranibizumab in Persistent Diabetic Macular Edema.

Purpose To compare the visual and anatomic outcomes in patients with persistent diabetic macular edema (DME) who switched from ranibizumab to aflibercept with those who continued with previous ranibizumab therapy. Methods In this retrospective comparative study, medical records of consecutive patients with center-involved DME ≥ 350 μm who had at least three recent consecutive monthly ranibizumab injections followed by as-needed therapy with either aflibercept or ranibizumab were reviewed. Data were collected at presentation (preinjection), at the intermediary visit, and at the last visit (at the end of the follow-up period). Results Forty-three eyes of 43 patients were divided into two groups: the switch group (n = 20) and the ranibizumab group (n = 23). Though no significant improvement was found in the mean BCVA from the intermediary visit to the last visit, there was a difference in the mean CMT in the switch group and the ranibizumab group (p < 0.001 and p = 0.03, resp.). The mean CMT decreased after the intermediary visit by 188.6 ± 120.5 μm in the switch group and by 60.3 ± 117.1 μm in the ranibizumab group (p = 0.003). Conclusions Both aflibercept and ranibizumab decreased CMT in patients with persistent DME who showed a poor response to ranibizumab injections. However, switching to aflibercept provided only morphologic improvement.

Long-Term Outcomes in Eyes Receiving Fixed-Interval Dosing of Anti–Vascular Endothelial Growth Factor Agents for Wet Age-Related Macular Degeneration

To report on long-term visual outcomes in patients receiving continuous fixed-interval dosing of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD). Single-practice retrospective chart review. One hundred nine eyes with exudative AMD receiving continuous fixed-interval dosing (every 4-8 weeks) of anti-VEGF therapy (ranibizumab, bevacizumab, or aflibercept) for at least 5 years. Eyes were excluded if they averaged fewer than 6.5 injections per year. Snellen visual acuity was recorded at baseline and all subsequent injections. Changes from baseline were calculated at yearly intervals. The primary outcome measure was mean change in letter score at 5, 6, and 7 years; secondary outcomes included the percentage of patients with 20/40 vision or better at 7 years and the mean change in letter score at each yearly time point based on baseline visual grouping (20/40 or better, 20/50-20/100, 20/200 or worse). Forty-four, 75, and 109 patients with 7, 6, and 5 years, respectively, of continuous treatment were identified. Mean change in letter score at year 5 was +14.0 letters (P = 3.9 × 10(-9)), +12.2 letters at 6 years (P = 1.5 × 10(-7)), and +12.1 letters at 7 years (P = 3.8 × 10(-5)). Driving vision (20/40 or better) was achieved in 43.2% of treated eyes. Subanalysis revealed that the greatest visual gains at 5 and 7 years were seen in those patients with baseline visual acuity worse than 20/200 (+24.5 and +25.5 letters), followed by those with 20/50 to 20/100 vision (+6.7 and +6.9 letters), and finally those with 20/20 to 20/40 (+3.7 and +3.4 letters). Patients received an average of 10.5 injections per year. Continuous fixed-interval dosing of anti-VEGF therapy in patients with exudative AMD results in favorable long-term preservation out to 7 years, with vision stabilizing or improving in 93.2% of eyes. Additionally, 43.2% of patients maintained driving vision in the treatment eye at 7 years compared with 10.1% at baseline. Our data suggest better outcomes with continuous therapy over published results with sporadic, as-needed therapy.

Comparative efficacy of tadalafil once daily in men with erectile dysfunction who demonstrated previous partial responses to as-needed sildenafil, tadalafil, or vardenafil

Objective:Phosphodiesterase type-5 inhibitors (PDE5Is) are first-line therapies for erectile dysfunction (ED). Sildenafil (SIL) and vardenafil (VAR) are approved for as-needed (PRN) dosing; tadalafil (TAD) is approved for both PRN and once-a-day (OaD) dosing for ED. Recent evidence suggests that TAD-OaD may be effective as therapy in men with an incomplete response to PRN-PDE5I therapy. This study evaluated whether TAD-OaD provides similar efficacy in men with ED who had previously demonstrated a partial response to PRN-PDE5I therapy.Research design and methods:In this randomized, double-blind, placebo-controlled trial, men with a ≥3 month ED history received SIL 100 mg, TAD 20 mg, or VAR 20 mg during a 4 week open-label lead-in period. Those with International Index of Erectile Function – Erectile Function (IIEF-EF) domain scores <26 following lead-in treatment completed a 4 week washout period, then randomized to TAD 2.5 mg up-titrated to 5 mg, TAD 5 mg, or placebo (PBO) OaD for 12 weeks. Main outcome measures obtained from patients treated with TAD-OaD were compared to PBO-treated patients. Additionally, results of treatment with TAD-OaD were compared to results obtained from 4 week PRN-PDE5I therapy to determine whether OaD and PRN regimens provided comparable efficacy.Clinical trial registration:NCT01130532.Main outcome measures:International Index of Erectile Function (IIEF) domain scores; Sexual Encounter Profile (SEP) questions 2–5.Results:Endpoint data was obtained from 590 men (391 TAD; 199 PBO). Results for all IIEF and SEP measures were significantly better for TAD-OaD (p < 0.001 for all) compared to PBO and were comparable to those observed during PRN-PDE5I treatment. TAD 2.5 mg and TAD 5 mg OaD therapy were safe and generally well tolerated.Conclusion:Tadalafil once daily is a viable alternative to as-needed PDE5I therapy in men with ED. Key limitations include the lack of a PRN PDE5I study group during the double-blind period, and that many more patients took tadalafil than sildenafil or vardenafil during the PRN period.

QUANTITATIVE CHANGES IN RETINAL PIGMENT EPITHELIAL DETACHMENTS AS A PREDICTOR FOR RETREATMENT WITH ANTI-VEGF THERAPY

To determine if quantitative changes in retinal pigment epithelial detachments (PEDs) predict the need for retreatment in eyes undergoing spectral domain optical coherence tomography (SD OCT)-guided as-needed therapy with anti-vascular endothelial growth factor drugs. Patients with vascularized PEDs undergoing SD OCT-guided treatment with anti-vascular endothelial growth factor drugs were retrospectively identified. The decision to retreat these cases was based on qualitative assessments of fluid in the macula. Spectral domain OCT images from visits in which the treatment was withheld were retrospectively analyzed. A novel algorithm was then used to measure the area and volume of PEDs at these visits. Fourteen eyes were identified, and retreatment was withheld at 57 visits. When the SD OCT algorithm was used to evaluate the scans from these visits, the PED volume increased at eight visits. At all of these eight visits, a treatment was needed at the next follow-up visit. For the remaining 49 visits in which the treatment was withheld, the PED volume did not increase and no treatment was needed at the next follow-up visit. Quantitation of the change in the PED volume and area may be useful in determining when to retreat eyes undergoing SD OCT-guided as-needed anti-vascular endothelial growth factor therapy.

The Efficacy of Intravenous Patient-Controlled Analgesia After Intracranial Surgery of the Posterior Fossa

Surgery of the posterior fossa often produces intense postoperative pain. However, this pain is infrequently treated because of concern that opioid administration may mask the postoperative neurologic examination and/or produce hypercarbia. In this prospective, randomized controlled trial, we sought to determine whether IV patient-controlled analgesia (PCA) would lead to reductions in postoperative pain after neurosurgical procedures of the posterior fossa compared with conventional IV nurse-administered as-needed (PRN) therapy. Eighty patients (age range, 18-82 years) undergoing elective posterior fossa surgery were randomized to receive postoperative IV fentanyl PRN 25 to 50 μg every 30 minutes or via PCA 0.5 μg/kg/dose, with a maximal dose limit of 50 μg, and 15-minute lockout (4 doses/hour). We measured pain (Numerical Rating Scale, 0-10), analgesic use, sedation (Ramsay Sedation Scale and Glasgow Coma Scale), respiration, hemodynamics, and adverse events hourly. Sixty-five patients completed the study. Thirty-one patients received IV PCA and 34 received PRN analgesia. Patient demographics did not differ between groups. Patients in the PCA group reported less pain at rest (mean [95% confidence interval]: 3.7 [3.0, 4.4] vs 5.2 [4.5, 5.8], P = 0.003) and received more fentanyl (mean [95% confidence interval]: 54.8 [42.1, 67.6] vs 29.9 [24.2, 35.7] μg/h, P = 0.002) than those in the PRN group. There were no differences in side effects and no adverse events related to analgesic therapy. IV PCA use resulted in reduction in postoperative pain compared with PRN analgesic therapy after surgery of the posterior fossa. Larger studies will be required to determine the safety of IV PCA in this patient population.

ORIGINAL RESEARCH—EJACULATORY DISORDERS: Acceptance of and Discontinuation Rate from Paroxetine Treatment in Patients with Lifelong Premature Ejaculation

ABSTRACT Introduction Selective serotonin reuptake inhibitors are the most widely used agents for delaying ejaculation in patients with premature ejaculation (PE). Aim The aim of this study was to assess the acceptance of and the discontinuation rate from paroxetine treatment in patients with lifelong PE. Methods We analyzed the acceptance of and discontinuation rates of 93 consecutive potent patients (mean age, 37.6 years) seeking medical treatment for lifelong PE. The patients were assessed with detailed medical and sexual history, self-reported intravaginal ejaculatory latency time, self-administered International Index of Erectile Function, complete physical examination, and the Meares–Stamey test. The patients received a paroxetine prescription (10 mg daily for 21 days and then 20 mg as needed) for the first 3 months. Thereafter, the patients could either stay with the same on-demand treatment or take paroxetine 10 mg daily for 3 months. The patients were evaluated at 3 and 6 months, and requested to complete multiple-choice global assessment questions regarding specific reasons for eventual therapy discontinuation. Main Outcome Measures The primary end point was acceptance and discontinuation rates for paroxetine treatment in patients seeking medical treatment for lifelong PE. The secondary end point was the reasons for nonacceptance of treatment or discontinuation. Results Twenty-eight (30.10%) patients decided not to start paroxetine. Fear of using an “antidepressant drug” was the main reason (42.9%) for treatment nonacceptance. Twenty (30.8%) patients who initiated therapy eventually discontinued it. Treatment effect below expectations was the main reason of treatment dropout (75%) during the first 3 months, followed by temporary loss of interest in sex because of relationship issues (15%) and side effects (10%). Of the patients who continued treatment, 77.8% preferred daily paroxetine, while 22.2% continued as-needed therapy. Conclusions Thirty percent of lifelong PE patients seeking medical treatment for complaints of early ejaculation freely decided not to start any paroxetine treatment, and roughly 30% of patients who started therapy eventually discontinued it.

A Contemporary Look at Classic Trials in Atrial Fibrillation: What Do They Really Show and How Might They Apply to Future Therapies?

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity, decreased exercise tolerance, and impairment of quality of life (QOL). Primary treatment objectives are either to restore and/or maintain sinus rhythm or to achieve satisfactory rate control. There are 5 landmark randomized trials comparing rhythm and rate control strategies that have reported equivalence in overall survival, and data from several trials suggest that the appropriate use of either approach leads to improvement in QOL. Study limitations (eg, trial design, analytic methodology, patient selection criteria, and lack of specificity of therapeutic intervention), however, have made the applicability of findings to a general AF patient population difficult. Although the optimal strategy remains unclear, an important first step in AF management is the proper identification and stratification of patients who require therapy. Given the currently available pharmacologic agents and procedures, as-needed therapy may be a reasonable approach in patients with intermittent AF, whereas the pursuit of sinus rhythm may be warranted in the balance of patients who remain symptomatic despite rate control therapy. The overarching treatment goal should be to provide individualized care based on patient characteristics at presentation, with appropriate consideration given to potential treatment-related adverse effects. Importantly, as the armamentarium of AF management strategies is broadened, the risk/efficacy balance must continue to be evaluated on a patient-specific basis.

Formoterol dry-powder inhaler for the treatment of asthma and chronic obstructive pulmonary disease

Formoterol, a long-acting β2-adrenergic agonist, is used as an inhaled bronchodilator therapy for patients with asthma or for the prevention of exercise-induced bronchospasm in children and in chronic obstructive pulmonary disease. Formoterol has unique characteristics of rapid onset and sustained duration of action compared with other bronchodilators. In addition to its effectiveness as regular maintenance therapy in asthma and chronic obstructive pulmonary disease, formoterol is also reported to be effective as an as-needed reliever therapy in patients with asthma. Formoterol is available in several different types of dry-powder inhalers and pressurized metered-dose inhalers.

Excess mortality in patients with asthma on long-acting 2-agonists

Asthma ranks among the most common of chronic diseases in the Western world. Although modern therapy has improved patient care, asthma still affects 5–10% of the population and, according to the World Health Organization, claims the lives of some 12,000 patients per year in Western Europe 1. β2-Agonists are potent bronchodilators and are the most widely prescribed drugs for asthma worldwide. National and international guidelines recommend short-acting β2-agonists as as-needed therapy for symptomatic relief in all stages of asthma. Long-acting β2-agonists (LABAs) have been recommended as controller medication for moderate and severe asthma. Nevertheless, the safety profile of short-acting β2-agonists has been questioned due to possible detrimental effects on asthma control 2–5. Recent evidence and meta-analysis suggest an increased risk for cardiovascular complications in patients using β2-agonists 6–8 and, in addition, there is evidence suggesting that the frequent use of these drugs might increase the risk of premature death 9–11. The hypothesis that β2-agonists can have fatal adverse effects was first demonstrated in the late 1960s 12. Inman and Adelstein 12 reported a 30–700% increase, depending on age, in asthma death in patients using pressurised aerosols containing, most often, isoprenaline. The excess mortality in patients with asthma at that time was attributed to overdosing (metered-dose aerosols were not widely available at the time). β2-Agonists came into focus again in the 1980s, when more selective β2-agonists were introduced in metered-dose inhalers. However, in the 1990s, case–control studies showed that the use of these drugs was associated with an increased risk of fatal asthma, even when inhaled from a metered-dose inhaler. A dose-dependent risk of death from asthma was reported, which increased up to 20-fold with …