Continuing Insurance Coverage for Flap-Based Breast Reconstruction: Is There a Reservation Cost Related to a Woman's Abdominal Flap Choice?

BACKGROUND: The recent proposed alterations to the Centers for Medicare and Medicaid Services regulations, although subsequently reversed on August 21, 2023, have engendered persistent concerns regarding the impact of insurance policies on breast reconstruction procedures coverage. This study aimed to identify factors that would influence women's preferences regarding autologous breast reconstruction to better understand the possible consequences of these coverage changes. METHODS: A survey of adult women in the United States was conducted via Amazon Mechanical Turk to assess patient preferences for breast reconstruction options, specifically deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flap surgery. The Cochrane-Armitage test evaluated trends in flap preferences concerning incremental out-of-pocket payment increases. RESULTS: Of 500 total responses, 485 were completed and correctly answered a verification question to ensure adequate attention to the survey, with respondents having a median (interquartile range) age of 26 (25-39) years. When presented with the advantages and disadvantages of DIEP versus TRAM flaps, 78% of respondents preferred DIEP; however, as DIEP's out-of-pocket price incrementally rose, more respondents favored the cheaper TRAM option, with $3804 being the "indifference point" where preferences for both procedures converged (P < 0.001). Notably, respondents with a personal history of breast reconstruction showed a higher preference for DIEP, even at a $10,000 out-of-pocket cost (P = 0.04). CONCLUSIONS: Out-of-pocket cost can significantly influence women's choices for breast reconstruction. These findings encourage a reevaluation of emergent insurance practices that could potentially increase out-of-pocket costs associated with DIEP flaps, to prevent cost from decreasing equitable patient access to most current reconstructive options.

From Case Reports to Molecular Insight: Examining the Outcomes and Underlying Mechanisms of Squamous Cell Carcinoma in Breast Implant Patients-A Systematic Review.

There is extensive coverage in the existing literature on implant-associated lymphomas like anaplastic large-cell lymphoma, but breast implant-associated squamous cell carcinoma (BIA-SCC) has received limited scholarly attention since its first case in 1992. Thus, this study aims to conduct a qualitative synthesis focused on the underexplored association between breast implants and BIA-SCC. A systematic review was conducted utilizing the PubMed, Web of Science, and Cochrane databases to identify all currently reported cases of BIA-SCC. Additionally, a literature review was performed to identify potential biochemical mechanisms that could lead to BIA-SCC. Studies were vetted for quality using the NIH quality assessment tool. From an initial pool of 246 papers, 11 met the quality criteria for inclusion, examining a total of 14 patients aged between 40 and 81 years. BIA-SCC was found in a diverse range of implants, including those with smooth and textured surfaces, as well as those filled with saline and silicone. The condition notably manifested a proclivity for aggressive clinical progression, as evidenced by a mortality rate approximating 21.4% within a post-diagnostic interval of six months. Our literature review reveals that chronic inflammation, driven by various external factors such as pathogens and implants, can initiate carcinogenesis through epigenetic modifications and immune system alterations. This includes effects from exosomes and macrophage polarization, showcasing potential pathways for the pathogenesis of BIA-SCC. The study highlights the pressing need for further investigation into BIA-SCC, a subject hitherto inadequately addressed in the academic sphere. This necessitates the urgency for early screening and intervention to improve postoperative outcomes. While the review is confined by its reliance on case reports and series, it serves as a valuable reference for future research endeavors.

Preferences and Barriers of Male Patients Seeking Aesthetic Procedures.

BACKGROUND: As social attitudes toward plastic surgery continue to evolve, the prevalence of men seeking plastic surgery has been increasing. By delving into the factors that encourage male patients to seek plastic surgery and the obstacles they encounter, this study aims to facilitate the development of more inclusive and effective approaches for this population. METHOD: An anonymous 41-question survey was conducted among adult men in the USA via the Amazon Mechanical Turk crowdsourcing platform. Questions assessed demographic information and identified factors that influenced males to seek plastic surgery care, the barriers they experienced while seeking care, and their preferences. Multivariate logistic regression was used to assess relationships between demographic variables and likelihood of undergoing cosmetic surgery. RESULTS: Four hundred and eleven complete responses were analyzed. The median (IQR) age of respondents was 32 (30, 40) years old. Of the respondents, 60% had undergone cosmetic surgery. Functional improvement (40%), personal aspiration (32%), and partners' opinions (22%) were the most commonly cited reasons for undergoing procedures. The most common barriers faced by this population were recovery time following a procedure (52%), perceived risk of complications (48%), cost (43%), fear of being identified as having had plastic surgery (32%), and surgeons not being able to meet expectations (31%). Eighty-nine percent of respondents who underwent plastic surgery procedures reported facing at least one barrier. Multivariate regression demonstrated that higher education levels were strongly associated with a likelihood of undergoing cosmetic surgery (p < 0.001). Income (p = 0.44) and region (p = 0.23) did not significantly affect the likelihood of undergoing plastic surgery. CONCLUSION: Despite improving societal stigma, many male patients continue to face barriers when obtaining plastic surgery care. Efforts may be made to alleviate these barriers and surgeons looking to expand their practice may benefit from increased outreach to male patients. This may be compounded with improved education targeting stigma and risks of procedures, increasing male-specific marketing communications to make them feel welcome in an industry predominantly focused on female patients, and offering male-tailored procedures. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Thrombotic and bleeding events, mortality, and anticoagulant use among 546,656 hospitalized patients with COVID-19 in the United States: a retrospective cohort study.

This study describes demographics, thrombotic and bleeding events, mortality, and anticoagulant use among hospitalized patients with COVID-19 in the United States. Premier Healthcare Database data were analyzed to identify inpatients with a discharge diagnosis for COVID-19 (ICD-10-CM code: U07.1) from April 1, 2020 to March 31, 2021, and matched historical controls without COVID-19 (inpatients discharged between April 1, 2018 and March 31, 2019). Thrombotic [including venous thromboembolism (VTE)] and bleeding events were based on ICD-10-CM discharge diagnosis codes. Of the 546,656 patients hospitalized with COVID-19, 20.1% were admitted to the ICU, 62.8% were aged ≥ 60 years, 51.5% were male, and 31.0% were non-white. Any thrombotic event was diagnosed in 10.0% of hospitalized and 20.8% of ICU patients with COVID-19 versus (vs) 11.5% and 24.4% for historical controls, respectively. More VTE events were observed in hospitalized and ICU patients with COVID-19 than historical controls (hospitalized: 4.4% vs 2.7%, respectively; ICU: 8.3% vs 5.2%, respectively; both P < 0.0001). Bleeding events were diagnosed in 10.2% of hospitalized and 21.8% of ICU patients with COVID-19 vs 16.0% and 33.2% for historical controls, respectively. Mortality among hospitalized (12.4%) and ICU (38.5%) patients with COVID-19 was higher vs historical controls (2.4%, P < 0.0001 and 9.4%, P < 0.0001, respectively) and higher in hospitalized patients with COVID-19 who had thrombotic events (29.4%) vs those without thrombotic events (10.8%, P < 0.0001). VTE and mortality were higher in hospitalized and ICU patients with COVID-19 vs historical controls. The presence of thrombotic events was associated with worse outcomes.

Pharmacokinetic-pharmacodynamic modeling of the effect of varenicline on nicotine craving in adult smokers.

INTRODUCTION: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics." Response was described as the net effect of the baseline, placebo, and drug responses. RESULTS: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. CONCLUSIONS: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline.

Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control.

INTRODUCTION: It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control. METHODS: Concentration-dependent functional effects of varenicline and nicotine at human α3ß4, α3α5ß4, α7, and α4ß2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype. RESULTS: Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of α3ß4, α4ß2 (<2%), α7 (<0.05%), and α3α5ß4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of α3ß4 (48%) and α3α5ß4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of α4ß2 nAChRs (42%-56%) and α7 nAChRs (16%) as varenicline. CONCLUSIONS: Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic α3ß4* nAChRs, while their functional profiles at α3ß4, α3α5ß4, α7, and α4ß2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified.

Enhancing Post-Mastectomy Care: Telehealth's Impact on Breast Reconstruction Accessibility for Breast Cancer Patients.

OBJECTIVE: To examine how the recent sharp rise in telemedicine has impacted trends in accessibility of breast reconstruction (BR). PATIENTS AND METHODS: A retrospective study reviewed patients who underwent a total mastectomy at our institution from 1 August 2016 to 31 January 2022. By comparing cohorts before and during the widespread implementation of telemedicine, we assessed telehealth's impact on healthcare accessibility, measured by distance from patients' residences to our institution. RESULTS: A total of 359 patients were included in this study. Of those, 176 received total mastectomy prior to the availability of telemedicine, and 183 in the subsequent period. There were similar baseline characteristics among patients undergoing mastectomy, including distance from place of residence to hospital (p = 0.67). The same proportion elected to receive BR between groups (p = 0.22). Those declining BR traveled similar distances as those electing the procedure, both before the era of widespread telemedicine adoption (40.3 and 35.6 miles, p = 0.56) and during the height of telemedicine use (22.3 and 61.3 miles, p = 0.26). When tracking follow-up care, significantly more patients during the pandemic pursued at least one follow-up visit with their original surgical team, indicative of the increased utilization of telehealth services. CONCLUSIONS: While the rate of BR remained unchanged during the pandemic, our findings reveal significant shifts in healthcare utilization, highly attributed to the surge in telehealth adoption. This suggests a transformative impact on breast cancer care, emphasizing the need for continued exploration of telemedicine's role in enhancing accessibility and patient follow-up in the post-pandemic era.

Redefining Surgical Materials: Applications of Silk Fibroin in Osteofixation and Fracture Repair.

Silk and silk derivatives have emerged as a possible alternative in surgical device development, offering mechanical strength, biocompatibility, and environmental sustainability. Through a systematic review following PRISMA guidelines, this study evaluated silk fibroin's application across pre-clinical and clinical settings, focusing on its role as screws and plates for osteofixation. A comprehensive search yielded 245 studies, with 33 subjected to full-text review and 15 ultimately included for qualitative analysis. The findings underscore silk fibroin's superior properties, including its tunable degradation rates and ability to be functionalized with therapeutic agents. In vivo and in vitro studies demonstrated its efficacy in enhancing bone healing, offering improved outcomes in osteofixation, particularly for craniofacial defects. Silk fibroin's remarkable attributes in biodegradation and drug release capabilities underscore its potential to enhance patient care. Ultimately, silk fibroin's integration into surgical practices promises a revolution in patient outcomes and environmental sustainability. Its versatility, coupled with the continuous progress in fabrication techniques, signals a promising horizon for its widespread acceptance in the medical field, potentially establishing a new benchmark in surgical treatment. Further research is expected to solidify the transition of silk products from basic science to patient care, paving the way for widespread use in various surgical applications.

Performance of an electronic health record-based predictive model to identify patients with atrial fibrillation across countries.

BACKGROUND: Atrial fibrillation (AF) burden on patients and healthcare systems warrants innovative strategies for screening asymptomatic individuals. OBJECTIVE: We sought to externally validate a predictive model originally developed in a German population to detect unidentified incident AF utilising real-world primary healthcare databases from countries in Europe and Australia. METHODS: This retrospective cohort study used anonymized, longitudinal patient data from 5 country-level primary care databases, including Australia, Belgium, France, Germany, and the UK. The study eligibility included adult patients (≥45 years) with either an AF diagnosis (cases) or no diagnosis (controls) who had continuous enrolment in the respective database prior to the study period. Logistic regression was fitted to a binary response (yes/no) for AF diagnosis using pre-determined risk factors. RESULTS: AF patients were from Germany (n = 63,562), the UK (n = 42,652), France (n = 7,213), Australia (n = 2,753), and Belgium (n = 1,371). Cases were more likely to have hypertension or other cardiac conditions than controls in all validation datasets compared to the model development data. The area under the receiver operating characteristic (ROC) curve in the validation datasets ranged from 0.79 (Belgium) to 0.84 (Germany), comparable to the German study model, which had an area under the curve of 0.83. Most validation sets reported similar specificity at approximately 80% sensitivity, ranging from 67% (France) to 71% (United Kingdom). The positive predictive value (PPV) ranged from 2% (Belgium) to 16% (Germany), and the number needed to be screened was 50 in Belgium and 6 in Germany. The prevalence of AF varied widely between these datasets, which may be related to different coding practices. Low prevalence affected PPV, but not sensitivity, specificity, and ROC curves. CONCLUSIONS: AF risk prediction algorithms offer targeted ways to identify patients using electronic health records, which could improve screening number and the cost-effectiveness of AF screening if implemented in clinical practice.

Efficacy, Safety, and Exposure of Apixaban in Patients with High Body Weight or Obesity and Venous Thromboembolism: Insights from AMPLIFY.

INTRODUCTION: As a result of limited clinical data, guidelines do not recommend the use of non-vitamin K antagonist oral anticoagulants in patients who weigh > 120 kg or have a body mass index (BMI) > 40 kg/m2. METHODS: This post hoc analysis of the AMPLIFY trial evaluated the efficacy (venous thromboembolism [VTE]/VTE-related death), safety (major and composite of major and clinically relevant non-major [CRNM] bleeding), and exposure of apixaban compared with enoxaparin followed by warfarin for the treatment of VTE by body weight (≤ 60, > 60 to < 100, ≥ 100 to < 120, ≥ 120 kg) and BMI (≤ 25, > 25 to 30, > 30 to 35, > 35 to 40, > 40 kg/m2). RESULTS: Among the AMPLIFY safety population, 5384 and 5359 patients had recorded body weight (range 28.9 to 222.0 kg; ≥ 120 kg, n = 290) and BMI (range 12.5-71.8 kg/m2; > 40 kg/m2, n = 263), respectively. The rates of recurrent VTE/VTE-related death for apixaban versus enoxaparin/warfarin were similar across body weight subgroups: relative risks (RR; 95% confidence intervals [CI]) were 0.63 (0.23, 1.72), 0.99 (0.65, 1.50), 0.77 (0.34, 1.72), and 0.20 (0.02, 1.72) for the ≤ 60, > 60 to < 100, ≥ 100 to < 120, and ≥ 120 kg groups, respectively (Pinteraction = 0.44). The rates of major bleeding were lower with apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.15 (0.02, 1.15), 0.41 (0.21, 0.77), not estimable, and 0.34 (0.04, 3.22), respectively (Pinteraction = not estimable). The rates of major/CRNM bleeding were significantly lower for apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.46 (0.24, 0.89), 0.49 (0.38, 0.63), 0.30 (0.16, 0.58), and 0.28 (0.12, 0.66), respectively (Pinteraction = 0.36). Similar trends were seen in the BMI subgroups. There was a modest, not clinically meaningful, decrease (< 30%) in the median predicted exposure with increasing body weight (n = 281). CONCLUSIONS: The findings of this post hoc analysis support the use of apixaban in patients with body weight ≥ 120 kg or BMI > 40 kg/m2. TRIAL REGISTRATION NUMBER: NCT00643201.

Adherence to treatment for tobacco dependence: association with smoking abstinence and predictors of adherence.

INTRODUCTION: Detailed analysis of adherence to tobacco cessation medications and predictors of adherence is sparse in published literature. In this analysis, we assessed adherence to tobacco dependence treatment, association of adherence with abstinence, and predictors of adherence. METHODS: We analyzed pooled results from 2 randomized controlled trials. Adult smokers (N = 2,045) who were randomly assigned to 12 weeks of treatment and took at least 1 dose of the assigned medication (varenicline [692], bupropion sustained release [669], or placebo [684]) were included. Treatment adherence was defined as any subject who took >or=1 dose of study drug for >or=80% days during the 12-week treatment period ("completers"). Smoking abstinence was assessed using carbon monoxide-confirmed 4-week continuous abstinence rate at end of treatment (Weeks 9-12). RESULTS: Adherence rates for completers who received varenicline, bupropion, and placebo groups, respectively, were 99.3%, 98.8%, and 99.2%. There was a positive correlation between adherence to treatment and tobacco abstinence in all treatment groups. Treatment effect sizes (odds ratios) for active therapy compared with placebo were similar whether considering all subjects or only the completer subset. Age, cigarettes per day, and Week-2 abstinence were significant predictors of adherence for all treatment groups (all p < .05), with Week-2 abstinence the strongest predictor. DISCUSSION: Adherence to pharmacotherapy for smoking cessation is highly correlated with improved tobacco abstinence. Early abstinence experience is a strong driver of adherence.

COPD exacerbations associated with the modified Medical Research Council scale and COPD assessment test among Humana Medicare members.

BACKGROUND: The Global initiative for chronic Obstructive Lung Disease guidelines recommend assessment of COPD severity, which includes symptomatology using the modified Medical Research Council (mMRC) or COPD assessment test (CAT) score in addition to the degree of airflow obstruction and exacerbation history. While there is great interest in incorporating symptomatology, little is known about how patient reported symptoms are associated with future exacerbations and exacerbation-related costs. METHODS: The mMRC and CAT were mailed to a randomly selected sample of 4,000 Medicare members aged >40 years, diagnosed with COPD (≥2 encounters with International Classification of Dis eases-9th Edition Clinical Modification: 491.xx, 492.xx, 496.xx, ≥30 days apart). The exacerbations and exacerbation-related costs were collected from claims data during 365-day post-survey after exclusion of members lost to follow-up or with cancer, organ transplant, or pregnancy. A logistic regression model estimated the predictive value of exacerbation history and symptomatology on exacerbations during follow-up, and a generalized linear model with log link and gamma distribution estimated the predictive value of exacerbation history and symptomatology on exacerbation-related costs. RESULTS: Among a total of 1,159 members who returned the survey, a 66% (765) completion rate was observed. Mean (standard deviation) age among survey completers was 72.0 (8.3), 53.7% female and 91.2% white. Odds ratios for having post-index exacerbations were 3.06, 4.55, and 16.28 times for members with 1, 2, and ≥3 pre-index exacerbations, respectively, relative to members with 0 pre-index exacerbations (P<0.001 for all). The odds ratio for high vs low symptoms using CAT was 2.51 (P<0.001). Similarly, exacerbation-related costs were 73% higher with each incremental pre-index exacerbation, and over four fold higher for high-vs low-symptom patients using CAT (each P<0.001). The symptoms using mMRC were not statistically significant in either model (P>0.10). CONCLUSION: The patient-reported symptoms contribute important information related to future COPD exacerbations and exacerbation-related costs beyond that explained by exacerbation history.

Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment-motivated heavy smokers.

RATIONALE: The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome. OBJECTIVES: This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design. METHODS: Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-min intervals. At 4-h post-administration, a cue exposure session obtained the same subjective measures at three time-points following the physical handling of a lit cigarette versus the sharpening and handling of a pencil. RESULTS: At 4-h post-administration, varenicline reduced tonic craving as well as craving across the smoking and neutral cue conditions, relative to placebo. By contrast, the capacity of the smoking cue to enhance craving relative to the neutral cue was unaffected by varenicline. Measures of withdrawal and positive and negative affect produced mixed results. CONCLUSIONS: Acute varenicline selectively attenuates tonic but not cue-provoked craving. This dissociation provides insight into the specific psychological processes that might mediate the effectiveness of varenicline, and highlights cue-provoked craving as a discrete target for advancing smoking cessation pharmacotherapy.

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex.

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.

Effects of varenicline on smoking cessation in patients with mild to moderate COPD: a randomized controlled trial.

BACKGROUND: Smoking is the most important risk factor for COPD and accelerates its progression. Despite the health implications, a large proportion of patients with COPD continue to smoke, so finding effective smoking cessation interventions for this population is paramount. To our knowledge, this is the first randomized clinical trial to compare the efficacy and safety of varenicline tartrate vs placebo in smokers with mild to moderate COPD. METHODS: In a 27-center, double-blind, multinational study, 504 patients with mild to moderate COPD (postbronchodilator FEV1/FVC, <70%; FEV1 percent predicted normal value, ≥50%) and without known psychiatric disturbances were randomized to receive varenicline (n=250) or placebo (n=254) for 12 weeks, with a 40-week nontreatment follow-up. The primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. A secondary end point was CAR for weeks 9 to 52. RESULTS: CAR for weeks 9 to 12 was significantly higher for patients in the varenicline group (42.3%) than for those in the placebo group (8.8%) (OR, 8.40; 95% CI, 4.99-14.14; P<.0001). CAR in the patients treated with varenicline remained significantly higher than in those treated with placebo through weeks 9 to 52 (18.6% vs 5.6%) (OR, 4.04; 95% CI, 2.13-7.67; P<.0001). Nausea, abnormal dreams, upper-respiratory tract infection, and insomnia were the most commonly reported adverse events (AEs) for patients in the varenicline group. Serious AEs were infrequent in both treatment groups. Two patients in the varenicline group and one patient in the placebo group died during the study. Reports of psychiatric AEs were similar for both treatment groups. CONCLUSIONS: Varenicline was more efficacious than placebo for smoking cessation in patients with mild to moderate COPD and demonstrated a safety profile consistent with that observed in previous trials. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00285012; URL: www.clinicaltrials.gov.

Predictors of post-treatment relapse to smoking in successful quitters: pooled data from two phase III varenicline trials.

BACKGROUND: Identifying predictors of smoking relapse helps to elucidate the challenges of long-term smoking cessation and provides direction for improved treatment development. METHODS: In this post hoc data analysis, we examined predictors of relapse from end-of-treatment (week 13) through 1-year follow-up (week 52) for treatment-responding participants who achieved the primary efficacy endpoint of 4-week continuous abstinence (weeks 9-12), during two phase III varenicline trials. RESULTS: Of 626 smokers classified as treatment responders for all treatment groups across both trials, 301 (48%) relapsed during follow-up (weeks 13-52). The odds of relapsing were almost 5 times greater (odds ratio [OR]=4.92, 95% confidence interval [CI]: 2.77-8.97; p<.001) for treatment responders who did not initiate continuous abstinence until the final 4 weeks of the treatment period compared with those who initiated continuous abstinence by their quit date. Participants who reported >30 days of abstinence during the year prior to study entry were significantly more likely to relapse than those who reported 0 days of abstinence (OR=2.38, 95% CI: 1.17-5.04; p=.013). CONCLUSION: Results of these analyses suggest that the ability to quit smoking on the initial quit date and maintain abstinence throughout the treatment period is a good prognostic indicator for long-term abstinence. The relationship between post-treatment relapse and longer pretreatment periods of abstinence is counterintuitive, yet not without precedence in the literature.

Immediate versus delayed quitting and rates of relapse among smokers treated successfully with varenicline, bupropion SR or placebo.

AIMS: We assessed to what degree smokers who fail to quit on the target quit date (TQD) or lapse following TQD eventually achieve success with continued treatment. DESIGN: A secondary analysis of pooled data of successful quitters treated with varenicline (306 of 696), bupropion (199 of 671) and placebo (121 of 685) from two identically-designed clinical trials of varenicline versus bupropion sustained-release and placebo. SETTING: Multiple research centers in the US. PARTICIPANTS: Adult smokers (n==2052) randomized to 12 weeks drug treatment plus 40 weeks follow-up. MEASUREMENT: The primary end-point for the trials was continuous abstinence for weeks 9-12. TQD was day 8. Two patterns of successful quitting were identified. Immediate quitters (IQs) were continuously abstinent for weeks 2-12. Delayed quitters (DQs) smoked during 1 or more weeks for weeks 2-8. FINDINGS: Cumulative continuous abstinence (IQs + DQs) increased for all treatments during weeks 3-8. Overall IQs and DQs for varenicline were (24%; 20%) versus bupropion (18.0%, P=0.007; 11.6%, P<0.001) or placebo (10.2%, P<0.001; 7.5%, P<0.001). However, DQs as a proportion of successful quitters was similar for all treatments (varenicline 45%; bupropion 39%; placebo 42%) and accounted for approximately one-third of those remaining continuously abstinent for weeks 9-52. No gender differences were observed by quit pattern. Post-treatment relapse was similar across groups. CONCLUSIONS: Our data support continuing cessation treatments without interruption for smokers motivated to remain in the quitting process despite lack of success early in the treatment.

Varenicline treatment for smoking cessation in Asian populations: a pooled analysis of placebo-controlled trials conducted in six Asian countries.

OBJECTIVE: A pooled analysis to evaluate the efficacy and safety of varenicline versus placebo for smoking cessation in Asian populations. A secondary objective was to compare the data to pooled trials among predominantly Western populations. RESEARCH DESIGN AND METHODS: Smokers (n = 893) in three randomized, double-blind, placebo-controlled, multicenter, phase IIb or III trials conducted in six Asian countries (Japan, Taiwan, Korea, China, Singapore, and Thailand), received varenicline (1 mg twice daily; n = 447) or placebo (n = 446) for 12 weeks. Non-treatment follow-up lasted 12 weeks (40 weeks in Japan). Primary endpoint was the carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9-12 (last 4 weeks of treatment). Secondary endpoint was CAR for weeks 9-24. RESULTS: CAR was higher for varenicline than placebo during weeks 9-12 (58.6 vs. 34.3%; odds ratio [OR]: 2.74; 95% confidence interval [CI]: 2.08-3.60; p < 0.0001), and through 12 weeks of follow-up (CAR weeks 9-24; 41.4 vs. 25.3%; OR: 2.08; 95% CI: 1.56-2.77; p < 0.0001). The most frequent adverse events (AEs) in the varenicline group (greater incidence than the placebo group) were: nausea (31.5%), headache (8.5%), dizziness (7.8%), insomnia (7.4%), and upper abdominal pain (5.4%). Serious AEs occurred in four varenicline and five placebo participants. Discontinuations due to AEs occurred in 3.6% of varenicline and 1.6% of placebo participants. Compared with the Western studies, abstinence rates for both varenicline and placebo were numerically higher in the Asian studies, although treatment effects were similar between the two populations. AEs reported in the Asian trials were largely similar to those in the Western populations. CONCLUSIONS: Varenicline significantly improved smoking abstinence in Asian populations from six countries. AEs were predominantly of mild or moderate intensity. These data were largely the same as those seen in Western populations, but the studies were not designed to explore racial or cultural differences.