Comprehensive literature review on the prevalence of comorbid conditions in patients with achondroplasia.

BACKGROUND: Achondroplasia (ACH) is a rare, genetic condition and is the most common skeletal dysplasia resulting in disproportionate short stature and numerous multi-systemic comorbidities. As we enter an era of new treatment options which may impact comorbidities, it is important to understand the background rates of these events to aid evaluation of potential treatment effects. Thus, the aim of this literature review was to provide a comprehensive quantification of prevalence estimates of comorbidities in achondroplasia by age for use as a compiled reference to assist in quantifying the risk/benefit of new treatment options and informing timely management of ACH. METHODS: PubMed and Embase databases were searched, complemented by manual bibliography searching, for peer-reviewed articles published between 1975 and 2021, guided by PRISMA principles. Number of patients and the prevalence of specific comorbidities by age were extracted. We calculated exact 95 %-confidence limits for the proportion of affected patients (prevalence) and data were presented visually using forest plots. An a priori decision was made not to utilise meta-analytic techniques to pool estimates as we intended to understand the variability in comorbidities by displaying each estimate separately. RESULTS: The literature search identified 206 articles of which 73 were eligible for inclusion. The majority of studies (n = 34) had been conducted in the USA or in Europe (n = 20). Study designs were mostly retrospective chart reviews (n = 33) or small cohort studies (n = 19). The availability of literature on particular conditions varied but trended towards a focus on assessment and prevention of severe conditions, such as respiratory conditions in children (21 studies), neurological manifestations (16 studies) and upper spine compression (15 studies). There was substantial heterogeneity in study design, type of clinical setting, populations and use of definitions in reporting comorbidities which need to be considered when interpreting study results. Despite the variability of the studies, comorbidity patterns by age were recognizable. In infants, a high prevalence (>20 %) was found for kyphosis, a range of neurological manifestations and sleep apnea. There was also an excess mortality in infancy (4-7.8/100 person-years). Conditions identified in infancy continued to prevail in childhood. Genu varum was highly prevalent from the age children started to walk (9-75 %). Other conditions started to emerge in children; those with a high prevalence (>20 %) were hearing loss and pain. In adolescence, neurological manifestations in the arm, neck or leg were reported (~15 %), consistent with symptomatic spinal stenosis or spinal compression. Fewer studies were available in older populations, especially in adults; however limited data suggest that pain and cardiovascular conditions, particularly excess weight and obesity, became more prevalent into adulthood. Mortality rates increased again in older age-groups. CONCLUSION: This review provides a reference base of current knowledge of the type and frequency of comorbidities in ACH. This not only allows future contextualisation of new treatment options but supports clinical decision-making on the timely medical management and intervention of ACH. This review also reflects the current medical priorities in the management of ACH, indicating a focus on pediatric care and the complex needs of individuals with ACH involving many different disciplines. Further studies into the natural history of this rare disease using more consistent definitions of comorbidities, especially into adulthood, are needed to elucidate the multi-systemic nature of this condition.

Patient Understanding of the Neuropsychiatric Risks Associated with Branded Bupropion Hydrochloride Products Used for Smoking Cessation.

BACKGROUND: Bupropion hydrochloride (Zyban) is an effective aid to smoking cessation; however, its use has previously been associated with neuropsychiatric adverse events. Here we report results of the patient Knowledge, Attitudes, and Behavior survey that forms part of the Year 7 Risk Evaluation and Mitigation Strategy (REMS) assessment for Zyban. OBJECTIVE: Assess participants' understanding of the neuropsychiatric risks associated with branded bupropion hydrochloride products that are used for smoking cessation, as described in the Medication Guides. METHODS: A cross-sectional study was conducted among patients ≥ 18 years of age, who had used or filled a prescription for branded bupropion hydrochloride for smoking cessation in the past 6 months. Participants were recruited through an online panel, pharmacy network, or by healthcare provider referral, and invited to complete a survey containing questions regarding the risks associated with the use of branded bupropion hydrochloride products, and whether they had received and read the Medication Guide. The study aimed for ≥ 80% of participants to respond correctly to each question regarding neuropsychiatric risks. RESULTS: From the 50,985 survey invitations distributed, 1017 participants responded, of whom 144 were eligible and 142 completed the survey. Over 80% of participants correctly responded to most neuropsychiatric risk questions. Approximately three-quarters of participants received the Medication Guide when they last filled their prescription, of whom over half read the Medication Guide at that time. CONCLUSIONS: Participants enrolled in this Year 7 REMS survey had good understanding of the neuropsychiatric risks associated with using branded bupropion hydrochloride products for smoking cessation.

Quantitative Testing of Prescriber Knowledge Regarding the Risks and Safe Use of Albiglutide.

BACKGROUND: The risk of pancreatitis and potential risk of medullary thyroid carcinoma associated with glucagon-like peptide-1 receptor agonists prompted the US Food and Drug Administration to require a Risk Evaluation and Mitigation Strategy for albiglutide, including education for prescribers and subsequent assessment of their knowledge of the risks and safe use of albiglutide via a quantitative survey. OBJECTIVE: The objective of this study was to assess prescribers' knowledge of the risks related to medullary thyroid carcinoma, pancreatitis, and the appropriate patient population for albiglutide. METHODS: Two Risk Evaluation and Mitigation Strategy surveys were conducted 18 months and 3 years after albiglutide was launched. Primary analyses evaluated correct response rates for each question. Secondary analyses evaluated the number of correct responses and the percentage of respondents scoring at/above the target comprehension thresholds (75% at 18 months; 80% at 3 years), which were selected based on discussion with the Food and Drug Administration and current standards for Risk Evaluation and Mitigation Strategy assessments, for each key risk message. RESULTS: The correct response rate for individual questions ranged from 68.2 to 97.9% (18-month survey) and from 69.4 to 98.1% (3-year survey). For the secondary analysis, 79.5, 86.7, and 86.7% of respondents in the 18-month survey answered ≥ 75% of the questions correctly and 70.8, 90.9, and 54.1% of respondents in the 3-year survey answered ≥ 80% of the questions correctly for key risk messages related to medullary thyroid carcinoma, pancreatitis, and appropriate patient population, respectively. CONCLUSIONS: Survey results indicated most, but not all, prescribers are knowledgeable regarding the risks and safe use of albiglutide. Additional education to address gaps in knowledge could further improve risk mitigation.

Survey of Physicians' Understanding of Specific Risks Associated with Retigabine.

BACKGROUND: Following reports of discoloration, including retinal pigmentation, in addition to known significant risks of urinary retention, central nervous system effects, and QTc prolongation, the retigabine indication was restricted to adjunctive treatment of partial onset seizures where other appropriate drug combinations have proved inadequate or have not been tolerated. OBJECTIVE: To ascertain the effectiveness of educational initiatives as reflected in physicians' understanding of retigabine-associated risks, management, and patient selection. METHODOLOGY: An online, cross-sectional survey, designated a post-authorization safety study (24/9/2014-30/1/2015), recruited retigabine prescribers (RP) and retigabine non-prescribers (RNP) in seven countries, who had been sent a retigabine Dear Health Care Professional letter (June 2013). Questions tested understanding of the significant risks associated with retigabine. RESULTS: 414/467 participants completed all questions (RP, n = 141; RNP, n = 273) and were included in the analysis. 74.2 % of these participants (RP, 77.3 %; RNP, 72.5 %) correctly identified the label indication. 81.9 % of participants (RP, 86.5 %; RNP, 79.5 %) recognized that specific retigabine-associated risks included pigment changes of ocular tissues, including the retina. 81.6 % of participants (RP, 87.2 %; RNP, 78.8 %) recognized that a comprehensive ophthalmologic examination is required. 99.8 % of participants (RP, 100.0 %; RNP, 99.6 %) acknowledged the requirement for action in case of retinal pigmentation or vision changes. RP and RNP results were similar to the overall participants' analysis, with a trend toward stronger understanding among RP. CONCLUSION: Most participants recognized the appropriate population for retigabine treatment and the requirement to monitor for adverse events including retinal pigmentation and vision changes. Understanding was satisfactory among RNP but stronger among RP.

An assessment of the association between carvedilol exposure and severe hypersensitivity reactions, angioedema, and anaphylactic reactions: a retrospective nested case-control analysis.

BACKGROUND: There is limited information in the literature regarding the risk of severe hypersensitivity reactions due to different ß-blocking agents. Most of the available information addresses the potential for increased severity of anaphylaxis or poor response to treatments among patients receiving ß-blocking agents. OBJECTIVE: The objective of this study was to estimate the incidence rates of severe hypersensitivity reactions (angioedema and anaphylactic reactions) for various ß-blockers and to examine the risk of severe hypersensitivity reactions in patients exposed to carvedilol extended-release compared with carvedilol and compared with other ß-blockers. METHODS: A case-control analysis nested within a cohort of ß-blocker users in the LabRx Database was conducted. A case was defined as an incident hypersensitivity reaction of either anaphylactic shock (International Classification of Diseases, 9th Revision [ICD-9] code 995.0) or angioneurotic edema (ICD-9 code 995.1). Three controls were matched to each case. Patients were classified according to their ß-blocker exposure in the 30 day-period before the index date. Conditional logistic regression was used to calculate odds ratios and 95% CIs. RESULTS: A total of 1,810,487 ß-blocker users were identified; 7811 hypersensitivity cases and 23,433 controls were included in this analysis. The mean (SD) age of the cohort was 53 (14) years, and 49% were men. The overall incidence rates of severe hypersensitivity reactions among various ß-blockers categories were similar to that in the overall ß-blocker users cohort (2.40 per 1000 person-years [95% CI, 2.35-2.45]). The odds ratios of severe hypersensitivity reaction for carvedilol extended-release compared with carvedilol and with other long-acting ß-blockers were 0.86 (95% CI, 0.48-1.53) and 1.10 (95% CI, 0.90-1.35), respectively. CONCLUSIONS: This retrospective database analysis of mostly middle-aged patients detected no statistically significant differences in the likelihood of severe hypersensitivity reactions among patients who received carvedilol extended-release versus carvedilol or other long-acting ß-blockers.

An assessment of the effect of thiazolidinedione exposure on the risk of myocardial infarction in type 2 diabetic patients.

PURPOSE: To determine the likelihood of myocardial infarction (MI) in type 2 diabetic patients exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic therapies. METHODS: A case-control analysis nested within the cohort of type 2 diabetic subjects from the Integrated Healthcare Information Services (IHCIS) claims database. Incident cases of MI were matched to three controls each on age (+/-5 years), gender, and year of first diabetes diagnosis. Subjects were classified according to their antidiabetic drug exposure in the 3, < 6, 6-12, and > 12 months prior to the index date. The adjusted odds ratios of MI were calculated for subjects exposed to rosiglitazone and pioglitazone, separately, compared to other antidiabetic agents. Risk factors adjusted for are age, ACE inhibitors, beta-blockers, diuretics, nitrates, diagnosis of hyperlipidemia, and hypertension and coronary artery disease (CAD). RESULTS: A total of 891 901 diabetic subjects (9870 cases and 29 610 control) identified from 1999 to 2006 were included in the analysis. The mean age was 63 years for the cases and controls. Compared to those treated with other antidiabetic therapies, the adjusted odds ratio of MI was 1.03 [95%CI: 0.93-1.12] for rosiglitazone and 0.92 [95%CI: 0.83-1.01] for pioglitazone in the 3 months prior to the index date. CONCLUSIONS: The results suggest that the risk of MI in subjects exposed to rosiglitazone or pioglitazone for < or = 12 months is not different from those exposed to other antidiabetic agents but exposure for > 12 months is associated with 15 and 13% increased risk of MI, respectively.

The risk of myopathy associated with thiazolidinediones and statins in patients with type 2 diabetes: a nested case-control analysis.

BACKGROUND: The implementation of more aggressive goals for low-density lipoprotein cholesterol lowering in subjects with type 2 diabetes (T2D) and the expected increase in the use of statins is likely to increase the concomitant use of thiazolidinediones (TZDs) and statins. OBJECTIVE: This study evaluated whether concomitant use of TZDs and statins is associated with an increased risk of myopathic events in subjects with T2D. METHODS: This was a nested case-control study in subjects with T2D. Cases and controls were identified from a cohort of 125,394 subjects with T2D in the Integrated Healthcare Information Services database. Each case with a myopathic event (rhabdomyolysis, myositis, myopathy, or myalgia) was matched to up to 6 controls by age (+/-5 years), sex, calendar year of diagnosis of a myopathic event, and length of follow-up in the database. Incident cases of myopathy were identified using the following International Classification of Diseases, Ninth Revision codes: 359.x for myopathy, 728.88 for rhabdomyolysis, and 729.1 for unspecified myalgia and myositis. Prescription claims were used as a proxy for drug exposure. Five categories of exposure were employed: statins only, TZDs only, concomitant TZDs and statins, other antidiabetic agents only, and neither statins nor antidiabetic agents. Exposure to statins and/or TZDs within 90 days before the case index date was defined as recent exposure, and exposure at any time before the case index date was defined as ever exposure. Concomitant exposure to TZDs and statins, either recent or ever, was defined by an overlap of at least 30 days in the days supply of TZDs and statins during the exposure period. RESULTS: The 3696 cases of myopathy were matched with 21,871 controls. The adjusted odds ratio (OR) for myopathic events for ever exposure to concomitant TZDs and statins compared with statins alone was 1.03 (95% CI, 0.83-1.26). Compared with neither statins nor antidiabetic agents, ever use of statins alone was associated with an increased likelihood of myopathic events (adjusted OR=1.36; 95% CI, 1.12-1.64). The likelihood of myopathic events was not significantly different for TZDs compared with other antidiabetic agents. CONCLUSION: In this population of subjects with T2D, concomitant use of statins and TZDs was not associated with an increased risk of myopathic events beyond that conferred by statins alone.

Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting.

OBJECTIVE: To assess the effects of antidiabetic drugs on the risk of heart failure in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study with a newly diagnosed diabetes cohort of 25,690 patients registered in the U.K. General Practice Research Database, 1988-1999. We categorized person-time drug exposures to monotherapies in insulin, sulfonylureas (SUs), metformins, and other oral hypoglycemic agents (i.e., acarbose, guar gum) and combination therapy including insulin, combination therapy without insulin, and triple combination therapy with or without insulin. A drug-free time interval served as a reference category. Cox interval-wise (piece-wise) regression analyses were used. The main outcome was incident heart failure. RESULTS: Among 43,390 drug exposure intervals for 25,690 patients who had a mean follow-up period of 2.5 years, 1,409 patients developed heart failure. Heart failure occurred most frequently in SU monotherapy exposure. After adjusting for duration of diabetes, the timing and order of treatments received, and known risk factors for heart failure, we found no differential effects among type-specific therapies. Patients with any drug use within the first year after diabetes diagnosis had a 4.75-fold higher risk (hazard ratio) for heart failure than those with drug-free status but had no increased risk during subsequent years. CONCLUSIONS: In conclusion, the use of any pharmacological therapy for type 2 diabetes appears to be associated with an increased risk of heart failure. This risk does not persist beyond the first year after diagnosis of diabetes and does not appear to differ among the types of drug therapy examined. This observation suggests that the severity of diabetes or the preclinical duration of diabetes and the need for drug therapy, and not the therapy itself, is an explanation for heart failure in patients with type 2 diabetes.

Medical resource use among patients treated for bipolar disorder: a retrospective, cross-sectional, descriptive analysis.

BACKGROUND: Detailed assessments of the direct costs related to bipolar disorder and of the burden it places on the health care system are limited. OBJECTIVE: In this retrospective, cross-sectional, descriptive analysis, we assessed prescription medication and other medical resource use in bipolar disorder in an insured population in the northeastern United States. METHODS: Number and types of prescription drugs, medical encounters, and respective costs were derived from a New England insurer database for 1996. This analysis was purely descriptive in nature and no statistical comparisons were made. RESULTS: Patients with bipolar disorder (N = 3120) were compared with a randomly selected age- and sex-matched nonbipolar population (N = 3120). A subgroup of patients with bipolar I disorder (n = 336), defined as having at least 1 hospital admission for mania, also were examined. A total of $2,803,673 was spent on all drugs for patients with bipolar disorder, who received a mean of 15 central nervous system (CNS) drug prescriptions per person, at an average cost of $582. This compares with $461,354 spent on drugs for nonbipolar patients, who received a mean of 1 CNS drug prescription per person, at an average cost of $33. Medical encounters for bipolar patients cost more than for nonbipolar patients ($16,230,840 vs $4,074,797). In patients with bipolar disorder, medical encounters for mental disorders accounted for 45.8% of costs. In nonbipolar patients, medical encounters for mental disorders accounted for 4.2% of costs. The inpatient cost for mental disorders in the bipolar patients was $4,846,311, with most of this cost (69.3%) attributed to patients with bipolar I disorder ($3,357,036). CONCLUSIONS: The number and cost of both prescriptions and health care encounters suggest that bipolar disorder, especially bipolar I, is both difficult and costly to manage.

Health care utilization and costs among privately insured patients with bipolar I disorder.

OBJECTIVE: This study examined health care resource utilization and direct health care costs among patients diagnosed with bipolar I disorder in a privately insured population. METHODS: Health care claims data for 2883 patients with a primary diagnosis of bipolar disorder were compared over a 1-year period (1997) with claims data for 2883 randomly selected, age- and sex-matched, non-bipolar patients, all covered under the same large private insurer in USA. Resource use (i.e. original and refill pharmaceutical dispensing, medical and procedural services received, inpatient hospitalization, outpatient services, physician visits and emergency room treatment) and their costs are described overall, as well as by bipolar disorder diagnosis (based on ICD-9 codes) and type of care (i.e. mental health versus non-mental health). RESULTS: Bipolar patients utilized nearly three to four times the health care resources and incurred over four times greater costs per patient compared with the non-bipolar group during the 1-year period ($7663 versus $1962). Inpatient care (hospitalizations) accounted for the greatest disparity between groups, as it was the single-most costly resource in the bipolar group ($2779 versus $398). Patients with bipolar depression (among the single bipolar diagnostic categories of mixed, manic or depressed) incurred the highest health care costs. While mental health care cost was a significant component of total cost in the bipolar group, it accounted for only 22% of the total per-patient cost; in comparison, it accounted for only 6% of the total per-patient cost in the non-bipolar group. CONCLUSION: Treatment of bipolar disorder, particularly inpatient care, is costly to patients and health insurers. Further study is needed to find ways to reduce the overall cost of managing these patients without jeopardizing patient care.