Trends in rates of acetaminophen-related adverse events in the United States.

PURPOSE: The goal of this study is to summarize trends in rates of adverse events attributable to acetaminophen use, including hepatotoxicity and mortality. METHODS: A comprehensive analysis of data from three national surveillance systems estimated rates of acetaminophen-related events identified in different settings, including calls to poison centers (2008-2012), emergency department visits (2004-2012), and inpatient hospitalizations (1998-2011). Rates of acetaminophen-related events were calculated per setting, census population, and distributed drug units. RESULTS: Rates of poison center calls with acetaminophen-related exposures decreased from 49.5/1000 calls in 2009 to 43.5/1000 calls in 2012. Rates of emergency department visits for unintentional acetaminophen-related adverse events decreased from 58.0/1000 emergency department visits for adverse drug events in 2009 to 50.2/1000 emergency department visits in 2012. Rates of hospital inpatient discharges with acetaminophen-related poisoning decreased from 119.8/100 000 hospitalizations in 2009 to 108.6/100 000 hospitalizations in 2011. After 2009, population rates of acetaminophen-related events per 1 million census population decreased for poison center calls and hospitalizations, while emergency department visit rates remained stable. However, when accounting for drug sales, the rate of acetaminophen-related events (per 1 million distributed drug units) increased after 2009. Prior to 2009, the rates of acetaminophen-related hospitalizations had been slowly increasing (p-trend = 0.001). CONCLUSIONS: Acetaminophen-related adverse events continue to be a public health burden. Future studies with additional time points are necessary to confirm trends and determine whether recent risk mitigation efforts had a beneficial impact on acetaminophen-related adverse events. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Measures to quantify the abuse of prescription opioids: a review of data sources and metrics.

PURPOSE: The abuse and nonmedical use of prescription opioids and its subsequent consequences are an important public health concern. This phenomenon has paralleled the increase in the therapeutic use of opioids for pain management. There is thus a need to measure prescription opioid abuse to understand trends over time and to compare abuse of one product to another. The purpose of this review is to provide an overview of the strengths and weaknesses of frequently used numerators and denominators in "abuse ratios" (ARs). METHODS: For this review, we critically evaluated the various measures to quantify drug availability and the available data sources to measure prescription opioid abuse. RESULTS: There are currently no commonly adopted metrics for measuring either the prevalence of opioid abuse, or abuse relative to drug availability. Because the settings, manifestations, and severity of abuse can vary from one person to the next, no one measure of abuse, abuse-related outcome, or drug exposure is ideal. Each measure of abuse captures a specific facet of abuse, but not the whole spectrum. Reliable estimation of population-adjusted or utilization-adjusted rates of abuse can be accomplished with a prescription opioid AR. This metric estimates the prevalence of abuse in a given population or abuse relative to how much drug is available, and, in certain cases, can be used to compare abuse among various opioid drugs. AR measurements in the literature vary in the inclusion of specific measures of abuse and availability, and there is little consensus in the field regarding which measures allow for the most appropriate approximation of the extent of abuse, and for comparisons among opioids. Crude numbers of outcomes related to abuse (e.g., emergency department visits, treatment admissions, and overdoses) cannot be properly understood without context as these may overestimate or underestimate the true scope and severity of prescription opioid abuse. They can, however, serve as numerators in properly constructed ARs. The denominator of the AR provides the necessary context by accounting for populations at risk or drug availability (e.g., prescriptions or tablets dispensed, unique recipients of dispensed drug, total patient days of therapy, or kilograms sold), and each comes with its own set of assumptions to consider. CONCLUSIONS: Moving forward, it is important that there be a common understanding in the scientific community regarding how to select appropriate measures to serve as numerators and denominators in AR calculations, and how to interpret the resultant findings. There is no single best measure of abuse for use as a numerator in an AR, and each must be chosen and interpreted in the context of what it measures. For public health considerations, one must always look at both absolute numbers and adjusted numbers. When conducting multiple analyses using different measures of exposure as denominators, differences in ARs are not unexpected, but one should explore why there are differences and assess the appropriateness of each of the denominators.

Medication Exposure in Pregnancy Risk Evaluation Program.

To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.

Keeping the Pharmacology in Pharmacoepidemiology.

The treatment of many medical conditions requires the use of multiple drugs. A study published recently in this journal nicely illustrates the need to consider the pharmacology of potentially interacting drugs when conducting pharmacoepidemiologic studies of patient safety outcomes associated with such interactions. By examining multiple streams of data, we can piece together the risks and the mechanisms of action underlying those risks, and provide useful information for clinicians and patients to use multiple pharmacotherapies safely.

Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.

PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks' duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure.

Use of antidepressant medications during pregnancy: a multisite study.

OBJECTIVE: This study was undertaken to provide information on the prevalence of use of antidepressant drugs among pregnant women in the United States. STUDY DESIGN: A retrospective study was conducted using the automated databases of 7 health plans. Women who delivered an infant in a hospital were identified. Antidepressant drug use was evaluated assuming a gestational duration of 270 days. RESULTS: Among the 118,935 deliveries occurring from 2001-2005, 6.6% of women were dispensed an antidepressant during pregnancy. Antidepressant drug use increased from 2.0% in 1996 to 7.6% of deliveries in 2004 and 2005. Selective serotonin reuptake inhibitor use increased from 1.5% in 1996 to 6.4% in 2004 and 6.2% in 2005. CONCLUSION: Our finding that nearly 8% of pregnant women were prescribed antidepressants drugs during the years 2004 and 2005 highlights the importance of understanding the effects of these medications on the developing fetus and on the pregnant woman.

Onset of acute myocardial infarction after use of non-steroidal anti-inflammatory drugs.

PURPOSE: To examine the association between cyclooxygenase-2 (COX-2) selective and traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and incident acute myocardial infarction (AMI), and to address unanswered questions regarding the contour of risk over time. METHODS: A cohort of new NSAID users aged 40-84 years was followed for the occurrence of first AMI. Data were collected within the General Practice Research Database (GPRD) from 1 January 1997 to 31 December 2004. RESULTS: The study population included 1185 AMI events (889 probable and 296 possible) from a cohort of 283 136 patients. After adjustment for demographic and cardiovascular risk factors, the hazard ratio (HR) for AMI was significantly increased for both coxib (2.11, 95% confidence interval (CI) 1.04-4.26) and non-coxib (2.24, 95%CI 1.13-4.42) COX-2 selective NSAIDs when compared to remote exposure to NSAIDs, but was not increased for traditional NSAIDs. Stratifying exposure into the first month of use versus use beyond 1 month, the risk of AMI was increased during the first month of COX-2 selective NSAIDs use, but not later (3.43, 95%CI 1.66-7.07 and 1.88, 95%CI 0.82-4.31, respectively p-value for interaction = 0.6). CONCLUSIONS: The results suggest that the use of coxib and non-coxib COX-2 selective NSAIDs was associated with an elevated risk of AMI within the first month of exposure. Recent past exposure to NSAID was not associated with a similar increase in risk.

Patterns of Immediate-Release and Extended-Release Opioid Analgesic Use in the Management of Chronic Pain, 2003-2014.

Importance: Many stakeholders are working to improve the safe use of immediate-release (IR) and extended-release/long-acting (ER/LA) opioid analgesics. However, little information exists regarding the relative use of these 2 formulations in chronic pain management. Objectives: To describe the distribution of IR and ER/LA opioid analgesic therapy duration and examine adding and switching patterns among patients receiving long-term IR opioid analgesic therapy, defined as at least 90 consecutive days of IR formulation use. Design, Setting, and Participants: A retrospective cohort study of 169 million individuals receiving opioid analgesics from across 90% of outpatient retail pharmacies in the United States from January 1, 2003, to December 31, 2014, using the IQVIA Health Vector One: Data Extract Tool. Analyses were conducted from March 2015 to June 2017. Exposures: Receipt of dispensed IR or ER/LA opioid analgesic prescription. Main Outcomes and Measures: Distribution of therapy frequency and duration of IR and ER/LA opioid analgesic use, and annual proportions of patients receiving long-term IR opioid analgesic therapy who added an ER/LA formulation while continuing to use an IR formulation, switched to an ER/LA formulation, or continued receiving IR opioid analgesic therapy only. Results: Among the 169 280 456 patients included in this analysis, 168 315 458 patients filled IR formulations and 10 216 570 patients filled ER/LA formulations. A similar percentage of women received ER/LA (55%) and IR (56%) formulations, although those receiving ER/LA formulations (72%) were more likely to be aged 45 years or older compared with those receiving IR formulations (46%). The longest opioid analgesic episode duration was 90 days or longer for 11 563 089 patients (7%) filling IR formulations and 3 103 777 patients (30%) filling ER/LA formulations. The median episode duration was 5 days (interquartile range, 3-10 days) for patients using IR formulations and 30 days (interquartile range, 21-74 days) for patients using ER/LA formulations. From January 1, 2003, to December 31, 2014, a small and decreasing proportion of patients with long-term IR opioid analgesic therapy added (3.8% in 2003 to 1.8% in 2014) or switched to (1.0% in 2003 to 0.5% in 2014) an ER/LA formulation. Conclusions and Relevance: Most patients receiving opioid analgesics, whether for short or extended periods, use IR formulations. Once receiving long-term IR opioid analgesic therapy, patients are unlikely to add or switch to an ER/LA formulation.

The concomitant prescribing of ethinyl estradiol/drospirenone and potentially interacting drugs.

BACKGROUND: Ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) contains a progestin drospirenone with antimineralocorticoid properties that may cause potassium retention leading to hyperkalemia. We estimated the percentage of EE/DRSP users prescribed concomitant potassium-sparing drugs [nonsteroidal antiinflammatory drugs, diuretics, angiotensin-converting enzyme inhibitors (with diuretics), angiotensin II agonists (with diuretics), and potassium chloride] between January 1, 2002, and March 31, 2005. STUDY DESIGN: We analyzed a population-based data set of 62,527 EE/DRSP users (Dimension Rx, Caremark). We compared the fill date and end date for each prescription (Rx) for an interacting drug to the start and end date for each EE/DRSP episode (linked Rxs). If a day of an interacting Rx overlapped with an EE/DRSP episode, concomitant prescribing was recorded. RESULTS: A total of 17.6% of the women concomitantly used EE/DRSP and an interacting drug. Twenty-nine percent of concomitant use occurred within a month of EE/DRSP initiation. Nonsteroidal antiinflammatory drugs and diuretics were most frequently used concomitantly with EE/DRSP. Forty percent of the women with concomitant use were 35 yearsof age or older at EE/DRSP initiation compared with 29% without concomitant use (p<.001). Obstetricians/gynecologists and family practitioners were the most common prescribers of EE/DRSP and potassium-sparing drugs, respectively. CONCLUSIONS: Concomitant prescribing of EE/DRSP and potassium-sparing drugs occurred frequently in our study population. As EE/DRSP becomes more widely used, physicians prescribing it should monitor patients for potassium-sparing drug use.

Trends in the Concomitant Prescribing of Opioids and Benzodiazepines, 2002-2014.

INTRODUCTION: Although many clinical guidelines caution against the combined use of opioids and benzodiazepines, overdose deaths and emergency department visits involving the co-ingestion of these drugs are increasing. METHODS: In this ecologic time series study, the IMS Health Total Patient Tracker was used to describe nationally projected trends of patients receiving opioids and benzodiazepines in the U.S. outpatient retail setting between January 2002 and December 2014. The IMS Health Data Extract Tool was used to examine trends in the concomitant prescribing of these two medication classes among 177 million individuals receiving opioids during this period. The annual proportion of opioid recipients who were prescribed benzodiazepines concomitantly was calculated and stratified by gender, age, duration of opioid use, immediate-release versus extended-release/long-acting opioids, and benzodiazepine molecule. The proportion of patients with concomitancy receiving opioids and benzodiazepines from the same prescriber was also analyzed. Analyses were conducted from April to June 2015. RESULTS: The nationally projected number of patients receiving opioids and benzodiazepines increased by 8% and 31%, respectively, from 2002 to 2014. During this period, the annual proportion of opioid recipients dispensed a benzodiazepine concomitantly increased from 6.8% to 9.6%, which corresponded to a relative increase of 41%. Approximately half of these patients received both prescriptions from the same prescriber on the same day. Concomitancy was more common in patients receiving opioids for ≥90 days, women, and the elderly. CONCLUSIONS: Concomitant prescribing of opioids and benzodiazepines is increasing and may play a growing role in adverse patient outcomes related to these medications.

Health plan administrative databases can efficiently identify serious myopathy and rhabdomyolysis.

OBJECTIVE: We evaluated the positive predictive values (PPVs) of specific criteria based upon International Classification of Diseases, 9th revision (ICD-9-CM) codes documented in health plan administrative databases for identification of cases of serious myopathy and rhabdomyolysis. STUDY DESIGN AND SETTING: We conducted a retrospective study among patients enrolled in 11 geographically dispersed managed care organizations. Cohorts of new users of specific statins and fibrates were identified by selecting patients with an initial dispensing of the drug during the period 1 January 1998 to 30 June 2001. Potential cases of serious myopathy or rhabdomyolysis were identified using specific criteria based upon ICD-9-CM codes suggesting a muscle disorder or acute renal failure. RESULTS: A total of 194 hospitalizations meeting the criteria for chart review selection were identified among 206,732 new users of statins and 15,485 new users of fibrates. Overall, 31 cases of serious, clinically important myopathy or rhabdomyolysis (18%) were confirmed through chart review. Of these, 26 (84%) had a claim including codes for myoglobinuria (ICD-9-CM 791.3) or other disorders of muscle, ligament, and fascia (ICD-9-CM 728.89). A PPV of 74% (26 of 35 patients meeting criteria) was found for a composite definition that included (1) a primary or secondary discharge code for myoglobinuria, (2) a primary code for "other disorders of muscle," or (3) a secondary code for "other disorders of muscle" accompanied by a claim for a CK test within 7 days of hospitalization or a discharge code for acute renal failure. CONCLUSION: For rare adverse events such as serious myopathy or rhabdomyolysis, large population-based databases that include diagnosis and laboratory test claims data can facilitate epidemiologic research.

Oral corticosteroid use among children in TennCare.

BACKGROUND: Lack of information about medication effects and use in children is a long-standing and troublesome policy issue. Documenting patterns of use for medications with potential for suboptimal use and adverse effects, such as oral corticosteroids, would be useful. OBJECTIVE: To describe the use of oral corticosteroids among children enrolled in TennCare, Tennessee's managed care program for Medicaid enrollees and uninsured individuals. DESIGN: A retrospective cohort study. DRUG EXPOSURE: Children enrolled in TennCare who had prescriptions filled in their name for oral corticosteroids during 1998 were identified. Descriptive information included age, race, sex, and county of residence. We identified possible indications for corticosteroid use for new users by searching encounter files for encounters temporally related to the index prescription. Subsequent use of corticosteroids was measured in the 365 days after the index prescription. RESULTS: Of 400 724 children continuously enrolled in TennCare during the study period, 29 362 (7327 per 100 000) children had a prescription filled for an oral corticosteroid. Steroid prescription filling was more common among young children and male children and less common among black children. Children in rural counties had oral corticosteroid prescriptions filled at a higher rate than children residing in urban counties. Nearly 75% of corticosteroid users filled only 1 prescription during the study period; 1319 children filled 4 or more prescriptions. Asthma was the most common indication for oral corticosteroid use (16%), whereas 1 in 5 users (22%) had an unknown indication for oral corticosteroid use. CONCLUSIONS: A large number of children enrolled in TennCare had a prescription for oral corticosteroids filled in 1998. Further population-based studies describing the development of adverse effects in users of corticosteroids would be important.

Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.

CONTEXT: Lipid-lowering agents are widely prescribed in the United States. Reliable estimates of rhabdomyolysis risk with various lipid-lowering agents are not available. OBJECTIVE: To estimate the incidence of rhabdomyolysis in patients treated with different statins and fibrates, alone and in combination, in the ambulatory setting. DESIGN, SETTING, AND PATIENTS: Drug-specific inception cohorts of statin and fibrate users were established using claims data from 11 managed care health plans across the United States. Patients with at least 180 days of prior health plan enrollment were entered into the cohorts between January 1, 1998, and June 30, 2001. Person-time was classified as monotherapy or combined statin-fibrate therapy. MAIN OUTCOME MEASURE: Incidence rates of rhabdomyolysis per 10,000 person-years of treatment, number needed to treat, and relative risk of rhabdomyolysis. RESULTS: In 252,460 patients treated with lipid-lowering agents, 24 cases of hospitalized rhabdomyolysis occurred during treatment. Average incidence per 10,000 person-years for monotherapy with atorvastatin, pravastatin, or simvastatin was 0.44 (95% confidence interval [CI], 0.20-0.84); for cerivastatin, 5.34 (95% CI, 1.46-13.68); and for fibrate, 2.82 (95% CI, 0.58-8.24). By comparison, the incidence during unexposed person-time was 0 (95% CI, 0-0.48; P = .056). The incidence increased to 5.98 (95% CI, 0.72-216.0) for combined therapy of atorvastatin, pravastatin, or simvastatin with a fibrate, and to 1035 (95% CI, 389-2117) for combined cerivastatin-fibrate use. Per year of therapy, the number needed to treat to observe 1 case of rhabdomyolysis was 22,727 for statin monotherapy, 484 for older patients with diabetes mellitus who were treated with both a statin and fibrate, and ranged from 9.7 to 12.7 for patients who were treated with cerivastatin plus fibrate. CONCLUSIONS: Rhabdomyolysis risk was similar and low for monotherapy with atorvastatin, pravastatin, and simvastatin; combined statin-fibrate use increased risk, especially in older patients with diabetes mellitus. Cerivastatin combined with fibrate conferred a risk of approximately 1 in 10 treated patients per year.

Effectiveness of risk management plans: a case study of pemoline using pharmacy claims data.

PURPOSE: To assess the effectiveness of a pharmaceutical risk management plan using pemoline as a case study and pharmacy claims as the data source. METHODS: Prescription claims from a continuously enrolled US population (September 1, 2000-September 30, 2002) from Caremark, a pharmacy benefit manager, were evaluated for patients with one or more pemoline claims. Patients were categorized using pemoline as second-line or first-line therapy depending on presence or absence of other central nervous system (CNS) stimulants prescriptions 90 days prior to the first pemoline claim. Logistic regression was performed to compare second-line and first-line usage with regard to patient age, gender and prescribing physician specialty and region of practice. RESULTS: Of 1,279,296 prescription claims for CNS stimulants, 17,256 (1.3%) were for pemoline. Nine hundred thirteen patients received pemoline and had 90 days or more prior enrollment. Overall, 10% of patients receiving pemoline received it as second-line therapy (95%CI: 8-12%). After adjusting for age, gender, specialty, and region, the odds of receiving pemoline as second-line therapy were significantly greater in pediatrics relative to adults (OR = 2.82, 95%CI: 1.58-5.03), and among those whose prescribers were psychiatrists versus primary care physicians (OR = 2.48, 95%CI: 1.37-4.50). Children treated by a psychiatrist had the greatest likelihood for use as second-line therapy (36%, 95%CI: 19-56%). CONCLUSIONS: Among patients who received pemoline, concordance with second-line therapy recommendations was low, even among the primary target audience of children. These results in a large geographically diverse patient population are consistent with an earlier regional study.

Duration of therapy with metoclopramide: a prescription claims data study.

PURPOSE: Metoclopramide-induced tardive dyskinesia is associated with cumulative drug exposure, which can result from prolonged use of the drug. We estimated therapy duration with metoclopramide, and measured the extent of therapy beyond the maximum time period of 12 weeks evaluated in the clinical trials and recommended in the label. METHODS: Prescription claims for metoclopramide from 2002 to 2004 were extracted for participants residing throughout the US and contained within the Caremark pharmacy benefit manager (PBM) database. An episode of therapy was defined as one or a series of consecutive claims with no more than a 30-day lag between the dispensing date of a new claim and the ending date of the preceding claim. Episode duration was calculated by subtracting the start date from the end date for each episode. RESULTS: During the study period, almost 80% of participants (total = 200 907) had only one episode of therapy. The length of the longest episode for most patients (85%) varied from 1 to 90 days, yet 15% of the patients appeared to have received prescriptions for metoclopramide for a period longer than 90 days. Cumulative therapy for longer than 90 days was recorded for almost 20% of the patients. CONCLUSIONS: These results suggest that despite the known risk of tardive dyskinesia and the labeled recommendations on duration of metoclopramide use, many patients appear to use the drug for relatively long time periods beyond the labeled recommendations. Physicians should carefully consider the risk-benefit profile of the drug and, if possible, avoid increased risk of tardive dyskinesia due to prolonged exposure.

Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey.

BACKGROUND: QT interval prolongation can lead to torsades de pointes, a potentially fatal arrhythmia. Although research exists on the relationship between QT prolongation and clinical outcome, few studies have described risk factors for prolonged QT interval in the general population. METHODS: The Third National Health and Nutrition Examination Survey (NHANES III) collected electrocardiogram interval data on 8561 subjects over 40 years of age and projected results to the US population. QT was corrected for heart rate using Fridericia's formula. Logistic regression analyses were performed to identify factors independently associated with prolonged QTc interval, defined as being in the upper 5% of the population QTc interval distribution. Analyses were conducted separately for women and men as a result of differences in the QT distribution between the sexes and also because of potential effect modification. Analytical variables included age, race/ethnicity, electrolyte measurements, body mass index, the recent use of QT-prolonging drugs and past medical histories of stroke, thyroid disease, hypertension, diabetes and myocardial infarction. RESULTS: Age, female sex, hypocalcemia (men), hypokalemia (women), and a history of thyroid disease and myocardial infarction (men) were associated with a prolonged QTc interval. In addition, taking QT-prolonging medications in the past month was associated with more than a twofold increase in the odds of prolonged QTc interval in both men and women. CONCLUSIONS: Healthcare practitioners should be aware that a prolonged QTc interval is a potential indicator of cardiovascular risk, and should exercise caution in prescribing potentially QT-prolonging medications to certain patients.

Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy.

CONTEXT: Elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) levels are established risk factors for cardiovascular disease (CVD). HMG-CoA reductase inhibitors (statins) are effective cholesterol-lowering drugs that are commonly prescribed to treat this condition. These drugs are often combined with another class of drugs, fibric acid derivatives, to lower both cholesterol and triglyceride levels. Rhabdomyolysis is a known, rare serious side effect of statin monotherapy and of statin-fibrate combination therapy. OBJECTIVE: To examine Food and Drug Administration's (FDA's) postmarketing database for cases of rhabdomyolysis in relation to monotherapy and combination use and calculate reporting rates for this event. DESIGN: Domestic cases of statin- and statin/gemfibrozil-associated rhabdomyolysis were culled from FDA's database and reviewed. Rhabdomyolysis was defined by CPK > or = 10,000 IU/L, myopathic signs and symptoms and clinical diagnosis of rhabdomyolysis. Reporting rates, consisting of number of reported cases/number of prescriptions for each drug, were then calculated to determine whether the reporting of rhabdomyolysis cases was commensurate with extent of use of each statin in the population. SETTING: Cases were obtained from the FDA adverse event reporting system (AERS) database. PATIENTS: NA. MAIN OUTCOME MEASURES: Number of rhabdomyolysis cases were evaluated, along with outcomes, such as renal failure, dialysis and death. RESULTS: Of 866 total reported cases, 482 (56%) were associated with monotherapy and 384 (44%) related to combination therapy. More than 80% of reported cases for each drug resulted in hospitalization for renal failure and dialysis. 80 patients expired from events related directly to rhabdomyolysis. Reporting rates for all statins, except for cerivastatin, were similar and much lower than 1 per 100,000 prescriptions. The cerivastatin-reporting rate was much higher at 4.24/100,000 prescriptions. CONCLUSIONS: Rhabdomyolysis is a rare, serious side effect of statin monotherapy and of statin-fibrate combination therapy. Clinicians need to remain cognizant of this potential adverse event and discuss signs and symptoms of muscle toxicity with patients in order improve the benefits-to-risks of treating dyslipidemia with statins.