Adverse Heart Effects of Rofecoxib May Have Been Identified Years Earlier

Clinical trial data indicated an association between the anti-inflammatory medication rofecoxib and cardiovascular risk as early as December 2000, before the product was taken off the market in September 2004, according to a report in the November 23 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Rofecoxib was introduced to the market in May 1999 and quickly became a commercial success, with sales reaching $2 billion annually, according to background information in the article. The manufacturer marketed the product (with the brand name Vioxx) as a safer alternative to traditional nonsteroidal anti-inflammatory drugs. However, concerns about its cardiovascular adverse effects reportedly existed during the drug development process. In September 2004, the manufacturer voluntarily withdrew the product from the market after one large trial was terminated early due to an increased risk of cardiovascular events.

In November 2004, the manufacturer’s chief executive testified before a U.S. Senate committee that until the halted trial, combined data from all randomized controlled clinical trials showed no difference in the risk of confirmed heart events between patients taking rofecoxib and those taking placebo. To assess whether and when analysis of published and unpublished clinical trial data could have revealed the cardiovascular risks of rofecoxib, Joseph S. Ross, M.D., M.H.S., of Mount Sinai School of Medicine, New York, and colleagues conducted a pooled analysis of all such trials conducted by the manufacturer before September 2004.

The researchers identified 30 randomized, placebo-controlled trials that enrolled a combined 20,152 individuals, lasted from four weeks to four years and assigned a range of 17 to 2,586 participants to take doses of rofecoxib ranging from 12.5 milligrams to 50 milligrams. The authors pooled the data from these studies and analyzed the cumulative results.

“As of December 2000, 21 of these trials had been completed (70 percent) and the risk of a cardiovascular thromboembolic [heart- or blood clot–related] adverse event or death was greater among subjects assigned to the rofecoxib group, raising concerns from a safety standpoint,” the authors write. “Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35-percent increased risk of a cardiovascular thromboembolic adverse event or death.” The association strengthened as additional data became available—as of April 2002 the pooled analysis showed a 39-percent increased risk, and as of September 2004, a 43-percent increased risk.

The analyses provide a roadmap for how drug safety can be assessed after a product has been introduced into the market, the authors note. New legislation requiring the public disclosure of trial results in the ClinicalTrials.gov database will make available substantial data that has not previously been used to understand drug safety or efficacy. Independent investigators will now be able to conduct comprehensive meta-analyses that can complement and corroborate surveillance done by the U.S. Food and Drug Administration.

“Physicians and the public deserve to be in a position to make informed choices about risks and benefits, and the disclosure and dissemination of information about potential risk immediately after its recognition is absolutely essential. Our study provides insight into what should have been known about the risks of rofecoxib,” the authors conclude. “If we are to detect harms early and protect the public’s health, while ensuring the availability of new, clinically effective therapeutics, a system must be established that makes full use of all existing evidence.”

Arch Intern Med. 2009;169[21]:1976-1985.

Psychotropic Medications Associated With Risk of Falls in Older Adults

Older adults who take several types of psychotropic medications—such as antidepressants or sedatives—appear more likely to experience falls, according to an analysis of previous studies reported in the November 23 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

More than 30 percent of individuals older than 65 will fall at least once a year, and falls and their complications are the fifth-leading cause of death in the developed world, according to background information in the article. Each year, 85 percent of all injury-related hospital admissions and more than 40 percent of nursing home admissions are related to falls, and the annual costs related to falls and their complications are estimated to be in the billions of dollars worldwide. Both internal and external risk factors contribute to falls, and medications have previously been implicated in the probability of falling and in the risk of sustaining a fracture.

John C. Woolcott, M.A., of University of British Columbia and Centre for Health Evaluation and Outcomes Sciences, Vancouver, Canada, and colleagues conducted a meta-analysis of 22 previously published studies conducted between 1996 and 2007. The studies involved 79,081 participants older than 60 years and evaluated nine drug classes: antihypertensive agents; diuretics; beta-blockers; sedatives and hypnotics; neuroleptics and antipsychotics; antidepressants; benzodiazepines; narcotics; and non-steroidal anti-inflammatory drugs.

When the data were pooled and results adjusted for other factors, the use of sedatives and hypnotics, antidepressants and benzodiazepines were significantly associated with the risk of falling in older adults.

“Given the divergent results shown by some observational assessments within specific medication classes, the results of our meta-analysis reiterate the need for caution when prescribing these medications to seniors,” the authors write. “It is hoped that future research in this area can be completed with larger sample sizes in both community and long-term care facility settings and thus improve the quality of information about fall risks that is available to physicians and pharmacists when they are deciding which types of pharmacotherapy to provide.”

Arch Intern Med. 2009;169[21]:1952-1960

Study Examines Challenges of Diagnosing Neurofibromatosis Type 1–like Syndrome

An analysis of patients with a syndrome similar to the genetic disorder, neurofibromatosis type 1, indicates that diagnosis may be difficult because of shared clinical findings, such as certain pigmentary characteristics, according to a study in the November 18 issue of JAMA.1

Neurofibromatosis type 1 (NF1), an autosomal dominant disorder affecting approximately 1 in 3,000 individuals worldwide, is characterized by multiple café au lait macules (CALMs; small areas of discoloration of the skin [light-brown]), skin-fold freckling and tumors of the nervous system. Other frequently observed features are certain bone abnormalities, short stature, macrocephaly (an abnormally large head) and learning problems, according to background information in the article.

NF1 diagnostic criteria were established by the National Institutes of Health (NIH) and are widely used to make the diagnosis using information obtained from physical examination, family history, and radiologic studies. A genetically distinct but similar disorder, caused by mutations of the gene SPRED1 was recently identified (and recently named Legius syndrome). The authors write that this disorder, characterized mainly with CALMs, axillary freckling and macrocephaly, may be underestimated.

Ludwine Messiaen, Ph.D., of the University of Alabama at Birmingham, and colleagues conducted a study to determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1–like syndrome (NFLS; Legius syndrome). The study included 23 unrelated probands (first affected family member who seeks medical attention for a genetic disorder) carrying a SPRED1 mutation identified through clinical testing, who participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1,318 unrelated anonymous blood samples collected in 2003-2007 from patients with a broad range of signs typically found in NF1 but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.

The researchers found that among 42 SPRED1-positive individuals from the clinical cohort, 20 (48 percent) fulfilled NIH NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. “None of the 42 SPRED1-positive individuals had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous [composed of or containing bone] lesions, or symptomatic optic pathway gliomas [brain tumors],” the researchers write.

“In the anonymous cohort of 1,318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73 percent) had an NF1 mutation and 18 (19 percent) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9 percent of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS.”

“The dermatologic phenotype in young children with a SPRED1 mutation could not be differentiated from NF1 and nearly half of individuals (20/42) with a SPRED1 mutation fulfilled the NF1 diagnostic criteria based on presence of more than 5 CALMs with or without skinfold freckling and with or without familial history,” they write.

The authors add that although an NF1 diagnosis may become apparent with the passage of time, the diagnosis will remain uncertain for individuals who do not develop other signs of NF1, and that molecular genetic testing can resolve the diagnosis in most such cases. “In case of diagnostic uncertainty, we recommend that NF1 should be analyzed first and, if negative, SPRED1 testing should be considered in patients with CALMs with or without freckling and no other NF1 diagnostic features.

Identification of a SPRED1 mutation may relieve a psychological burden from families who otherwise would be in a waiting mode for potential serious NF1-associated manifestations.”

“… it is important that clinicians, including general practitioners, clinical geneticists, pediatricians, ophthalmologists, dermatologists, neurologists, and oncologists, who are involved in the care, diagnosis, and treatment of individuals with NF1, should be aware that Legius syndrome can resemble NF1.”

In an accompanying editorial, David Stevenson, M.D., and David Viskochil, M.D., Ph.D., of the University of Utah, Salt Lake City, comment on the findings of this study. 2

“The study by Messiaen et al provides important information about Legius syndrome and enables clinicians to use good clinical judgment in situations where it is now realized that there is phenotypic overlap for distinct disorders. As new genes resulting in phenotypes similar to NF1 and Legius syndrome are discovered, clinicians must adapt diagnostic approaches and clinical management protocols to meet the needs of patients affected with these disorders.”

References:
1. JAMA. 2009;302[19]:2111-2118.

Prevalence of High LDL, or ‘Bad’ Cholesterol Levels Decreases in U.S.

Prevalence of High LDL, or ‘Bad’ Cholesterol Levels Decreases in U.S.

Between 1999 and 2006, the prevalence of adults in the U.S. with high levels of LDL cholesterol, the “bad” cholesterol, decreased by about one-third, according to a study in the November 18 issue of JAMA.1 But a high percentage of adults still are not being screened or treated for high cholesterol levels.

Elevated levels of low-density lipoprotein cholesterol (LDL-C), the major atherogenic lipoprotein, are a primary focus for cholesterol management of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). “The guidelines set LDL-C target levels that are based on the history of coronary heart disease (CHD) or risk for developing CHD in the next 10 years,” the authors write. Few studies have described the prevalence of high LDL-C levels and the use of lipid-lowering medications across all CHD risk categories, according to background information in the article.

Elena V. Kuklina, M.D., Ph.D., of the Centers for Disease Control and Prevention, Atlanta, and colleagues investigated trends in the prevalence of screening, current use of cholesterol-lowering medication, and high LDL-C levels across 4 study cycles (1999-2000, 2001-2002, 2003-2004, and 2005-2006). The researchers used data from the National Health and Nutrition Examination Survey (NHANES), and restricted the study sample to fasting participants age 20 years or older (n = 8,018), excluded pregnant women (n = 464) and participants with missing data (n = 510), with the final study sample consisting of 7,044 participants.

Overall prevalence for high LDL-C levels decreased from 31.5 percent in 1999-2000 to 21.2 percent in 2005-2006. “However, this prevalence varied substantially by risk category. The highest prevalence of high LDL-C levels was observed in the high-risk ATP III category with 69.4 percent and 58.9 percent during the first and last cycles, respectively,” the authors write. Participants with a self-reported history of CHD, angina, heart attack, stroke, and diabetes mellitus or participants with a fasting blood glucose level of 126 mg/dL or greater were placed in the high ATP III risk category.

There were no significant changes observed in the weighted age-standardized screening rates from 1999-2000 to 2005-2006. Among participants with high LDL-C levels, 35.5 percent were unscreened, 24.9 percent undiagnosed, and 39.6 percent untreated or inadequately treated in 2005-2006. In the high-risk category, about one-fifth of participants were eligible for lipid-lowering drug therapy but were not receiving it in 2005-2006.

“Self-reported use of lipid-lowering medications increased from 8.0 percent to 13.4 percent, but screening rates did not change significantly, remaining less than 70 percent during the study periods,” the authors note. They add that the goal of improving screening rates may be hindered by the lack of consensus regarding the age at which screening should start.

In an accompanying editorial2, J. Michael Gaziano, M.D., M.P.H., of the VA Boston Healthcare System and Brigham and Women’s Hospital, Boston, and Contributing Editor, JAMA; and Thomas A. Gaziano, M.D., M.Sc., of Brigham and Women’s Hospital and Harvard School of Public Health, Boston, write that cholesterol guidelines need to be simplified.

“Even though there has been progress in identifying and treating patients with dyslipidemia, the current guidelines are overly complicated, and a simplified risk-based approach is supported by the current data. Abandoning the fixed LDL-C threshold and targets used in many guidelines is justified by the linear relationship of cholesterol lowering and the benefit of the intervention for preventing cardiovascular disease. The use of a simplified risk-based approach could increase the ease of implementation of treatment and increase the number of patients receiving beneficial lipid-lowering therapy.”

References:
1. JAMA. 2009;302[19]:2104-2110.
2. JAMA. 2009;302[19]:2148-2149

Treatment With Folic Acid, Vitamin B12 Associated With Increased Risk of Cancer, Death

Patients with heart disease in Norway, a country with no fortification of foods with folic acid, had an associated increased risk of cancer and death from any cause if they had received treatment with folic acid and vitamin B12, according to a study in the November 18 issue of JAMA.1

Most epidemiological studies have found inverse associations between folate (a B vitamin) intake and risk of colorectal cancer, although such associations have been inconsistent or absent for other cancers, according to background information in the article.

“Experimental evidence suggests that folate deficiency may promote initial stages of carcinogenesis, whereas high doses of folic acid may enhance growth of cancer cells. Since 1998, many countries, including the United States, have implemented mandatory folic acid fortification of flour and grain products to reduce the risk of neural-tube birth defects,” the authors write.

“Recently, concerns have emerged about the safety of folic acid, in particular with respect to cancer risk.”

Marta Ebbing, M.D., of Haukeland University Hospital, Bergen, Norway, and colleagues analyzed the results of two Norwegian homocysteine-lowering trials among patients with ischemic heart disease, where there was a statistically nonsignificant increase in cancer incidence in the groups assigned to folic acid treatment. The researchers examined whether folic acid treatment was associated with cancer outcomes and all-cause mortality after extended follow-up. “Because there is no folic acid fortification of foods in Norway, this study population was well suited for such an investigation,” they write.

The two randomized, placebo-controlled clinical trials included 6,837 patients with ischemic heart disease who were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. Patients were randomized to receive oral treatment with folic acid (0.8 mg/d), plus vitamin B12 (0.4 mg/d), plus vitamin B6 (40 mg/d) (n = 1,708); folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) (n = 1,703); vitamin B6 alone (40 mg/d) (n = 1,705); or placebo (n = 1,721). During study treatment, median (midpoint) serum folate concentration increased more than 6-fold among participants given folic acid.

The researchers found that after a median 39 months of treatment and an additional 38 months of post-trial observational follow-up, 288 participants (8.4 percent) who did not receive folic acid plus vitamin B12 vs. 341 participants (10.0 percent) who received such treatment were diagnosed with cancer, a 21 percent increased risk. A total of 100 patients (2.9 percent) who did not receive folic acid plus vitamin B12 vs. 136 (4.0 percent) who received such treatment died from cancer, a 38 percent increased risk. A total of 16.1 percent of patients who received folic acid plus vitamin B12 vs. 13.8 percent who did not receive such treatment died from any cause.
“Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B12. Vitamin B6 treatment was not associated with any significant effects,” the authors write.

“Our results need confirmation in other populations and underline the call for safety monitoring following the widespread consumption of folic acid from dietary supplements and fortified foods.”

Bettina F. Drake, Ph.D., M.P.H., and Graham A. Colditz, M.D., Dr.P.H., of the Alvin J. Siteman Cancer Center and Washington University in St. Louis School of Medicine, write in an accompanying editorial that longer-term studies are needed.2

“Preventive interventions require long-term evaluation. While the report by Ebbing et al provides important short-term data, the findings do not nullify the potential long-term benefits that folic acid fortification may have on population health. The time frame for benefit for some preventive interventions may span decades, although smoking cessation may be unique among lifestyle changes that produce a rapid reduction in cancer risk.”

References:
1. JAMA. 2009;302[19]:2119-2126
2. JAMA. 2009;302[19]:2152-2153.

Surgical Errors Remain a Challenge In and Out of the Operating Room

Despite a national focus on reducing surgical errors, surgery-related adverse events continue to occur both inside and outside the operating room, according to an analysis of events at Veterans Health Administration Medical Centers published in the November issue of Archives of Surgery, one of the JAMA/Archives journals.

An estimated five to 10 incorrect surgical procedures occur daily in the United States, some with devastating effects, according to background information in the article. Surgery can be performed on the wrong site, wrong side of the body, using an incorrect procedure or on the wrong patient.

“The Veterans Health Administration developed and implemented a pilot program to reduce the risk of incorrect surgical events in April 2002, which resulted in the dissemination of a national directive in January 2003,” the authors write. The rule was further updated in 2004.

Julia Neily, R.N., M.S., M.P.H., of Veterans Health Administration (VHA), White River Junction, Vt., and colleagues reviewed reported surgical adverse events occurring at 130 VHA facilities between January 2001 and June 2006. Events were categorized by location (inside the operating room vs. outside, at a location such as a procedure room at a clinic or at the patient’s bedside), specialty departments, body segments, severity and several other characteristics.

Overall, the researchers reviewed 342 reported events, including 212 adverse events (any surgical procedure performed unnecessarily, such as a procedure performed on the wrong patient or wrong site) and 130 close calls (in which a recognizable step toward an adverse event occurred but the patient was not subjected to the unnecessary procedure). Of the adverse events, 108 (50.9 percent) occurred in an operating room and 104 (49.1 percent) occurred elsewhere.

“When examining adverse events only, ophthalmology and invasive radiology were the specialties associated with the most reports (45 [21.2 percent] each), whereas orthopedics was second to ophthalmology for the number of reported adverse events occurring in the operating room,” the authors write. “Pulmonary medicine cases (such as wrong-side thoracentesis [removing fluid from chest]) and wrong-site cases (such as wrong spinal level) were associated with the most harm. The most common root cause of events was communication (21.0 percent).”

The results indicate that communication problems often occur early in surgical procedures, and interventions such as a final “time-out” moments before incision may occur too late to correct them. “Incorrect surgical procedures are not only an operating room challenge but also a challenge for events occurring outside of the operating room,” the authors conclude. “We support earlier communication based on crew resource management to prevent surgical adverse events.”

Arch Surg. 2009;144[11]:1028-1034.

Uninsured More Likely to Die after Trauma

Americans without health insurance appear more likely to die following admission to the hospital for trauma than those with health care coverage, according to a report in the November issue of Archives of Surgery, one of the JAMA/Archives journals.

In 2007, 45.7 million Americans were uninsured, according to background information in the article. “Uninsured patients currently face health-related disparities in screening, hospital admission, treatment and outcomes,” the authors write. “Uninsured adults have a 25 percent higher risk of mortality than insured adults, accounting for approximately 18,000 deaths per year in excess. Evidence regarding the effects of lack of insurance on traumatically injured patients suggests that they are at added risk.”

Heather Rosen, M.D., M.P.H., of Children’s Hospital Boston and Harvard Medical School, and colleagues analyzed records from the National Trauma Data Bank, which contains information from 2.7 million patients admitted for traumatic injury to more than 900 U.S. trauma centers. Demographic, medical history, injury severity, outcomes and charges were assessed for 687,091 patients age 18 and older admitted between 2002 and 2006. Patients were divided into five insurance categories: uninsured, a managed care organization, commercial indemnity insurance, Medicare or Medicaid.

Overall, uninsured patients had the highest rate of death following admission for trauma, even after controlling for age, sex, race and severity and mechanism of injury. An analysis of patients age 18 to 30—selected because they were less likely to have co-occurring illnesses—revealed that uninsured patients in this group still had the highest odds of death. The same was true in a subanalysis of only patients with head injuries and in another analysis of those with one or more co-occurring illnesses.

Lack of insurance may increase the risk of death after trauma in several ways, the authors note. Uninsured patients may experience treatment delay; receive different care, including fewer diagnostic tests; or possess a lower rate of health literacy.
“Most recent research has concentrated on decreased (or lack of) access to care as a result of being uninsured,” the authors write. “However, we found that, even after admission to a hospital, trauma patients can have worse outcomes based on insurance status. This concerning finding warrants more rigorous investigation to determine why such variation in mortality would exist in a system where equivalent care is not only expected but mandated by law.”

“In addition, treatment often is initiated before payer status is recognized; thus, this provokes the question of whether differences exist in processes of care during the hospital stay,” they conclude. “We can only speculate as to the mechanism of the disparities we have exposed; the true causes are still unclear. Although the lack of insurance may not be the only explanation for the disparity in trauma mortality, the accidental costs of being uninsured in the United States today may be too high to continue to overlook.”

Arch Surg. 2009;144[11]:1006-1011.