Washington – A daily dose of strontium ranelate is associated with a significant delay in joint space narrowing in adults with symptomatic primary knee osteoarthritis, based on data from the phase III Strontium Ranelate Knee Osteoarthritis Trial (SEKOIA). Strontium renalate is not approved for treating osteoporosis in the United States but is in more than 100 countries, said Dr. Jean-Yves Reginster, head of bone and cartilage research at the University of Liège (Belgium). Data from nonclinical studies have shown that strontium's bone-building activity has a positive impact on cartilage as well, he noted at the annual meeting of the American College of Rheumatology. Dr. Reginster and his colleagues randomized 1,683 adults with symptomatic primary knee osteoarthritis (OA) to 1 g of strontium ranelate per day (566 patients), 2 g/day (558 patients), or a placebo (559 patients). Complete data were available for 1,371 patients. The average age of the patients was 63 years, and 69% were women. Overall, treatment with either dose of strontium was associated with a significant delay in the radiographic progression of knee OA, which was assessed by measuring the radiological joint space narrowing (JSN) of the medial tibiofemoral compartment of the knee joint. After 1 year, joint space width decreased by 0.27 mm in the 2-g/day group, 0.23 mm in the 1-g/day group, and 0.37 mm in the placebo group. The differences between the 2-g/day and 1-g/day groups and the placebo group were 0.10 mm and 0.14 mm, respectively. Significantly less radiological progression was noted in both strontium groups, compared with the placebo group. The percentage of patients with radiological progression (defined as JSN of at least 0.5 mm) was 26% in the 2-g/day group, 22% in the 1-g/day group, and 33% in the placebo group. “The structural effect is translated clinically into a lower number of patients having a radiological progression over thresholds predictive of OA-related surgery,” Dr. Reginster said. The findings suggest that strontium ranelate could reduce the need for knee surgery in OA patients, he added. In addition, significantly more patients in the 2-g/day group exceeded the minimally perceptible clinical improvement (MCPI) threshold, compared with the placebo patients, on subscores of pain, stiffness, and physical function. The percentage of patients in the 1-g/day group above this threshold was not significantly higher than in the placebo group. No significant difference in adverse events was observed among the three groups, and the incidence of serious adverse events was 17% in all groups. The study findings also appeared online in the Annals of Rheumatic Diseases. The study was sponsored by Servier. Dr. Reginster disclosed financial relationhips with multiple companies, including Servier.

A 100-mg daily dose of aspirin significantly reduced the rate of major vascular events but had no significant impact on reducing the rate of recurrence of venous thromboembolism, in a study including 822 patients. The findings were simultaneously published in the New England Journal of Medicine and presented at the annual meeting of the American Heart Association in Los Angeles. The ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism) study examined the effect of a 100-mg daily dose of aspirin in 822 patients who had a history of a unprovoked VTE and had completed initial anticoagulation therapy. Participants were randomized to a placebo or aspirin at 56 sites in five countries. Roughly half of the patients were male, 56% had a proximal deep-vein thrombosis as an index event, 29% had pulmonary embolism as an index event, and 14% had both conditions as an index event (N. Engl. J. Med. 2012;367:1979-87). Overall, VTE recurred in 14% of the aspirin group and 18% of the placebo group, a nonsignificant difference. However, the rates of two secondary composite outcomes were significantly reduced in patients who took aspirin compared with those on placebo. The rate of a composite outcome including VTE, myocardial infarction, stroke, or cardiovascular death was reduced 5% per year in the aspirin group vs. 8% per year for placebo. The rate of a composite outcome including VTE, myocardial infarction, stroke, major bleeding, or death from any cause was 6% per year for aspirin vs. 9% per year for placebo. No significant difference in serious adverse events or in the rates of major or clinically relevant nonmajor bleeding was observed between the aspirin and placebo groups, the researchers noted. The ASPIRE data alone were not enough to show a significant reduction in the recurrence of VTE, they said. However, when the ASPIRE data were combined with data from a similar patient population of 402 adults in the WARFASA (Warfarin and Aspirin) study, the researchers found “a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.” The combined results support the use of low-dose aspirin to prevent both recurrent VTE and major vascular events in patients who have had a first episode of unprovoked VTE, the researchers said. The studies suggest that aspirin has the double benefit of significantly reducing not only the rate of VTE recurrence but also the rate of a composite of major vascular events, said Dr. Theodore Warkentin, a professor of pathology and molecular medicine at McMaster University in Hamilton, Ont. “Before physicians consider prescribing aspirin for patients who have had acute unprovoked venous thromboembolism, it is important that they treat the patients with effective anticoagulation for at least 3 months, to avoid the high risk of early recurrence,” he said. “For patients who then wish to stop anticoagulation, a switch to aspirin at a dose of 100 mg daily will reduce by one-third the risk of recurrent venous thromboembolism, as well as of arterial cardiovascular events, and may also attenuate the early burst of thrombosis recurrence after cessation of oral anticoagulation,” he said. Aspirin requires no monitoring, and does not accumulate in patients with renal insufficiency, Dr. Warkentin added. The study's lead author, Dr. Timothy A. Brighton of the University of Sydney, Australia, disclosed serving as a consultant for Pfizer, GlaxoSmithKline, and other companies. The study was supported by the National Health and Medical Research Council (Australia), the Health Research Council (New Zealand), the National Heart Foundation of Australia, Bayer HealthCare (Germany), and the Australasian Society of Haematology and Thrombosis. Dr. Warkentin has served as a consultant for GlaxoSmithKline and as a speaker for Pfizer Canada, and he has received grants from Bayer.

Clostridium difficile infections have reached an all-time high in the United States, and 94% of these infections begin with medical care, according to data from the Centers for Disease Control and Prevention. C. difficile–related deaths increased from 3,000 in 1999–2000 to 14,000 in 2006-2007, according to the CDC. The data were published as a CDC Vital Signs report and were presented in a telebriefing on March 6. C. difficile is “a formidable opponent,” and a patient safety issue everywhere that medical care is provided, said Dr. Clifford McDonald, a CDC epidemiologist and the lead author of the report. The CDC's data show that 25% of C. difficile infections first appear in hospitalized patients, while 75% occur either in nursing home residents or in people recently treated in doctors' offices or clinics. People most at risk are those who take antibiotics and receive care in an outpatient setting. In general, the risk of developing C. difficile increases with age. Although half of C. difficile infections occur in people younger than 65 years, 90% of C. difficile-related deaths occur in those aged 65 years and older, said Dr. McDonald. He said that clinicians can help reduce C. difficile infections by following six steps: ▸Prescribe antibiotics judiciously▸Be proactive about testing patients for C. difficile if they develop diarrhea while taking antibiotics.▸Isolate patients with C. difficile.▸Wear gloves and gowns when treating C. difficile patients, even for short visits.▸Clean surfaces in exam and treatment rooms with bleach or other spore-killing products.▸When a patient transfers to another facility, notify the medical team about a C. difficile infection. Also, be sure to order the appropriate cultures to determine whether antibiotics are really needed, Dr. McDonald suggested, and watch for signs that signal C. difficile. “Antibiotic-associated diarrhea is very common,” but C. difficile accounts for only about one-third of that, he said. However, certain clues suggest C. difficile, including more than three unformed stools in 24 hours, fever, abdominal pain, diarrhea that continues once an antibiotic has been discontinued, or diarrhea that began only once an antibiotic was discontinued, he said. If someone has been on antibiotics, think about C. difficile early and get the person tested, whether in an inpatient or an outpatient facility, Dr. McDonald emphasized. To determine the current prevalence of C. difficile, CDC researchers reviewed data from their Emerging Infections Program, which conducted population-based surveillance from eight geographic areas, and the National Healthcare Safety Network (NHSN). In 2010, a total of 10,342 cases of C. difficile infection were identified via the Emerging Infections Program in 2010, and a total of 42,157 incident laboratory-identified C. difficile events were reported via the NHSN. On a positive note, early results from state-led programs in Illinois, Massachusetts, and New York showed that hospital collaboration can reduce C. difficile infections, Dr. McDonald said. The 71 hospitals in these states that participated in C. difficile-prevention programs reduced infection rates by 20% over 21 months. “These promising results follow similar efforts in England, a nation that dropped C. difficile infections by more than 50% during a recent 3-year period,” the CDC researchers said in the full report (MMWR doi:mm6109a3). For additional information about tracking HAIs infections, contact the Emerging Infections Program or the NHSN. Dr. McDonald had no financial conflict of interest to disclose.

Thrombolysis with intravenous tissue plasminogen activator for the treatment of acute ischemic stroke does not increase the risk of brain hemorrhage in patients who are also taking warfarin, according to an observational study of more than 23,000 patients. The patients had an international normalized ratio (INR) of 1.7 or lower, which is the same population of warfarin-treated patients for whom intravenous tissue plasminogen activator (TPA) is recommended in the current American Heart Association/American Stroke Association guidelines. Symptomatic intracranial hemorrhage (sICH) is associated with intravenous TPA and may occur more often in patients receiving warfarin, according to Dr. Ying Xian, who was lead investigator on the study in JAMA. But “the true absolute risk of sICH in this population remains a matter of significant debate,” and previous studies of bleeding risk associated with warfarin have been small, with inconsistent results, wrote Dr. Xian of the Duke Clinical Research Institute in Durham, N.C., and his colleagues. The investigators reviewed data from 23,437 adults in the American Heart Association's Get With the Guidelines – Stroke Registry. The study participants were treated with intravenous TPA at 1,203 registry hospitals between April 2009 and June 2011 (JAMA 2012;307:2600–8). A total of 1,802 (8%) of the patients were receiving warfarin at the time of treatment with TPA. A total of 1,107 patients (5%) developed sICH after TPA. Although the unadjusted rate of hemorrhage was significantly higher in warfarin-treated patients (6% vs. 5%, P less than .001), there was no significant difference in hemorrhage rates after risk adjustment (adjusted odds ratio, 1.01). The results were similar regardless of whether or not the patients' scores on the National Institutes of Health Stroke Scale (NIHSS) were excluded from the risk adjustment, the researchers noted. Similarly, there was no significant difference in the rates of life-threatening or serious systemic hemorrhage between the warfarin and nonwarfarin groups (0.9% for both) and no significant differences between the two groups in TPA complications (11% vs. 8%, respectively) or in-hospital mortality (11% vs. 8%, respectively). “We found the potential for substantial undertreatment, because up to 50% of warfarin-treated patients who might have been eligible for reperfusion therapy did not receive intravenous TPA,” the researchers wrote. The results also indicated that there was no significant relationship between warfarin use and sICH in a subgroup analysis of patients with INRs between 1.5 and 1.7 or in an exploratory analysis of patients with INRs of 2.0 or lower. The higher unadjusted incidence of sICH in warfarin patients may be a result of the differences in risk profiles between the warfarin and non-warfarin patients, because those receiving warfarin were significantly older and had higher NIHSS scores, the researchers noted. The study was limited by several factors, including its retrospective design and a lack of NIHSS information for all patients. More research is needed to explore the effectiveness of intravenous TPA for patients with INRs outside of the range recommended by the guidelines, they added. In an accompanying editorial (JAMA 2012;307:2637–8), Dr. Mark J. Alberts wrote that the findings support the use of TPA for eligible patients. “The real risk is in not treating otherwise eligible patients, who may then have prolonged morbidity from their stroke,” said Dr. Alberts of Northwestern University in Chicago. Boehringer Ingelheim, Merck, Bristol-Myers Squibb, and Sanofi-Aventis have supported the Get With the Guidelines – Stroke program and Janssen Pharmaceutical Companies does currently. Several coauthors disclosed financial relationships with companies.