Jyotsna Garg

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

Telaprevir for Previously Treated Chronic HCV Infection

BACKGROUND Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment. METHODS We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa-ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs). RESULTS The rates of sustained virologic response in the three telaprevir groups--51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group--were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%). CONCLUSIONS In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone. (ClinicalTrials.gov number, NCT00420784.)

A novel bioresorbable polymer paclitaxel-eluting stent for the treatment of single and multivessel coronary disease: primary results of the COSTAR (Cobalt Chromium Stent With Antiproliferative for Restenosis) II study.

OBJECTIVES The aim was to compare safety and effectiveness of the CoStar drug-eluting stent (DES) (Conor MedSystems, Menlo Park, California) with those of the Taxus DES (Boston Scientific, Maple Grove, Minnesota) in de novo single- and multivessel percutaneous coronary intervention (PCI). BACKGROUND Paclitaxel elution from a stent coated with biostable polymer (Taxus) reduces restenosis after PCI. The CoStar DES is a novel stent with laser-cut reservoirs containing bioresorbable polymer loaded to elute 10 microg paclitaxel/30 days. METHODS Patients undergoing PCI for a single target lesion per vessel in up to 3 native epicardial vessels were randomly assigned 3:2 to CoStar or Taxus. Primary end point was 8-month major adverse cardiac events (MACE), defined as adjudicated death, myocardial infarction (MI), or clinically driven target vessel revascularization (TVR). Protocol-specified 9-month angiographic follow-up included 457 vessels in 286 patients. RESULTS Of the 1,700 patients enrolled, 1,675 (98.5%) were evaluable (CoStar = 989; Taxus = 686), including 1,330 (79%) single-vessel and 345 (21%) multivessel PCI. The MACE rate at 8 months was 11.0% for CoStar versus 6.9% for Taxus (p < 0.005), including adjudicated death (0.5% vs. 0.7%, respectively), MI (3.4% vs. 2.4%, respectively), and TVR (8.1% vs. 4.3%, respectively). Per-vessel 9-month in-segment late loss was 0.49 mm with CoStar and 0.18 mm with Taxus (p < 0.0001). Findings were consistent across pre-specified subgroups. CONCLUSIONS The CoStar DES is not noninferior to the Taxus DES based on per-patient clinical and per-vessel angiographic analyses. The relative benefit of Taxus is primarily attributable to reduction in TVR. Follow-up to 9 months showed no apparent difference in death, MI, or stent thrombosis rates.

Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery

BACKGROUND Despite the routine use of prophylactic systemic antibiotics, surgical-site infection continues to be associated with significant morbidity and cost after colorectal surgery. The gentamicin-collagen sponge, an implantable topical antibiotic agent, is approved for surgical implantation in 54 countries. Since 1985, more than 1 million patients have been treated with the sponges. METHODS In a phase 3 trial, we randomly assigned 602 patients undergoing open or laparoscopically assisted colorectal surgery at 39 U.S. sites to undergo either the insertion of two gentamicin-collagen sponges above the fascia at the time of surgical closure (the sponge group) or no intervention (the control group). All patients received standard care, including prophylactic systemic antibiotics. The primary end point was surgical-site infection occurring within 60 days after surgery, as adjudicated by a clinical-events classification committee that was unaware of the study-group assignments. RESULTS The incidence of surgical-site infection was higher in the sponge group (90 of 300 patients [30.0%]) than in the control group (63 of 302 patients [20.9%], P=0.01). Superficial surgical-site infection occurred in 20.3% of patients in the sponge group and 13.6% of patients in the control group (P=0.03), and deep surgical-site infection in 8.3% and 6.0% (P=0.26), respectively. Patients in the sponge group were more likely to visit an emergency room or surgeons office owing to a wound-related sign or symptom (19.7%, vs. 11.0% in the control group; P=0.004) and to be rehospitalized for surgical-site infection (7.0% vs. 4.3%, P=0.15). The frequency of adverse events did not differ significantly between the two groups. CONCLUSIONS Our large, multicenter trial shows that the gentamicin-collagen sponge is not effective at preventing surgical-site infection in patients who undergo colorectal surgery; paradoxically, it appears to result in significantly more surgical-site infections. (Funded by Innocoll Technologies; ClinicalTrials.gov number, NCT00600925.)

Effect of an Implantable Gentamicin-Collagen Sponge on Sternal Wound Infections Following Cardiac Surgery: A Randomized Trial

CONTEXT Despite the routine use of prophylactic systemic antibiotics, sternal wound infection still occurs in 5% or more of cardiac surgical patients and is associated with significant excess morbidity, mortality, and cost. The gentamicin-collagen sponge, a surgically implantable topical antibiotic, is currently approved in 54 countries. A large, 2-center, randomized trial in Sweden reported in 2005 that the sponge reduced surgical site infection by 50% in cardiac patients. OBJECTIVE To test the hypothesis that the sponge prevents infection in cardiac surgical patients at increased risk for sternal wound infection. DESIGN, SETTING, AND PARTICIPANTS Phase 3 single-blind, prospective randomized controlled trial, 1502 cardiac surgical patients at high risk for sternal wound infection (diabetes, body mass index >30, or both) were enrolled at 48 US sites between December 21, 2007, and March 11, 2009. INTERVENTION Single-blind randomization to insertion of 2 gentamicin-collagen sponges (total gentamicin of 260 mg) between the sternal halves at surgical closure (n = 753) vs no intervention (control group: n = 749). All patients received standardized care including prophylactic systemic antibiotics and rigid sternal fixation. MAIN OUTCOME MEASURES The primary end point was sternal wound infection occurring through 90 days postoperatively as adjudicated by a clinical events classification committee blinded to study treatment group. The primary study comparison was done in the intent-to-treat population. Secondary outcomes included (1) superficial wound infection (involving subcutaneous tissue but not extending down to sternal fixation wires), (2) deep wound infection (involving the sternal wires, sternal bone, and/or mediastinum), and (3) score for additional treatment, presence of serous discharge, erythema, purulent exudate, separation of the deep tissues, isolation of bacteria, and duration of inpatient stay (ASEPSIS; minimum score of 0 with no theoretical maximum). RESULTS Of 1502 patients, 1006 had diabetes (67%) and 1137 were obese (body mass index >30) (76%). In the primary analysis, there was no significant difference in sternal wound infection in 63 of 753 patients randomized to the gentamicin-collagen sponge group (8.4%) compared with 65 of 749 patients randomized to the control group (8.7%) (P = .83). No significant differences were observed between the gentamicin-collagen sponge group and the control group, respectively, in superficial sternal wound infection (49/753 [6.5%] vs 46/749 [6.1%]; P = .77), deep sternal wound infection (14/753 [1.9%] vs 19/749 [2.5%]; P = .37), ASEPSIS score (mean [SD], 1.9 [6.4] vs 2.0 [7.2]; P = .67), or rehospitalization for sternal wound infection (23/753 [3.1%] vs 24/749 [3.2%]; P = .87). CONCLUSION Among US patients with diabetes, high body mass index, or both undergoing cardiac surgery, the use of 2 gentamicin-collagen sponges compared with no intervention did not reduce the 90-day sternal wound infection rate. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00600483.

Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial

AIMS There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors. METHODS AND RESULTS Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11). CONCLUSION Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS). OBJECTIVE To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes. DESIGN, SETTING, AND PARTICIPANTS TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015. INTERVENTIONS Patients were randomized to sitagliptin vs placebo added to standard care. MAIN OUTCOMES AND MEASURES Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death. RESULTS Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors (P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity (I2 = 44.9, P = .16). CONCLUSIONS AND RELEVANCE Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00790205.

Accuracy of Fibroscan, Compared With Histology, in Analysis of Liver Fibrosis in Patients With Hepatitis B or C: A United States Multicenter Study

BACKGROUND & AIMS Liver biopsy is invasive and associated with complications, sampling errors, and observer variability. Vibration-controlled transient elastography (VCTE) with FibroScan can be used to immediately assess liver stiffness. We aimed to define optimal levels of liver stiffness to identify patients with chronic viral hepatitis and significant fibrosis, advanced fibrosis, or cirrhosis. METHODS In a prospective, 2-phase study, patients with chronic hepatitis C or B underwent VCTE followed by liver biopsy analysis from January 2005 through May 2008 at 6 centers in the United States. In phase 1 we identified optimal levels of liver stiffness for identification of patients with stage F2-F4 or F4 fibrosis (the development phase, n = 188). In phase 2 we tested these cutoff values in a separate cohort of patients (the validation phase, n = 560). All biopsies were assessed for METAVIR stage by a single pathologist in the phase 1 analysis and by a different pathologist in the phase 2 analysis. Diagnostic performances of VCTE were assessed by area under the receiver operating characteristic curve (AUROC) analyses. RESULTS In phase 1 of the study, liver stiffness measurements identified patients with ≥ F2 fibrosis with AUROC value of 0.89 (95% confidence interval, 0.83-0.92) and identified patients with F4 fibrosis with AUROC value of 0.92 (95% confidence interval, 0.87-0.95). Liver stiffness cutoff values (kPa) in phase 1 were 8.4 for ≥ F2 (82% sensitivity, 79% specificity) and 12.8 for F4 (84% sensitivity, 86% specificity). In the phase 2 analysis, the liver stiffness cutoff values identified patients with ≥ F2 fibrosis with 58% sensitivity (P < .0001 vs phase 1) and 75% specificity (nonsignificant difference vs phase 1); they identified patients with F4 fibrosis with 76% sensitivity (P < .0001 vs phase 1) and 85% specificity (nonsignificant differences vs phase 1). VCTE had an interobserver agreement correlation coefficient of 0.98 (n = 26) and an intraobserver agreement correlation coefficient of 0.95 (n = 34). CONCLUSIONS In a large U.S. multicenter study, we confirmed that VCTE provides an accurate assessment of liver fibrosis in patients with chronic viral hepatitis. Our findings are similar to those from European and Asian cohorts.