Standardizing care for acute decompensated heart failure in a large megatrial: the approach for the Acute Studies of Clinical Effectiveness of Nesiritide in Subjects with Decompensated Heart Failure (ASCEND-HF).

Acute decompensated heart failure (ADHF) is a major public health issue and remains a heterogeneous, complex, and difficult condition to manage. Although novel acute therapies are being tested in large randomized clinical trials, opportunities exist to improve the standard of care by ensuring optimal adherence to currently established evidence-based interventions for HF. Consideration of the goals of therapy and practical application of current methods to assess for clinical improvement may lead to improved patient management and possibly improved outcomes for patients with ADHF. This review provides key practical information regarding the current standard of care for patients with ADHF including the goals of therapy, management of acute and chronic medications, and discharge/transition of care planning.

The effect of wound instillation of a novel purified capsaicin formulation on postherniotomy pain: a double-blind, randomized, placebo-controlled study.

BACKGROUND: Acute postoperative pain is common after most surgical procedures. Despite the availability of many analgesic options, postoperative pain management is often unsatisfactory. Purified capsaicin (ALGRX 4975 98% pure) has demonstrated prolong inhibition of C-fiber function in in vitro, preclinical, and clinical studies, and may be an effective adjunct to postoperative pain management. METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study of the analgesic efficacy of a single intraoperative wound instillation of 1000 microg ultrapurified capsaicin (ALGRX 4975) after open mesh groin hernia repair in 41 adult male patients. The primary end-point was average daily visual analog scale (VAS) pain scores during the first week after surgery assessed as area under the curve (AUC). Pain was recorded twice daily in a pain diary for 4 wk. Physical examination and laboratory tests were done before and 1 wk after surgery, together with recordings of adverse events up to 28 days. Adverse events were recorded. Data were also analyzed using a mixed-effects analysis with NONMEM. RESULTS: VAS AUC was significantly lower during the first 3 days postoperatively (P < 0.05), but not for the whole 1 or 4 wk postoperatively. Mixed-effects analysis with NONMEM revealed that pain scores were significantly lower (P < 0.05) in the capsaicin group during the first 4 days. No clinically significant serious adverse events were observed, although a mild transient increase in liver enzymes was seen more often in the capsaicin-treated group. CONCLUSION: In the setting of a well-defined analgesic protocol standard, VAS AUC analysis and a mixed-effect analysis showed superior analgesia of capsaicin relative to placebo during the first 3-4 days after inguinal hernia repair.

The PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) trial: study rationale, design, and baseline patient characteristics.

BACKGROUND: Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia. METHODS: PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days. RESULTS: Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005. CONCLUSIONS: The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.

Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery: PREVENT IV: a randomized controlled trial.

CONTEXT: Coronary artery bypass graft (CABG) surgery with autologous vein grafting is commonly performed. Progressive neointimal hyperplasia, however, contributes to considerable vein graft failure. Edifoligide is an oligonucleotide decoy that binds to and inhibits E2F transcription factors and thus may prevent neointimal hyperplasia and vein graft failure. OBJECTIVE: To assess the efficacy and safety of pretreating vein grafts with edifoligide for patients undergoing CABG surgery. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized, double-blind, placebo-controlled trial of 3014 patients undergoing primary CABG surgery with at least 2 planned saphenous vein grafts and without concomitant valve surgery, who were enrolled between August 2002 and October 2003 at 107 US sites. INTERVENTION: Vein grafts were treated ex vivo with either edifoligide or placebo in a pressure-mediated delivery system. The first 2400 patients enrolled were scheduled for 12- to 18-month follow-up angiography. MAIN OUTCOME MEASURES: The primary efficacy end point was angiographic vein graft failure (> or =75% vein graft stenosis) occurring 12 to 18 months after CABG surgery. Other end points included other angiographic variables, adverse events through 30 days, and major adverse cardiac events. RESULTS: A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829). Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80-1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64-1.08]; P = .16). CONCLUSIONS: Failure of at least 1 vein graft is quite common within 12 to 18 months after CABG surgery. Edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to determine whether edifoligide has delayed beneficial effects, to understand the mechanisms and clinical consequences of vein graft failure, and to improve the durability of CABG surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00042081.

Needle-free powder lidocaine delivery system provides rapid effective analgesia for venipuncture or cannulation pain in children: randomized, double-blind Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial.

OBJECTIVE: The Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial was a randomized, single-dose, double-blind, phase 3 study investigating whether a needle-free powder lidocaine delivery system (a sterile, prefilled, disposable system that delivers lidocaine powder into the epidermis) produces effective local analgesia within 1 to 3 minutes for venipuncture and peripheral venous cannulation procedures in children. METHODS: Pediatric patients (3-18 years of age) were randomly assigned to treatment with the needle-free powder lidocaine delivery system (0.5 mg of lidocaine and 21 +/- 1 bar of pressure; n = 292) or a sham placebo system (n = 287) at the antecubital fossa or the back of the hand 1 to 3 minutes before venipuncture or cannulation. All patients rated the administration comfort of the needle-free systems and the pain of the subsequent venous access procedures with the Wong-Baker Faces Pain Rating Scale (from 0 to 5). Patients 8 to 18 years of age also provided self-reports with a visual analog scale, and parents provided observational visual analog scale scores for their child's venous access pain. Safety also was assessed. RESULTS: Immediately after administration, mean Wong-Baker Faces scale scores were 0.54 and 0.24 in the active system and sham placebo system groups, respectively. After venipuncture or cannulation, mean Wong-Baker Faces scale scores were 1.77 +/- 0.09 and 2.10 +/- 0.09 and mean visual analog scale scores were 22.62 +/- 1.80 mm and 31.97 +/- 1.82 mm in the active system and sham placebo system groups, respectively. Parents' assessments of their child's procedural pain were also lower in the active system group (21.35 +/- 1.43 vs 28.67 +/- 1.66). Treatment-related adverse events were generally mild and resolved without sequelae. Erythema and petechiae were more frequent in the active system group. CONCLUSIONS: The needle-free powder lidocaine delivery system was well tolerated and produced significant analgesia within 1 to 3 minutes.

Outcomes associated with the use of secondary prevention medications after coronary artery bypass graft surgery.

BACKGROUND: Secondary prevention medications are beneficial after acute coronary syndromes, but these benefits are less clear after coronary artery bypass graft surgery. We investigated whether greater use of secondary prevention medications after coronary artery bypass graft surgery is associated with improved clinical outcomes. METHODS: Patients undergoing coronary artery bypass graft surgery in the PREVENT IV trial (n = 2970) were surveyed for use of antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and lipid-lowering agents after hospital discharge and at 1 year. Patients were categorized based on their percentage use of indicated medications after hospital discharge. Cox modeling was used to determine the association between medication use categories and rates of death or myocardial infarction through 2 years after adjustment for clinical factors, the number of indicated medications, and treatment propensity. RESULTS: Rates of use of antiplatelet agents and lipid-lowering agents were high at discharge and at 1 year, but use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was suboptimal. There was a stepwise association between medication use at discharge and patient outcomes (p for trend = 0.014). Patients taking 50% or less of indicated medications at discharge had a significantly higher 2-year rate of death or myocardial infarction (8.0% versus 4.2%; adjusted hazard ratio, 1.69; 95% confidence interval, 1.12 to 2.55; p = 0.013) than those taking all indicated medications. CONCLUSIONS: Greater use of indicated secondary prevention medications after coronary artery bypass graft surgery is associated with a lower 2-year rate of death or myocardial infarction. These data underscore the importance of appropriate secondary prevention measures to improve long-term clinical outcomes after coronary artery bypass graft surgery.

Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults.

BACKGROUND: Many individuals do not respond to a three-dose series of hepatitis B vaccine (HBV) and most do not achieve a protective antibody response until after dose 2 or 3. METHODS: Healthy, seronegative 18-28 year old adults were randomly assigned in equal numbers to receive two doses of the experimental vaccine (HBV-ISS without alum) (0, 8 weeks) and placebo (24 weeks) or Engerix-B (0, 8, 24 weeks). Adverse events were collected during the first week and at 4 weeks after each injection. Antibodies were measured 4 weeks after dose 1; before, 1 and 4 weeks after dose 2, and before, 1 and 4 weeks after dose 3 and at 1 year. RESULTS: Ninety-nine participants were enrolled (65% female; mean age 22.6 years). 79% of HBV-ISS and 12% of Engerix-B recipients had a protective antibody response 4 weeks post dose 1 (geometric mean concentration [GMC] 23.0 and 1.87 mIU/mL, respectively). By 1 week post dose 2, 100% of HBV-ISS and 18% Engerix-B recipients had protective levels (GMC 1603 versus 2.40 mIU/mL). Rates of adverse events were low and similar in both groups; headache and fatigue were the most common systemic adverse events in up to 1/3 of both groups. Mild injection-site tenderness was more common after HBV-ISS than Engerix-B after both doses (74-77% compared to 34-58%; p