Theressa J. Wright

Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE : Further evidence for survival and safety and implications for early treatment

Objective:To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis. Design:Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003. Setting:ENHANCE took place in 25 countries at 361 sites. Patients:Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol. Interventions:Drotrecogin alfa (activated) was infused at a dose of 24 &mgr;g/kg/hr for 96 hrs. Measurements and Main Results:The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0–24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01). Conclusions:ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)

The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained‐release (SR) moxonidine, an imidazoline receptor agonist.

Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis.

Objectives To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. Design Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. Setting Forty community or academic medical institutions in United States and Canada. Patients One hundred thirty-one adult patients with severe sepsis. Interventions Intravenous infusion of rhAPC (12, 18, 24, or 30 &mgr;g/kg/hr) or placebo for 48 or 96 hrs. Measurements and Main Results No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p > .999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p = .021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. Conclusions rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 &mgr;g/kg/hr for 96 hrs was selected for use in future clinical studies.

Design and Methods of the Raloxifene Use for The Heart (RUTH) Study

Raloxifene is a selective estrogen receptor modulator that lowers total and low-density lipoprotein (LDL) cholesterol, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. The Raloxifene Use for The Heart (RUTH) trial is designed to determine whether raloxifene 60 mg/day compared with placebo: (1) lowers the risk of the coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI); and (2) reduces the risk of invasive breast cancer in women at risk for a major coronary event. RUTH is a double-blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women aged > or =55 years from 26 countries. Women are eligible for randomization if they are postmenopausal and have documented coronary heart disease (CHD), peripheral arterial disease, or multiple risk factors for CHD. Use of estrogen within the previous 6 months is an exclusion factor. The study will be terminated after a minimum of 1,670 participants experience a primary coronary end point. Secondary end points include cardiovascular death, myocardial revascularization, noncoronary arterial revascularization, stroke, all-cause hospitalization, all-cause mortality, all breast cancers, clinical fractures, and venous thromboembolic events, in addition to the individual components of the composite primary coronary end point. RUTH will provide important information about the risk-benefit ratio of raloxifene in preventing acute coronary events and invasive breast cancer, as well as information about the natural history of CHD in women at risk of major coronary events.

The effects of chronic, sustained-release moxonidine therapy on clinical and neurohumoral status in patients with heart failure

AIMS Congestive heart failure (CHF) is characterized by elevated plasma norepinephrine (PNE) associated with a poor prognosis. Moxonidine selectively stimulates medullary imidazoline receptors which centrally inhibit sympathetic outflow and potently suppress levels of circulating PNE. This study was designed to evaluate the effects of central sympathetic inhibition on clinical and neurohumoral status in patients with CHF. METHODS AND RESULTS This study evaluated 25 patients (age=69+/-7 years, 20 males) with symptomatic CHF (NYHA II-III), stabilized on standard therapy. The mean ejection fraction was 28+/-7% at baseline. Patients were titrated in a double-blind fashion to 11 weeks of oral therapy with placebo (n=9) or sustained-release (SR) moxonidine 0.9 mg bid (n=16). Clinical and neurohumoral status were evaluated at baseline, on chronic therapy at the target dose, and during cessation of therapy. All patients completed the trial and reached the target dose. Dry mouth, symptomatic hypotension, and asthenia were more frequent in the moxonidine SR-treated group. PNE was substantially reduced after 6 weeks at the maximum dose (0.9 mg bid) by 50% vs. placebo (P<0. 0005). A reduction in 24-h mean heart rate (P<0.01) was correlated to the reduction in PNE (r=0.70, P<0.05). A 36% increase in the standard deviation of normal-to-normal intervals (SDNN) was observed in the moxonidine SR group vs. a 2% decrease for placebo (P=0.06); for the root mean square of successive differences (rMSSD), there was a 21% increase for moxonidine SR vs. a 19% decrease for placebo (P<0.05). Abrupt cessation of chronic therapy resulted in substantial increases in PNE, blood pressure, and heart rate. CONCLUSIONS Chronic therapy with a sustained-release formulation of moxonidine in patients with CHF was well tolerated, with substantial and sustained reductions in PNE. The tachyarrhythmias were attenuated, with evidence of improved autonomic tone. Due to the observed effects following moxonidine discontinuation, tapering of therapy is recommended.

Prevention of sudden cardiac death in the young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium

&NA; This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses important issues regarding sudden cardiac death in the young (SCDY), a problem that does not discriminate by gender, race, ethnicity, education, socioeconomic level, or athletic status. The occurrence of SCDY has devastating impact on families and communities. Sudden cardiac death in the young is a matter of national and international public health, and its prevention has generated deep interest from multiple stakeholders, including families who have lost children, advocacy groups, academicians, regulators, and the medical industry. To promote scientific and clinical discussion of SCDY prevention and to germinate future initiatives to move this field forward, a Cardiac Safety Research Consortium–sponsored Think Tank was held on February 21, 2015 at the US Food and Drug Administrations White Oak facilities, Silver Spring, MD. The ultimate goal of the Think Tank was to spark initiatives that lead to the development of a rational, reliable, and sustainable national health care resource focused on SCDY prevention. This article provides a detailed summary of discussions at the Think Tank and descriptions of related multistakeholder initiatives now underway: it does not represent regulatory guidance.

The Second Annual Think Tank on Prevention of Sudden Cardiac Death in the Young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium

Abstract Sudden cardiac death in the young (SCDY) spans gender, race, ethnicity, and socioeconomic class. The loss of any pediatric patient is a matter of national and international public health concern, and focused efforts should be aimed at preventing these burdensome tragedies. Prepared by members of the Cardiac Safety Research Consortium, this White Paper summarizes and reports the dialogue at the second Think Tank related to the issues and the proposed solutions for the development of a national resource for screening and prevention of SCDY. This Think Tank, sponsored by the Cardiac Safety Research Consortium and the United States Food and Drug Administration, convened on February 18, 2016, in Miami, FL, to identify and resolve the barriers that prevent early identification of patients at risk for SCDY. All potential stakeholders including national and international experts from industry, medicine, academics, engineering, and community advocacy leaders had an opportunity to share ideas and collaborate.