Mark Y. Chan

A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor

Summary.u2002 Background:u2002Active and safe reversibility of anticoagulation is an unmet need in clinical care. Factor IXa, required for rapid thrombin generation on platelet surfaces, is a novel target for modulating coagulation. REG1 comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding FIXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson–Crick base pairing, neutralizing its anti‐FIXa activity. Objective:u2002To test the multiple repeat‐dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of REG1. Methods:u2002We randomized 39 healthy volunteers to receive either three consecutive weight‐adjusted, drug–antidote treatment cycles, or double placebo. Each treatment cycle included an intravenous bolus of 0.75u2003mgu2003kg−1 RB006, followed 60u2003min later by a descending dose of RB007, ranging from a 2u2003:u20031 to 0.125u2003:u20031 antidote/drug ratio (1.5u2003mgu2003kg−1 to 0.094u2003mgu2003kg−1 RB007). Serial clinical assessments and coagulation measurements were performed through 14u2003days postrandomization. Results:u2002Repeat doses of RB006 achieved highly reproducible activated partial thromboplastin time (APTT) levels with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 5.8 at 15u2003min postdose), while repeat doses of RB007 reversed the APTT levels dose‐dependently and reproducibly. There was no major bleeding and there were no other serious adverse events. Conclusions:u2002This is the first human study demonstrating multiple repeat‐dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of an RNA aptamer–oligonucleotide antidote pair. The results lay the foundation for studying the translation of this novel anticoagulation platform to a wide variety of clinical applications.

Prevalence, Predictors, and Impact of Conservative Medical Management for Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Who Have Angiographically Documented Significant Coronary Disease

OBJECTIVESnWe sought to characterize the utilization and impact of a conservative medical management strategy for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and significant coronary artery disease on early angiography.nnnBACKGROUNDnPractice guidelines recommend an early invasive management strategy for NSTE ACS, but revascularization procedures may not always be performed after early angiography, even when significant coronary artery disease is present.nnnMETHODSnWe evaluated 8,225 intermediate- to high-risk NSTE ACS patients with at least 1 coronary lesion >50% stenosis on early angiography from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial (2001 to 2003), comparing patients treated with conservative medical management with those who underwent in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 7 days of randomization.nnnRESULTSnA total of 2,633 patients (32%) were medically managed, 4,294 (52%) underwent PCI, and 1,298 (16%) underwent CABG. The strongest independent predictors of conservative medical management versus any intervention were prior CABG, lower body weight, lack of a reinfarction between randomization and catheterization, and 3-vessel disease. With conservative medical management, the cumulative risk of 1-year mortality after discharge increased rapidly during the first 90 days and thereafter remained higher at 7.7% compared with that seen in patients treated with PCI (3.6%) or CABG (6.2%).nnnCONCLUSIONSnOne-third of patients with NSTE ACS and significant coronary disease on early angiography were managed without in-hospital revascularization in the SYNERGY trial, and these patients had an increased risk of late mortality. These findings highlight the need for novel treatment approaches for NSTE ACS patients who are not candidates for revascularization. (SYNERGY trial; NCT00043784).

Noninvasive, medical management for non–ST-elevation acute coronary syndromes

Despite emphasis on the use of invasive management strategies for patients with non-ST-elevation acute coronary syndromes (NSTE ACS) in recent practice guidelines, 27% to 56% of NSTE ACS patients do not undergo diagnostic angiography, and a further 45% to 78% do not undergo revascularization procedures during the initial hospitalization. These medically managed patients (also termed noninvasive management) have a greater frequency of medical comorbidities and high-risk clinical characteristics and are less likely to receive guideline-recommended medications, compared with patients who undergo revascularization procedures. The rates of short and long-term adverse outcomes are also substantially higher in medically managed NSTE ACS patients, but more widespread implementation of contemporary medical therapies in this population is limited by exclusion of medically managed patients from many randomized clinical trials.