The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.

The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.

A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent.

BACKGROUND: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen. OBJECTIVES: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2. PATIENTS/METHODS: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg(-1); cohort 2 (n = 6) received 1.0 mg kg(-1); cohort 3 (n = 6) received 3.0 mg kg(-1); and cohort 4 (n = 8) received 2.0 mg kg(-1) . In cohorts 1-3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single-dose (n = 4) or multidose (n = 4) anivamersen. RESULTS: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 µg mL(-1) at 84 h, 5.19 µg mL(-1) at 72 h, 9.32 µg mL(-1) at 90 h, and 32.5 µg mL(-1) at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half-life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed. CONCLUSIONS: In our first-in-human study, REG2 was well tolerated and provided dose-proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics.

Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent: translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design.

We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 µg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

Time-limited efficacy of pacing electrodes following open heart surgery.

Temporary epicardial pacing electrodes have been utilised since the 1960s in the postoperative management of cardiac surgical patients, both as a diagnostic tool and therapeutic intervention. To determine the efficacy of the epicardial pacing wires over time after open heart surgery, 30 patients (20M/10F) who underwent coronary artery bypass surgery, were evaluated by standard 12-lead EKG, atrial electrogram, and atrial and ventricular pacing thresholds immediately after surgery and on postoperative day 5. Both atrial and ventricular pacing thresholds were significantly increased on postoperative day 5 as compared to baseline. The ability for effective AAI, VVI and DDD pacing was lost in 38.89 percent, 37.5 percent and 61.11 percent of patients, respectively, on postoperative day 5. We conclude that both atrial and ventricular pacing wires have limited efficacy after postoperative day 4 for pacing after open heart surgery due to a marked increase in pacing thresholds over this time period.

Radiofrequency catheter ablation of atrial flutter: procedural success and long-term outcome.

The objective of this study was to describe the procedural success and clinical recurrences after radiofrequency catheter ablation of atrial flutter. A deflectable catheter with a 4 or 5 mm tip was positioned in the posterior right atrium. Radiofrequency energy was delivered sequentially from the tricuspid annulus to the inferior vena cava. Catheter ablation during 18 sessions for 16 patients resulted in abrupt atrial flutter termination and noninducibility in all patients. Successful sites were near the os of the coronary sinus but had no distinguishing electrographic features. During a follow-up period of 8 +/- 5 months, 4 (25%) patients had recurrence of atrial flutter; 3 of 4 underwent successful repeat ablation. By actuarial analysis, 87% of patients remained in normal sinus rhythm 6 months after the initial procedure. The only distinguishing feature of those with recurrence compared with those whose sinus rhythm was maintained was the induction of nonclinical atrial arrhythmia (50% vs 0%, respectively; p < 0.05). One patient had resolution of presumed tachycardia-related cardiomyopathy. Catheter ablation by an anatomic approach was highly successful in terminating type 1 atrial flutter and was associated with good long-term response. This technique may represent a meaningful alternative for restoration and maintenance of normal sinus rhythm. However, further investigation is warranted to define its clinical role fully.

Value of the P-wave signal-averaged ECG for predicting atrial fibrillation after cardiac surgery.

BACKGROUND: Atrial fibrillation (AF) is a commonly encountered arrhythmia in clinical practice, and it occurs frequently after cardiac surgery. The P-wave signal-averaged (SA) ECG noninvasively detects atrial conduction delay. Prior studies have described greater P-wave prolongation in patients with a history of AF, but prospective studies have not been performed. METHODS AND RESULTS: Consecutive patients undergoing cardiac surgery were enrolled. The P-wave SAECG was recorded before surgery from three orthogonal leads using a sinus P-wave template and a cross-correlation function. The averaged P wave was filtered with a least-squares-fit filter and combined into a vector magnitude, and total P-wave duration was measured. Patients were observed after cardiac surgery for the development of AF. One hundred thirty patients were enrolled, and 33 (25%) developed AF 2.6 +/- 2.0 days after surgery. Patients with AF more often had left ventricular hypertrophy on ECG (P < .05) and had a lower ejection fraction (P < .05). The P-wave duration on the SAECG was significantly longer in the AF patients than in those without AF: 152 +/- 18 versus 139 +/- 17 milliseconds (P < .001). An SAECG P-wave duration > 140 milliseconds predicted AF with sensitivity of 77%, specificity of 55%, positive predictive accuracy of 37%, and negative predictive accuracy of 87%. The likelihood of experiencing AF was increased 3.9-fold if the SAECG P-wave duration was prolonged. P-wave SAECG results were independent of other clinical variables by multivariate analysis. CONCLUSIONS: The P-wave duration recorded with the SAECG is a potent, accurate, and independent predictor of AF after cardiac surgery.

The relationship of anticoagulation level and complications after successful percutaneous transluminal coronary angioplasty.

The degree of anticoagulation and its effect on the frequency of abrupt coronary artery closure, coronary ischemia, bleeding complications requiring transfusion, and death were examined in 336 patients after elective percutaneous transluminal coronary angioplasty (PTCA). All patients received a bolus of 10,000 U of heparin at the beginning of the procedure followed by a continuous infusion of 2000 U/hr. At the conclusion of the procedure the infusion was reduced to 1000 U/hr and continued for 18 to 24 hours at which time the heparin infusion was suspended to allow removal of arterial and venous access sheaths. Partial thromboplastin time (PTT) was examined while patients continued to receive the heparin infusion. There was a variable degree of PTT prolongation in response to a standard dose of heparin with a range of 34 seconds to "greater than 150 seconds." Patients were divided into two groups according to the degree of heparin-induced PTT prolongation: group A included 271 patients with PTT greater than or equal to 3 times the control value, and group B comprised 65 patients with PTT less than 3 times the control value. Ischemic complications were analyzed on day 1 after PTCA and at hospital discharge. Bleeding complications and mortality were examined only at hospital discharge. There was a significant reduction in the incidence of abrupt coronary artery closure in group A on day 1 (1.5% vs 10.7%, p less than 0.001) and at hospital discharge (2.6% vs 10.7%, p less than 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)