pyrimidinones and Acute-Coronary-Syndrome

TAK-442 is an oral direct factor Xa inhibitor. We sought to determine the dose-dependent effect of TAK-442 on major bleeding when added to standard treatment in stabilised patients with acute coronary syndrome (ACS). In this phase II double-blind study, 2,753 ACS patients were randomised to TAK-442 or placebo in addition to usual care using a three-stage adaptive design. Patients were randomised to placebo in all stages, but doses of TAK-442 escalated from 10 mg BID, 20 mg twice-daily (BID), or 40 mg once-daily (QD) in stage 1; to 40 mg BID, 80 mg QD, or 80 mg BID in stage 2; and to 160 mg QD or 120 mg BID in stage 3. Study drug was started 36 hours after emergent treatment of ACS and within seven days of admission, and continued for 24 weeks. The primary endpoint was incidence of TIMI (thrombolysis in myocardial infarction) major bleeding. TIMI major bleeding incidence was low, but higher with the pooled TAK-442 doses than with placebo (17 [0.9%] vs 4 [0.5%]; p=0.47), although the difference was neither significant nor dose-dependent. However, a dose response was evident when using the modified ISTH scale. The incidence of cardiovascular events was similar among TAK-442 dose groups and placebo. When administered over a wide range of doses after an ACS event, TAK-442 treatment did not result in a dose-dependent increase in TIMI major bleeding, but increased bleeding was observed when a more sensitive bleeding scale was used. There was no evidence for efficacy.

Topics: Acute Coronary Syndrome; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrimidinones; Sulfones; Treatment Outcome

Intravenous amiodarone (AMD) has been used for the treatment of ventricular tachycardia/fibrillation (VT/VF) in emergency care medicine. However, AMD acts slowly and is occasionally accompanied by hypotension and bradycardia. The antiarrhythmic effect of intravenous nifekalant (NIF) was assessed in patients with VT/VF complicating acute coronary syndrome (ACS) according to our study protocol.. Among a series of 1,143 ACS patients, 41 patients who suffered sustained VT/VF were enrolled; 19 failed to respond to a preceding lidocaine (LID) injection. NIF was given first as an intravenous bolus injection (0.2 mg/kg) and then as a continuous intravenous infusion at a relatively low dose level (0.2 mg x kg(-1) x h(-1)). Sustained VT/VF was successfully inhibited by NIF in 34 patients (83%). In subgroup analysis, NIF achieved VT/VF inhibition in 79% of patients who received preceding LID and in 86% of patients who received direct NIF. There were no significant changes in systolic blood pressure or heart rate following NIF therapy. A corrected QT interval was significantly prolonged (P<0.01), whereas torsade de pointes developed in only 1 patient (2%).. An intravenous bolus injection and subsequent continuous infusion of NIF at a relatively low dosage were effective in treating severe ventricular tachyarrhythmias complicating ACS, reducing the potential risk of proarrhythmia.

Topics: Acute Coronary Syndrome; Aged; Amiodarone; Anti-Arrhythmia Agents; Blood Pressure; Electrocardiography; Emergency Medical Services; Female; Heart Rate; Humans; Infusions, Intravenous; Injections, Intravenous; Lidocaine; Male; Middle Aged; Pyrimidinones; Tachycardia, Ventricular; Torsades de Pointes; Ventricular Fibrillation

A 75-year-old female complained of severe chest pain and was emergently admitted to our hospital because of anterior acute myocardial infarction. Emergent coronary angiography was performed and revealed occlusion in segment 7, so a stent was implanted. Lidocaine, carvedilol, amiodarone, magnesium, and nifekalant were administered successively because non-sustained ventricular tachycardia (NSVT) frequently appeared like an electrical storm. After nifekalant administration, QTc was significantly prolonged and torsades de pointes was induced. Overdrive pacing was performed and finally the NSVT was completely controlled. If fatal arrhythmias such as NSVT show resistance to medication, overdrive pacing should be considered to stabilize the arrhythmia associated with acute coronary syndrome.

Topics: Acute Coronary Syndrome; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Drug Resistance; Female; Humans; Myocardial Infarction; Pyrimidinones; Stents; Tachycardia, Ventricular; Treatment Outcome