The two DIAMOND studies were 3-year trials comparing the effects of TIKOSYN and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether TIKOSYN could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, TIKOSYN did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of TIKOSYN in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose (see CLINICAL STUDIES, DIAMOND Patients with Atrial Fibrillation).

In both DIAMOND studies, patients were randomized to 500 mcg BID of TIKOSYN, but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI.

In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded.

DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to TIKOSYN (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the TIKOSYN group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving TIKOSYN. The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on TIKOSYN and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on TIKOSYN and 290/756 (38%) on placebo required hospitalization because of worsening heart failure.

DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to TIKOSYN (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the TIKOSYN group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving TIKOSYN. Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on TIKOSYN and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on TIKOSYN and 205/761 (27%) on placebo required hospitalization because of worsening heart failure.

DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to TIKOSYN and 257 randomized to placebo). DIAMOND AF patients randomized to TIKOSYN received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the TIKOSYN group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on TIKOSYN and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on TIKOSYN and 102/257 or 40% for placebo.

Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the TIKOSYN group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the TIKOSYN group and 42% of the placebo group remained in normal sinus rhythm for one year.

In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the TIKOSYN-treated patients (see ADVERSE REACTIONS), TIKOSYN, given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome.