Anderson J L, Platia E V, Hallstrom A, Henthorn R W, Buckingham T A, Carlson M D, Carson P E
University of Utah, LDS Hospital, Salt Lake City 84143.
Circulation. 1994 Dec;90(6):2843-52. doi: 10.1161/01.cir.90.6.2843.
The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos.
CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01).
Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.
心律失常抑制试验（CAST）旨在验证心肌梗死后使用抗心律失常药物抑制室性早搏可降低心律失常性猝死发生率这一假说。可被恩卡胺、氟卡尼或莫雷西嗪抑制室性早搏的患者被随机分配接受活性药物或安慰剂治疗。由于死亡率过高，该研究中恩卡胺和氟卡尼组于1989年（CAST - I）停止，莫雷西嗪组于1991年（CAST - II）停止。为探究这些不良结局的机制，我们比较了接受恩卡胺、氟卡尼或莫雷西嗪治疗与接受各自安慰剂治疗的患者基线特征与治疗风险的相互作用。
CAST - I包括755例分配至氟卡尼或恩卡胺组的患者以及743例分配至安慰剂组的患者，而在CAST - II中，502例患者接受莫雷西嗪治疗，491例患者接受安慰剂治疗。接受活性药物治疗和接受安慰剂治疗的患者的临床及实验室基线变量相似。在CAST - I患者中，对于非Q波心肌梗死，活性治疗与全因死亡/心脏骤停以及心律失常性死亡/心脏骤停均存在显著相互作用（Q波梗死与非Q波梗死的总死亡率风险比分别为1.8和7.9，P = 0.03）。室性早搏（VPD）频率≥50次/小时和心率≥74次/分钟仅与总死亡率/心脏骤停存在显著相互作用。在病情较重的CAST - II患者（射血分数≤40%）中，仅基线时使用利尿剂与莫雷西嗪治疗在全因死亡/心脏骤停以及心律失常性死亡/心脏骤停方面存在显著相互作用（总死亡率风险比，使用利尿剂与未使用利尿剂分别为1.9和0.7，P = 0.01）。
尽管在CAST - I中，几乎所有基线变量下活性治疗的死亡率均高于安慰剂，但对于非Q波心肌梗死患者以及（就总死亡率而言）频发室性早搏和心率较高的患者，治疗风险高于预期，这表明当存在缺血和电不稳定时，恩卡胺或氟卡尼治疗的不良反应更大。在病情较重的CAST - II人群中，使用利尿剂的患者接受莫雷西嗪治疗的相对风险更高。因此，尽管这些药物具有共同的抑制心肌梗死后室性早搏的能力，但它们对生存的有害影响在不同人群中可能由不同机制介导，这凸显了与抗心律失常药物治疗相关的复杂且了解不足的风险。
