Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Seidman Laboratory, Department of Genetics, Harvard Medical School, Boston, MA, USA.
Department of Cardiology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Lancet Diabetes Endocrinol. 2015 Feb;3(2):123-31. doi: 10.1016/S2213-8587(14)70241-4. Epub 2014 Dec 19.
No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy.
In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654.
Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline.
Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals.
目前尚无可靠的医学治疗方法能够阻止或逆转肥厚型心肌病的疾病进展，但几项试点研究的结果表明血管紧张素 II 受体阻滞剂对左心室肥厚和纤维化有有益作用，而左心室肥厚和纤维化是不良预后的预测因素。我们旨在评估血管紧张素 II 受体阻滞剂氯沙坦对肥厚型心肌病患者左心室肥厚和纤维化的影响。
在这项单中心、随机、双盲、安慰剂对照试验中，通过基于计算机的系统将 18 岁及以上的梗阻性或非梗阻性肥厚型心肌病成年患者随机分配至氯沙坦（每天 100 毫克）或安慰剂组，治疗 12 个月。患者和研究人员对分配的治疗方案均不知情。主要终点是通过心脏磁共振成像（CMR）或 CT 评估的左心室质量变化。根据改良意向治疗人群（所有在 12 个月随访时具有数据的患者）进行疗效分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01447654。
在 2011 年 12 月 1 日至 2013 年 5 月 1 日期间，对 318 名患者进行了筛查。有 133 名患者（平均年龄 52 岁[标准差 13]，35%为女性）同意并被随机分配至安慰剂组（n=69）或氯沙坦组（n=64）。124 名（93%）患者完成了研究并被纳入主要终点的改良意向治疗分析。治疗 12 个月后，我们注意到安慰剂组和氯沙坦组之间左心室质量的变化无显著差异（平均差异 1 克/平方米，95%CI-3 至 6；p=0.60）。氯沙坦组的收缩压下降（从平均 127 毫米汞柱[标准差 12]降至 121 毫米汞柱[14]；p=0.0001）证实了药物依从性；安慰剂组的血压没有下降。在随访期间，有 2 名（2%）患者，均在安慰剂组，死于心脏性猝死。氯沙坦组有 1 名（1%）患者出现血管性水肿，1 名（1%）患者肾功能恶化，1 名（1%）患者出现高钾血症。基线时有左心室流出道梗阻的患者对治疗耐受良好。
我们的研究结果对普遍认为血管紧张素 II 受体阻滞剂可减少心脏肥大的观点提出了挑战。氯沙坦的治疗是安全的，这表明它可以用于肥厚型心肌病患者的其他适应证，无论其梗阻生理学如何。还需要进行额外的研究来评估血管紧张素 II 受体阻滞剂在临床前肥厚型心肌病中的作用，例如在基因型阳性但表型阴性的个体中。
