Safety and clinical outcome in combination therapy for high-risk elderly hypertensive patients
Safety and clinical outcome in combination therapy for high-risk elderly hypertensive patients
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高危老年高血压患者联合治疗的安全性和临床结果
DOI：
10.1038/hr.2014.166
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发表时间：
2015
影响因子：
5.4
通讯作者：
Seiji Umemoto
中科院分区：
文献类型：
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作者：
Yokokawa T;Ujiie Y;Kaneko H;Seino Y;Kijima M;Takeishi Y;Seiji Umemoto
为了达到预防心血管事件的最佳目标血压水平（o 140/90 mm Hg），通常需要各种降压药物的组合。1荟萃分析显示，不同类别药物的降压作用具有叠加性，噻嗪类利尿剂、β受体阻滞剂和钙通道阻滞剂（CCBs）的不良反应与剂量密切相关，而血管紧张素受体阻滞剂（ARBs）的不良反应不增加。2联合使用两种不同类别的药物所带来的额外血压降低大约是将一种药物的剂量加倍的5倍，3而联合使用两种药物的症状发生率低于加和性，并且在标准剂量的一半时不良代谢影响可以忽略不计，这表明低剂量联合治疗增加了治疗效果并减少了药物不良反应。2根据现行日本高血压学会高血压管理指南（JSH 2014），1如果降压效果不足，在两种药物的联合治疗中，推荐使用血管紧张素转换酶（ACE）抑制剂或ARB+ CCB、ACE抑制剂或ARB+噻嗪类利尿剂和CCB+噻嗪类利尿剂。据报告，根据日本抗高血压药物处方的趋势，最常处方的两类抗高血压药物为ARB和CCB，噻嗪类利尿剂的处方率有所增加，但在研究期间其增加率保持不变。4在本期中，Saruta et al. 5报告了关于安全性和耐受性的发现，作为奥美沙坦联合用药（COLM）研究的亚组分析。很少有临床研究前瞻性地比较老年高血压患者联合治疗的方案。在收缩性高血压患者中通过联合治疗避免心血管事件（ACCOMPLISH）试验涉及双盲临床试验中的固定剂量药物组合6，并且是迄今为止在所有患者中直接比较两种固定组合的唯一试验。本研究发现，ACE抑制剂+ CCB比贝那普利+噻嗪类利尿剂具有显著的优越性，即使在老年人中也是如此。6此外，COLM研究7是一项前瞻性随机开放盲态终点（PROBE）研究，在日本老年高危高血压患者中采用反应依赖性剂量滴定方案。在COLM研究中，ARB与CCB或噻嗪类利尿剂联合使用，观察到的安全性和耐受性特征表明，即使在非常低的剂量下，ARB+ CCB也可能优于ARB+噻嗪类利尿剂。5然而，COLM研究无法检测到两个治疗组之间心血管发病率和死亡率（包括肾脏事件）的主要复合终点的统计学显著差异，因为心血管事件的发生率较低，这在日本的临床试验中经常发生。8，9两项试验中血压控制与临床结局相关性的相反结论可能是由于西方国家和东亚国家（尤其是日本）之间遗传背景和/或生活方式的差异，在日本，心血管事件的发生率较低，而中风的发生率高于冠状动脉疾病的发生率，
To achieve the optimal target blood pressure level (o140/90 mm Hg) for the prevention of cardiovascular events, various combinations of antihypertensive drugs are often required. 1 Meta-analysis demonstrated that the blood pressure reduction effects of different categories of drugs were additive and adverse symptoms attributable to thiazide diuretics, β-blockers and calcium channel blockers (CCBs) were strongly dose related, whereas angiotensin receptor blockers (ARBs) caused no increase in symptoms. 2 The extra blood pressure reduction from combining drugs from two different classes is approximately five times greater than doubling the dose of one drug, 3 whereas the prevalence of symptoms with two drugs in combination was less than additive and adverse metabolic effects were negligible at half the standard dose, indicating that lowdose combination treatment increases the efficacy of treatment and reduces adverse drug reactions. 2 According to the current Japanese Society of Hypertension Guideline for the Management of Hypertension (JSH 2014), 1 if antihypertensive effects are insufficient, among the combinations of two drugs, those of angiotensin-converting enzyme (ACE) inhibitor or ARB+ CCB, ACE inhibitor or ARB+ thiazide diuretic and CCB+ thiazide diuretic are recommended. It is reported that, according to the trends in the prescription of antihypertensive drugs in Japan, the two most prescribed classes of antihypertensive drugs were ARBs and CCBs, and the prescription rate for thiazide diuretics has increased, but the rate of its increase was unchanged during the study period. 4In this issue, Saruta et al. 5 reported findings regarding safety and tolerability as a subanalysis of the Combinations of OLMesartan (COLM) study. Few clinical studies have prospectively compared regimens for combination therapy in elderly hypertensive patients. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial involves fixed-dose drug combinations in a double-blind clinical trial6 and is so far the only trial directly comparing two fixed combinations in all patients. This study found that ACE inhibitor+ CCB had significant superiority over benazepril+ thiazide diuretic, even in the elderly. 6 In addition, the COLM study7 was a Prospective Randomized Open Blinded End point (PROBE) study with a response-dependent dose titration scheme in elderly Japanese high-risk hypertensive patients. In the COLM study, ARB was combined with CCB or thiazide diuretic and the safety and tolerability profiles observed suggested that ARB+ CCB may be preferable to ARB+ thiazide diuretic even at a very low dose. 5 However, the COLM study was not able to detect statistically significant differences in the primary composite end points of cardiovascular morbidity and mortality, including renal events, between the two treatment arms due to the low incidence of cardiovascular events, as often occurs in clinical trials in Japan. 8, 9 The opposite conclusions with regard to the association of blood pressure control with clinical outcomes between the two trials may be explained by the differences in genetic background and/or lifestyle between Western countries and East Asian countries, especially Japan, where the incidence of cardiovascular events is lower and the incidence of stroke is higher than the incidence of coronary artery disease due to