Smith David H G
Integrium, Tustin, California 92780, USA.
Am J Cardiovasc Drugs. 2007;7(5):347-56. doi: 10.2165/00129784-200707050-00004.
Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are an effective initial antihypertensive monotherapy in many patients. However, when initial ARB monotherapy fails to achieve the recommended BP goal, there is some controversy as to whether dose uptitration or the addition of a diuretic is more appropriate. This article addresses this issue by reviewing the dose-response characteristics of olmesartan medoxomil and other ARBs, as well as the relationship between ARB uptitration and BP goal attainment. Two types of trial designs are used to assess dose response: dose-ranging studies (usually a parallel design using different doses across different patient groups), which are used to establish the optimal dose for US FDA registration purposes, and dose-titration studies (increased dosing within the same patients and treating to goal BP). Since dose titration is within the same patient, it may be considered more appropriate for demonstrating dose-response characteristics and demonstration of BP goal attainment. While results from dose-ranging studies suggest that the dose-response curve for some ARBs may be flat, dose-titration studies indicate that significant improvements in BP control and BP goal attainment can be achieved with ARB uptitration. In an integrated analysis of seven US and European randomized, placebo-controlled, dose-ranging trials involving 3055 patients with stage 2 hypertension treated with olmesartan medoxomil 2.5-80 mg/day or placebo for 8 weeks, all olmesartan medoxomil doses were significantly more effective than placebo in lowering the mean DBP and mean SBP (p<or=0.001); notably, optimal BP-lowering efficacy was observed at higher dosages. In fact, the 20 mg/day (recommended starting dose) and 40 mg/day (maximum approved dose) dosages were significantly (p<or=0.001) more effective in lowering mean BP than the 5 mg/day dosage (optional starting dose in volume-depleted patients), and the 40 mg/day dosage was significantly (p<0.01) more effective than the 20 mg/day dosage. The BP decreases observed with the uptitration of olmesartan medoxomil from 20 to 40 mg/day doses resulted in substantial additional mean BP reductions from baseline. Such BP reductions have been shown to translate into a clinically relevant increase in the number of patients who achieve BP goal. In conventional clinical studies, the shallow dose-response findings often attributed to ARBs may be an artifact resulting from the inclusion of both treatment responders and nonresponders within each dose group. However, this may not accurately reflect the results that are actually obtained in clinical practice. The efficacy of certain ARBs, such as olmesartan medoxomil, is dose-dependent, with greater reductions being attained at higher doses; higher BP goal attainment rates are achieved with the higher doses. Thus, ARB monotherapy, with appropriate uptitration as needed, is an excellent initial treatment option for patients with hypertension.
血管紧张素受体拮抗剂（血管紧张素受体阻滞剂；ARB）对许多患者而言是一种有效的初始抗高血压单一疗法。然而，当初始ARB单一疗法未能达到推荐的血压目标时，关于增加剂量还是加用利尿剂更为合适存在一些争议。本文通过回顾奥美沙坦酯及其他ARB的剂量反应特征，以及ARB剂量增加与血压目标达成之间的关系来探讨这一问题。有两种试验设计用于评估剂量反应：剂量范围研究（通常为平行设计，在不同患者组中使用不同剂量），用于确定美国食品药品监督管理局（FDA）注册所需的最佳剂量；剂量滴定研究（在同一患者内增加剂量并治疗至目标血压）。由于剂量滴定是在同一患者内进行，因此可能被认为更适合证明剂量反应特征和血压目标的达成情况。虽然剂量范围研究的结果表明某些ARB的剂量反应曲线可能是平坦的，但剂量滴定研究表明，增加ARB剂量可显著改善血压控制并实现血压目标。在一项对7项美国和欧洲随机、安慰剂对照、剂量范围试验的综合分析中，涉及3055例2期高血压患者，他们接受奥美沙坦酯2.5 - 80 mg/天或安慰剂治疗8周，所有奥美沙坦酯剂量在降低平均舒张压和平均收缩压方面均显著优于安慰剂（p≤0.001）；值得注意的是，在较高剂量时观察到最佳的降压效果。事实上，20 mg/天（推荐起始剂量）和40 mg/天（最大批准剂量）在降低平均血压方面比5 mg/天（血容量减少患者的可选起始剂量）显著更有效（p≤0.001），且40 mg/天比20 mg/天显著更有效（p<0.01）。将奥美沙坦酯剂量从20 mg/天增加到40 mg/天所观察到的血压下降导致平均血压从基线进一步大幅降低。这种血压降低已被证明可转化为实现血压目标的患者数量在临床上的显著增加。在传统临床研究中，常归因于ARB的剂量反应浅的发现可能是由于每个剂量组中既包括治疗反应者又包括无反应者而产生的假象。然而，这可能无法准确反映临床实践中实际获得的结果。某些ARB，如奥美沙坦酯，其疗效是剂量依赖性的，较高剂量可实现更大幅度的降低；较高剂量可实现更高的血压目标达成率。因此，根据需要适当增加剂量的ARB单一疗法是高血压患者的一种优秀初始治疗选择。
