Colquitt J L, Jones J, Tan S C, Takeda A, Clegg A J, Price A
Southampton Health Technology Assessments Centre, Wessex Institute for Health Research and Development, University of Southampton, UK.
Health Technol Assess. 2008 May;12(16):iii-iv, ix-201. doi: 10.3310/hta12160.
To assess the clinical effectiveness and cost-effectiveness of ranibizumab and pegaptanib for subfoveal choroidal neovascularisation (CNV) associated with wet age-related macular degeneration (AMD).
Electronic databases were searched from inception to September 2006. Experts in the field were consulted and manufacturers' submissions were examined.
The quality of included studies was assessed using standard methods and the clinical effectiveness data were synthesised through a narrative review with full tabulation of results. A model was developed to estimate the cost-effectiveness of ranibizumab and of pegaptanib (separately), compared with current practice or best supportive care, from the perspective of the NHS and Personal Social Services. Two time horizons were adopted for each model. The first adopted time horizons determined by the available trial data. The second analysis extrapolated effects of treatment beyond the clinical trials, adopting a time horizon of 10 years.
The combined analysis of two randomised controlled trials (RCTs) of pegaptanib [0.3 mg (licensed dose), 1.0 mg and 3.0 mg] versus sham injection in patients with all lesion types was reported by three publications (the VISION study). Three published RCTs of ranibizumab were identified (MARINA, ANCHOR, FOCUS), and an additional unpublished RCT was provided by the manufacturer (PIER). Significantly more patients lost less than 15 letters of visual acuity at 12 months when taking pegaptanib (0.3 mg: 70% of patients; 1.0 mg: 71% of patients; 3.0 mg: 65% of patients) or ranibizumab (0.3 mg: 94.3-94.5%; 0.5 mg: 94.6-96.4%) than sham injection patients (55% versus pegaptanib and 62.2% versus ranibizumab) or, in the case of ranibizumab, photodynamic therapy (PDT) (64.3%). The proportion of patients gaining 15 letters or more (a clinically important outcome having a significant impact on quality of life) was statistically significantly greater in the pegaptanib group for doses of 0.3 and 1.0 mg but not for 3.0 mg, and for all ranibizumab groups compared to the sham injection groups or PDT. This was also statistically significant for patients receiving 0.5 mg ranibizumab plus PDT compared with PDT plus sham injection. Pegaptanib patients lost statistically significantly fewer letters after 12 months of treatment than the sham group [mean letters lost: 7.5 (0.3 mg), 6.5 (1.0 mg) or 10 (3.0 mg) vs 14.5 (sham)]. In the MARINA and ANCHOR trials, ranibizumab patients gained letters of visual acuity at 12 months whereas patients with sham injection or PDT lost about 10 letters (p<0.001) and in the PIER study, ranibizumab patients lost significantly fewer than the sham injection group. Significantly fewer patients receiving pegaptanib or ranibizumab deteriorated to legal blindness compared with the control groups. Adverse events were common for both pegaptanib andranibizumab but most were mild to moderate. Drug costs for 1 year of treatment were estimated as 4626 pounds for pegaptanib and 9134 pounds for ranibizumab. Non-drug costs accounted for an additional 2614 pounds for pegaptanib and 3120 pounds for ranibizumab. Further costs are associated with the management of injection-related adverse events, from 1200 pounds to 2100 pounds. For pegaptanib compared with usual care, the incremental cost-effectiveness ratio (ICER) ranged from 163,603 pounds for the 2-year model to 30,986 pounds for the 10-year model. Similarly, the ICERs for ranibizumab for patients with minimally classic and occult no classic lesions, compared with usual care, ranged from 152,464 pounds for the 2-year model to 25,098 pounds for the 10-year model.
Patients with AMD of any lesion type benefit from treatment with pegaptanib or ranibizumab on measures of visual acuity when compared with sham injection and/or PDT. Patients who continued treatment with either drug appeared to maintain benefits after 2 years of follow-up. When comparing pegaptanib and ranibizumab, the evidence was less clear due to the lack of direct comparison through head-to-head trials and the lack of opportunity for indirect statistical comparison due to heterogeneity. The cost-effectiveness analysis showed that the two drugs offered additional benefit over the comparators of usual care and PDT but at increased cost. Future research should encompass trials to compare pegaptanib with ranibizumab and bevacizumab, and to investigate the role of verteporfin PDT in combination with these drugs. Studies are also needed to assess adverse events outside the proposed RCTs, to consider the optimal dosing regimes of these drugs and the benefits of re-treatment after initial treatment, and to review costing in more detail. Health state utilities and their relationship with visual acuity and contrast sensitivity, the relationship between duration of vision loss and the quality of life and functional impact of vision loss, behavioural studies of those genetically at risk are other topics requiring further research.
评估雷珠单抗和培加替尼治疗湿性年龄相关性黄斑变性（AMD）所致黄斑中心凹下脉络膜新生血管（CNV）的临床疗效和成本效益。
检索了自数据库建立至2006年9月的电子数据库。咨询了该领域的专家并查阅了制造商提交的资料。
采用标准方法评估纳入研究的质量，并通过叙述性综述对临床疗效数据进行综合分析，同时完整列出结果。建立了一个模型，从英国国家医疗服务体系（NHS）和个人社会服务的角度，估计雷珠单抗和培加替尼（分别）与当前治疗方法或最佳支持治疗相比的成本效益。每个模型采用了两个时间范围。第一个时间范围由现有试验数据确定。第二次分析将治疗效果外推至临床试验之外，采用10年的时间范围。
三项出版物（VISION研究）报道了两项培加替尼[0.3mg（许可剂量）、1.0mg和3.0mg]与假注射治疗所有病变类型患者的随机对照试验（RCT）的综合分析。确定了三项已发表的雷珠单抗RCT（MARINA、ANCHOR、FOCUS），制造商还提供了一项未发表的RCT（PIER）。与假注射组患者（55%，培加替尼组为62.2%，雷珠单抗组为64.3%）相比，服用培加替尼（0.3mg：70%的患者；1.0mg：71%的患者；3.0mg：65%的患者）或雷珠单抗（0.3mg：94.3 - 94.5%；0.5mg：94.6 - 96.4%）的患者在12个月时视力下降少于15行字母的比例显著更高；对于雷珠单抗，与光动力疗法（PDT）（64.3%）相比也是如此。对于0.3mg和1.0mg剂量的培加替尼组，视力提高15行或更多（这是对生活质量有重大影响的一个临床重要结果）的患者比例在统计学上显著高于假注射组，但3.0mg剂量组不显著；与假注射组或PDT组相比，所有雷珠单抗组的该比例在统计学上也显著更高。与PDT加假注射相比，接受0.5mg雷珠单抗加PDT的患者的该比例在统计学上也显著更高。培加替尼治疗12个月后的患者视力下降的字母数在统计学上显著少于假注射组[平均视力下降字母数：7.5（0.3mg）、6.5（1.0mg）或10（3.0mg），假注射组为14.5]。在MARINA和ANCHOR试验中，雷珠单抗治疗的患者在12个月时视力提高，而假注射或PDT治疗的患者视力下降约10行（p<0.001）；在PIER研究中，雷珠单抗治疗的患者视力下降显著少于假注射组。与对照组相比，接受培加替尼或雷珠单抗治疗后恶化至法定失明的患者显著减少。培加替尼和雷珠单抗的不良事件都很常见，但大多数为轻至中度。培加替尼1年治疗的药物成本估计为4626英镑，雷珠单抗为9134英镑。培加替尼的非药物成本额外为2614英镑，雷珠单抗为3120英镑。与注射相关不良事件的管理相关的进一步成本为1200英镑至2100英镑。与常规治疗相比，培加替尼的增量成本效益比（ICER）在2年模型中为163,603英镑，在10年模型中为30,986英镑。同样，对于最小经典型和隐匿性无经典病变的患者，雷珠单抗与常规治疗相比的ICER在2年模型中为152,464英镑，在10年模型中为25,098英镑。
与假注射和/或PDT相比，任何病变类型的AMD患者接受培加替尼或雷珠单抗治疗后视力均有改善。继续接受这两种药物治疗的患者在随访2年后似乎仍保持疗效。在比较培加替尼和雷珠单抗时，由于缺乏直接的头对头试验比较以及因异质性而缺乏间接统计比较的机会，证据不太明确。成本效益分析表明，这两种药物与常规治疗和PDT相比提供了额外的益处，但成本增加。未来的研究应包括比较培加替尼与雷珠单抗和贝伐单抗的试验，以及研究维替泊芬PDT与这些药物联合使用的作用。还需要研究评估拟开展的RCT之外的不良事件，考虑这些药物的最佳给药方案以及初始治疗后再次治疗的益处，并更详细地审查成本核算。健康状态效用及其与视力和对比敏感度的关系、视力丧失持续时间与生活质量的关系以及视力丧失的功能影响、对有遗传风险者的行为研究是其他需要进一步研究的主题。
