1、2015 BMC medicine OA 安全处方NSAID 共识 徐胜前NSAIDs 治疗骨关节患者的安全处方专家共识BMC Med. 2015 Mar. Pfizer Confidential 2 Scarpignato C, et al. BMC Med. 2015 Mar 19;13:55. BMC medicine. 影响因子 IF=7.276 该文主要是非甾体抗炎药用于骨关节炎患者的安全性处方 强调获益及胃肠道和心血管风险的专家共识背景1 ：基于疗效和安全性证据的指南更新 不断更新的疼痛指南 1-3 越来越关注于有效的治疗 用药安全性更是指南的核心内容，特别是需要长期治疗的慢性疾
2、病，例如OA 然而，上述指南中并无一例针对性揭示了COX-2选择性和非选择性NSAID下 消化道风险和他们与阿司匹林联合使用时的GI和CV安全性 为此，一个由多学科学者组成的专家组召集审查现有证据，目的 在于致力编写和制定可以解决这些特殊问题的声明和指南，以期 帮助临床医生在为不同病人选择抗炎药物时可以做出基于偱征证 据的决策 Pfizer Confidential 3 1. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 20
3、12 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:46574. 2. Simon LSL AG, Jacox AK, Caudill-Slosberg M, Gill LH, Keefe FJ, Kerr KL, et al. Pain in osteoarthritis, rheumatoid arthritis, an
4、d juvenile chronic arthritis. Glenview, III: American Pain Society. In: Clinic Practice Guidelines, no 2. 2 nded. Illinois: Glenview; 2002. p. 1179. 3. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 2003: an evidence based approach to the management o
5、f knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003;62:114555.基于疗效差和并不安全 1 既往OA指南 2 推荐首选的镇痛药物对乙酰氨基酚，在越来越多的 新指南中不再被提及 3-4 超过3g/天 FDA肝毒性警告 5 网式病例对照研究：任何剂量的对乙酰氨基酚虽轻度，但均显著增加上GI并发症(RR, 1.3;
6、95% CI, 1.11.5)，超过2g/日RR为3.6 6 常规剂量对乙酰氨基酚对男性和女性均有增加高血压风险 7-8 冠心病患者服用3g/天显著升高动态血压 9 Pfizer Confidential 4 背景2 ：对乙酰氨基酚并非像认为中的安全 1 1. Scarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH; International NSAID Consensus Group. Safe prescribing of non-steroidal anti-inflammatory drugs in patie
7、nts with osteoarthritis-an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015 Mar 19;13:55. 2. 中华医学会骨科学分会. 骨关节炎诊治指南（2007 年版） 3. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recom
8、mendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:46574. 4. Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013 Sep;21(9):571-
9、6. doi: 10.5435/JAAOS-21-09-571. Review. Gonzalez-Perez A, Rodriguez LA. Upper gastrointestinal complications among users of paracetamol. Basic Clin Pharmacol Toxicol. 2006;98:297303 5. Graham GG, Day RO, Graudins A, Mohamudally A. FDA proposals to limit the hepatotoxicity of paracetamol (acetaminop
10、hen): are they reasonable?Inflammopharmacology. 2010;18:4755. 6. Gonzalez-Perez A, Rodriguez LA. Upper gastrointestinal complications among users of paracetamol. Basic Clin Pharmacol Toxicol. 2006;98:297303. 7. Curhan GC, Willett WC, Rosner B, Stampfer MJ. Frequency of analgesic use and risk of hype
11、rtension in younger women. Arch Intern Med.2002;162:22048. 8. Forman JP, Rimm EB, Curhan GC. Frequency of analgesic use and risk of hypertension among men. Arch Intern Med. 2007;167:3949. 9. Sudano I, Flammer AJ, Periat D, Enseleit F, Hermann M, Wolfrum M, et al. Acetaminophen increases blood pressu
12、re in patients with coronary artery disease. Circulation. 2010;122:178996.背景3 ： 炎症参与OA 疼痛和软骨降解 1 许多炎症介质，比如细胞因子和前列腺素增加软骨细胞中基质金属蛋白酶，从 而引发OA的第一步“炎症” 2-3 众多炎症介质与OA疼痛和深层软骨的退化相关 4 因此OA这种年龄相关的疾病 5 ，在它的慢性过程中，并非 像人 们既往认为的那样，仅有低程度（局部和全身性）的炎症反应 4 选择性COX-2抑制剂和其他NSAID的镇痛和抗炎疗效可能会对 其发病有一定作用 Pfizer Confidential 5 1
13、. Scarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH; International NSAID Consensus Group. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis-an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 20
14、15 Mar 19;13:55 . 2. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets.Arthritis Rheum. 2001;44:123747. 3. Pincus T. Clinical evidence for osteoarthritis as an inflammatory disease. Curr Rheumato
15、l Rep. 2001;3:52434. 4. Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage. 2013;21:1621. 5. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:4926.背景4 ：关注NSAID 的全消化道副作用 NSAID的消化道副作用包含非常广泛的临床症状，包括： 消化不良、烧心、腹部不适和更为严
16、重的副作用，如消化性溃疡，威胁 生命的出血、穿孔并发症 1-2 在过去10年中，NSAID相关上消化道不良事件的发生有下降趋势，但下 消化道并发症呈上升趋势 3-7 。 Pfizer Confidential 6 1. Lanas A, Hunt R. Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies. Ann Med. 2006;38:41528. 2. Scarpignato C, Hunt RH. Nonste
17、roidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am. 2010;39:43364. 3. Steen KS, Nurmohamed MT, Visman I, Heijerman M, Boers M, Dijkmans BA, et al. Decreasing incidence of symptomatic gastrointestinal
18、ulcers and ulcer complications in patients with rheumatoid arthritis. Ann Rheum Dis.2008;67:2569. 4. Zhao Y, Encinosa W. Hospitalizations for gastrointestinal bleeding in 1998 and 2006: statistical brief #65. Healthcare Cost and Utilization Project (HCUP) statistical briefs. Rockville, MD: Agency fo
19、r Health Care Policy and Research; 2008. 5. Lanas A, Garcia-Rodriguez LA, Polo-Tomas M, Ponce M, Alonso-Abreu I, Perez-Aisa MA, et al. Time trends and impact of upper and lowergastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009;104:163341. 6. Laine L, Yang H, Cha
20、ng SC, Datto C. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol. 2012;107:11905. 7. Cavallaro LG, Monica F, German B, Marin R, Sturniolo GC, Saia M. Time trends and outcome of gastrointestinal bleeding in the Veneto
21、 region: a retrospective population based study from 2001 to 2010. Dig Liver Dis.2014;46:3137.背景5 ：质子泵抑制剂 不能阻止NSAID 相关的肠粘膜损伤 质子泵抑制剂 不能阻止NSAID相关的肠粘膜损伤 一些选择性COX-2 抑制剂在与传统NSAID的对照实验中， 无论是否加用抑酸药，均显示出较好的肠道耐受性。 1-2 Pfizer Confidential 7 1. Scarpignato C, Hunt RH. Nonsteroidal antiinflammatory drug-related
22、 injury to the gastrointestinal tract: clinical picture, athogenesis, and prevention. Gastroenterol Clin North Am. 2010;39:43364. 2. Lanas A, Sopena F. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications. Gastroenterol Clin North Am. 2009;38:33352.背景6 ：大量OA 患者面临NSAID 相关心血管风
23、险 继罗非昔布撤市，人们开始对NSAID心血管风险密切关注 无论是RCT还是观察性研究，选择性COX-2抑制剂CV风险均被记录。 人们发现 CV风险与剂量相关 一些非选择NSAID也伴有CV风险增加 1-4 最高达44%的OA患者合并心血管疾病 OA受试者中伴随心血管疾病人群17,000 21.4%在同时使用小剂量阿司匹林治疗 5-7 Pfizer Confidential 8 1. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the ob
24、servational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006;296:163344. 2. McGettigan P, Henry D. Cardiovascular risk with non-steroidal antiinflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011;8:e1001098. 3. Kear
25、ney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C.Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis?Meta-analysis of randomised trials. BMJ. 2006;332:13028. 4. Trelle S, Reichenbach S, Wandel S, Hildebrand
26、 P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs:network meta-analysis. Br Med J. 2011;342:c7086. 52. 5. Singh G, Miller JD, Lee FH, Pettitt D, Russell MW. Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoart
27、hritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care. 2002;8:S38391. 6. Lanas A, Tornero J, Zamorano JL. Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann Rheum Dis. 2010;69:14538.
28、 7. Lanas A, Garcia-Tell G, Armada B, Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med. 2011;9:38.Pfizer Confidential 9 声明1 ：OA 影响生活质量与生命周期；应该给予恰当治疗BMC Med. 20
29、15 Mar. OA对诸多方面的生活质量的影响均有影响 包括睡眠，行走，上下台阶，开启储存物品，准备食物，自我照顾 1 包括OA在内的肌肉骨骼关节系统疾病对生活质量的影响大于其他慢性疾病 如：心血管、呼吸系统、脑血管、神经和消化系统慢性疾病，和肿瘤 2 OA对寿命的影响：证据来源于三个大规模、综合性研究证实 3-6 躯体功能的下降，特别是行走能力的下降是OA患者的主要死亡危险因素 4 治疗有助于改善OA关节功能、疼痛、僵硬、和评分 7-9 ：证据来源于大型观察性 研究，RCTs和数据库 推荐等级：强烈推荐 证据等级：B 1. Crichton B, Green M. GP and patien
30、t perspectives on treatment with nonsteroidal anti-inflammatory drugs for the treatment of pain in osteoarthritis. Curr Med Res Opin. 2002;18:926. 2. Sprangers MA, de Regt EB, Andries F, van Agt HM, Bijl RV, de Boer JB, et al. Which chronic conditions are associated with better or poorer quality of
31、life? J Clin Epidemiol. 2000;53:895907. 3. Johansson SE, Sundquist J. Change in lifestyle factors and their influence on health status and all-cause mortality. Int J Epidemiol. 1999;28:107380. 4. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and disease specific mortality i
32、n patients with knee or hip osteoarthritis: population based cohort study. BMJ. 2011;342:d1165. 5. Tsuboi M, Hasegawa Y, Matsuyama Y, Suzuki S, Suzuki K, Imagama S. Do musculoskeletal degenerative diseases affect mortality and cause of death after 10 years in Japan? J Bone Miner Metab. 2011;29:21723
33、 6. Torrance N, Elliott AM, Lee AJ, Smith BH. Severe chronic pain is associated with increased 10 year mortality. A cohort record linkage study. Eur J Pain. 2010;14:3806. 7. Schein JR, Kosinski MR, Janagap-Benson C, Gajria K, Lin P, Freedman JD. Functionality and health-status benefits associated wi
34、th reduction of osteoarthritis pain. Curr Med Res Opin. 2008;24:125565. 8. Barthel HR, Peniston JH, Clark MB, Gold MS, Altman RD. Correlation of pain relief with physical function in hand osteoarthritis: randomized controlled trial post hoc analysis. Arthritis Res Ther. 2010;12:R7. 9. Kosinski M, Ja
35、nagap C, Gajria K, Schein J, Freedman J. Pain relief and pain-related sleep disturbance with extended-release tramadol in patients with osteoarthritis. Curr Med Res Opin. 2007;23:161526.Pfizer Confidential 10 声明2 ：许多接受NSAIDs 治疗的OA 患者因为药物的GI( 胃肠道) 不良事件风险而未能获得恰当治疗 BMC Med. 2015 Mar. 推荐等级：强烈推荐 证据等级：A 多
36、指南推荐，对于消化道高风险患者处方NSAID时应联合胃粘膜保护剂 1-2 消化道高风险至少包括：消化性溃疡病史，高龄（大于等于60-65岁），合并用药（特 别是小剂量阿司匹林和抗凝剂），幽门螺杆菌感染 3 多个Cohort研究发现，仅有极少数患者被处方胃保护剂 4-8 荷兰1996年只2006年数据分析 9 正确处方率：从6.9%上升至39.4% 过度处方率：从2.9%上升至12.3% 美国数据分析 10 只有27.2%的高危患者被处方了胃保护剂 对指南的服从性 2个危险因素服从性：39.7% 3个危险因素服从性：41.8% 持续处方超过90天的服从性：更低 1. Pendleton A, A
37、rden N, Dougados M, Doherty M, Bannwarth B, Bijlsma JW, et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2000;59:93644. 2. Schnitzer TJ. U
38、pdate of ACR guidelines for osteoarthritis: role of the coxibs. J Pain Symptom Manage. 2002;23:S2430. Discussion S3124. 3. Wilcox CM, Allison J, Benzuly K, Borum M, Cryer B, Grosser T, et al. Consensus development conference on the use of nonsteroidal antiinflammatory agents, including cyclooxygenas
39、e-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol. 2006;4:10829 . 4. Vonkeman HE, Fernandes RW, van de Laar MA. Under-utilization of gastroprotective drugs in patients with NSAID-related ulcers. Int J Clin Pharmacol Ther. 2007;45:2818. 5. Van der Linden MW, Gaugris S, Kuipers EJ, Van den
40、 Bemt BJ, van Herk-Sukel MP, Herings RM. Gastroprotection among new chronic users of nonsteroidal anti-inflammatory drugs: a study of utilization and adherence in The Netherlands. Curr Med Res Opin. 2009;25:195204 . 6. Sturkenboom MC, Burke TA, Tangelder MJ, Dieleman JP, Walton S, Goldstein JL. Adhe
41、rence to proton pump inhibitors or H2-receptor antagonists during the use of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2003;18:113747 . 7. Sturkenboom MC, Burke TA, Dieleman JP, Tangelder MJ, Lee F, Goldstein JL. Underutilization of preventive strategies in patients receiving NS
42、AIDs. Rheumatology (Oxford). 2003;42:iii2331. 8. van Soest EM, Valkhoff VE, Mazzaglia G, Schade R, Molokhia M, Goldstein JL, et al. Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases. Gut
43、. 2011;60:16509. 9. Valkhoff VE, van Soest EM, Sturkenboom MC, Kuipers EJ. Time-trends in gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs ). Aliment Pharmacol Ther. 2010;31:121828. 10. Abraham NS, El-Serag HB, Johnson ML, Hartman C, Richardson P, Ray WA, et al. National adherence
44、to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gastroenterology. 2005;129:11718.Pfizer Confidential 11 声明2 ：许多接受NSAIDs 治疗的OA 患者因为药物的GI( 胃肠道) 不良事件风险而未能获得恰当治疗 BMC Med. 2015 Mar. 患者依从性也是NSAID合理用药的障碍 1/3的患者未按处方服用胃保护剂 1 用药短于3个月的患者，依从性同上或略好 2-3 其他情况依从性更差 4-5 依从性
45、差的患者将面临更大GI风险 2-3，6 欧洲数据库分析 7 上GI 事件 上GI 出血 低依从性（少于20%时间应用胃保护剂）患者 VS 高依从性（多于80%时间应用胃保护剂）患者 OR 值 2.39 (95% CI, 1.66 3.44) OR 值1.89 (95% CI,1.093.28) 1. Sturkenboom MC, Burke TA, Tangelder MJ, Dieleman JP, Walton S, Goldstein JL. Adherence to proton pump inhibitors or H2-receptor antagonists during th
46、e use of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2003;18:113747. 2. Goldstein JL, Howard KB, Walton SM, McLaughlin TP, Kruzikas DT. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. Clin Gastroenterol Hepato
47、l. 2006;4:133745. 3. Lanas A, Polo-Tomas M, Roncales P, Gonzalez MA, Zapardiel J. Prescription of and adherence to non-steroidal anti-inflammatory drugs and gastroprotective agents in at-risk gastrointestinal patients. Am J Gastroenterol. 2012;107:70714. 4. Vonkeman HE, Fernandes RW, van de Laar MA.
48、 Under-utilization of gastroprotective drugs in patients with NSAID-related ulcers. Int J Clin Pharmacol Ther. 2007;45:2818. 5. Van der Linden MW, Gaugris S, Kuipers EJ, Van den Bemt BJ, van Herk-Sukel MP, Herings RM. Gastroprotection among new chronic users of nonsteroidal anti-inflammatory drugs: a study of utilization and adherence in The Netherlands. Curr Med Res Opin. 2009;25:195204. 6. van Soest EM, Sturkenboom MC, Dieleman JP, V
