辞旧迎新，SPC逐鹿高血压再下一城
＊本文专业内容仅供医学专业人士参考阅读
中国“十二五”高血压抽样调查[1]显示，我国年龄≥18岁成人高血压患病人数达2.45亿，而高血压的知晓率、治疗率和控制率仅为46.9%、40.7%和15.3%，进一步提高血压达标率是当务之急。联合降压治疗是提升血压达标率的重要手段，SPC和自由联合孰优孰劣、如何优化联合治疗方案一直是高血压领域的热点话题。
SPC和自由联合在依从性、降低血压和达标方面不同研究结果占比2020年6月发表在Journal of Hypertension杂志的另一篇系统性综述也得出了类似的结论[3]。该研究入选2013年1月11日至2019年1月11日期间SPC治疗成年高血压患者的研究，最后纳入29项研究。结果显示，与自由联合相比，SPC的治疗依从性更高，达标率也更高。
SPC降压达标率优于自由联合
尽管SPC降压效果和治疗依从性都很好，大规模的调查研究仍然显示，目前我国SPC的应用率仅为8.5%[9]，且42.9%的患者仍在接受传统固定复方制剂。一篇发表在Journal of Hypertension的SPC临床应用专家共识[10]指出，阻碍SPC治疗的因素来自医患双方。一是由于医生缺乏使用SPC的医疗经验、对SPC的优势认知不足，以及对SPC相关治疗建议的不信任；二是由于患者对SPC的认知较少。因此，未来仍需要大规模开展医患教育，传递规范化的降压治疗理念，同时也要优化SPC的治疗方案，优先推荐强效、长效、明确降低心血管事件风险的SPC药物。
参考文献：[1] Wang Z, Chen Z, Zhang L, et al. Status of Hypertension in China: Results From the China Hypertension Survey, 2012-2015. Circulation. 2018; 137:2344-56.[2] Parati G, Kjeldsen S, Coca A, Cushman WC, Wang J. Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension: A Systematic Review and Meta-Analysis. Hypertension. 2021 Jan 4:HYPERTENSIONAHA12015781.[3] Tsioufis K, Kreutz R, Sykara G, van Vugt J, Hassan T. Impact of single-pill combination therapy on adherence, blood pressure control, and clinical outcomes: a rapid evidence assessment of recent literature. J Hypertens. 2020 Jun;38(6):1016-1028.[4] Rabi DM, McBrien KA, Sapir-Pichhadze R, Nakhla M, Ahmed SB, Dumanski SM, Butalia S, Leung AA, Harris KC, Cloutier L, Zarnke KB, Ruzicka M, Hiremath S, Feldman RD, Tobe SW, Campbell TS, Bacon SL, Nerenberg KA, Dresser GK, Fournier A, Burgess E, Lindsay P, Rabkin SW, Prebtani APH, Grover S, Honos G, Alfonsi JE, Arcand J, Audibert F, Benoit G, Bittman J, Bolli P, Côté AM, Dionne J, Don-Wauchope A, Edwards C, Firoz T, Gabor JY, Gilbert RE, Grégoire JC, Gryn SE, Gupta M, Hannah-Shmouni F, Hegele RA, Herman RJ, Hill MD, Howlett JG, Hundemer GL, Jones C, Kaczorowski J, Khan NA, Kuyper LM, Lamarre-Cliche M, Lavoie KL, Leiter LA, Lewanczuk R, Logan AG, Magee LA, Mangat BK, McFarlane PA, McLean D, Michaud A, Milot A, Moe GW, Penner SB, Pipe A, Poppe AY, Rey E, Roerecke M, Schiffrin EL, Selby P, Sharma M, Shoamanesh A, Sivapalan P, Townsend RR, Tran K, Trudeau L, Tsuyuki RT, Vallée M, Woo V, Bell AD, Daskalopoulou SS. Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2020 May;36(5):596-624.[5]Joint Committee for Guideline Revision. 2018 Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension. J Geriatr Cardiol. 2019 Mar;16(3):182-241.[6] Task Force of the Latin American Society of Hypertension. Guidelines on the management of arterial hypertension and related comorbidities in Latin America. J Hypertens. 2017 Aug;35(8):1529-1545.[7] Tay JC, Sule AA, Chew EK, Tey JS, Lau T, Lee S, Lee SH, Leong CK, Lim ST, Low LP, Oh VM, Phoon KY, Tan KW, Wu A, Yeo LS. Ministry of Health Clinical Practice Guidelines: Hypertension. Singapore Med J. 2018 Jan;59(1):17-27. doi: 10.11622/smedj.2018007. PMID: 29376186.[8]Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71(6):e13-e115.[9] Chen X, Xu SK, Guo QH, Hu Z, Wang HY, Yu J, Li WH, Tang GB, Zhang HF, Li Y, Wang JG. Barriers to blood pressure control in China in a large opportunistic screening. J Clin Hypertens (Greenwich). 2020 May;22(5):835-841.[10] Campana E, Cunha V, Glaveckaite S, Gruev I, Lamirault G, Lehmann E, Masi S, Mfeukeu Kuate L, Mishshenko L, Ona DID, Oo MZ, Tautu OGF, Vachulova A, Vintila AM, Wolf J, Zvartau N, Narkiewicz K, Laurent S. The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice. J Hypertens. 2020 Dec;38(12):2369-2377.[11] 美国FDA网站药品说明书：www.fda.gov[12] Karpov YA, Gorbunov VM, Deev AD. Effectiveness of Fixed-Dose Perindopril/Amlodipine on Clinic, Ambulatory and Self-Monitored Blood Pressure and Blood Pressure Variability: An Open-Label, Non Comparative Study in the General Practice. High Blood Press Cardiovasc Prev. 2015 Dec;22(4):417-25.[13] Abdelhady A, Khader S, Sinnuqrut S, Albow A. The Efficacy of Perindopril/Amlodipine in Reaching Blood Pressure Targets: Results of the CONTROL Study. Clin Drug Investig. 2016 May;36(5):357-66.[14] Glezer MG. [Antihypertensive Effect of Switching to a Fixed Perindopril/Amlodipine Combination in Patients Ineffectively Treated by Free Sartan-Containing Combinations. Results of the AVANGARD Study]. Kardiologiia. 2019 Oct 14;59(10):31-38. Russian.[15] Dahlöf B, Sever P S, Poulter N R, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BP[J]. Lancet, 2005, 366(9489):895-906.[16] Gupta A, Mackay J, Whitehouse A, et al. Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial. Lancet. 2018 Sep 29;392(10153):1127-1137.
陈瑞珍 教授复旦大学附属中山医院心内科主任医师，教授，医学博士，博士生导师。上海市心血管病研究所中心实验室副主任，教育部新世纪优秀人才计划入选者，上海市优秀学术带头人。国际心脏研究会会员、欧洲心脏病学会会员、欧洲心力衰竭协会会员、中华医学会心血管病学分会心力衰竭学组委员、ISHR中国转化医学工作委员会委员、中国医疗保健国家交流促进会精准心血管病分会常务委员、中国医师协会中西医结合分会心脏康复专家委员会委员、中国中药协会心血管药物临床研究专业委员会委员、中国心衰中心联盟委员。主要从事内科心血管疾病的临床与基础研究，尤其是对病毒性心肌炎与扩张型心肌病、心力衰竭、高血压等有长期深入的研究。主持国家自然科学基金课题6项，作为负责人或主要PI承担国家及省部级科研课题20余项。在Circulation、Circulation Research、Europe Heart Failure、J Viol、IJC等杂志发表SCI收录论著70余篇，中文核心期刊发表论著100余篇。获国家科技进步二等奖、省部级科技进步奖十余项以及上海市巾帼创新奖、明治乳业生命科学奖、上海市三八红旗手标兵等。- End -
中国“十二五”高血压抽样调查[1]显示，我国年龄≥18岁成人高血压患病人数达2.45亿，而高血压的知晓率、治疗率和控制率仅为46.9%、40.7%和15.3%，进一步提高血压达标率是当务之急。联合降压治疗是提升血压达标率的重要手段，SPC和自由联合孰优孰劣、如何优化联合治疗方案一直是高血压领域的热点话题。 新桃换旧符：解读SPC VS. 自由联合
最新当代证据
2021年1月，Hypertension杂志发表了一篇综述[2]，第一次系统性比较成年高血压患者接受单片复方制剂（SPC）和等效成分自由联合在降压疗效和依从性等方面的差异。综述共纳入发表于2014-2020年的44项研究，与早期发表的研究相比，能较好反应目前临床常用的联合治疗方案。总体来看，78.3%的研究和87.5%的研究分别显示SPC治疗依从性和持续性显著优于自由联合，停药的概率更低，同时SPC较自由联合降低12周收缩压（SBP）、舒张压（DBP）的幅度也更大（SBP/DBP -3.99/1.54 mmHg，P=0.0076%），而且33.3%的研究显示SPC能带来高的血压达标率。
SPC和自由联合在依从性、降低血压和达标方面不同研究结果占比2020年6月发表在Journal of Hypertension杂志的另一篇系统性综述也得出了类似的结论[3]。该研究入选2013年1月11日至2019年1月11日期间SPC治疗成年高血压患者的研究，最后纳入29项研究。结果显示，与自由联合相比，SPC的治疗依从性更高，达标率也更高。
SPC降压达标率优于自由联合从指南到实践有多远？
基于SPC在降压疗效、服药简便性和依从性方面较自由联合更具优势[4-8]，最新修订的国内外高血压指南更加重视和优先推荐SPC。其中2020年发布的ISH全球高血压实践指南最佳治疗路径推荐优选A+C SPC，A中的ACEi和ARB有所不同，ACEi在降低心肌梗死和全因死亡方面具有更明确的证据。同时ACEi+CCB具有机制互补、增强疗效、减少不良反应、达标率更高、心血管保护证据多等优势，是优选的联合治疗方案之一。表1 国内外权威指南推荐SPC治疗
尽管SPC降压效果和治疗依从性都很好，大规模的调查研究仍然显示，目前我国SPC的应用率仅为8.5%[9]，且42.9%的患者仍在接受传统固定复方制剂。一篇发表在Journal of Hypertension的SPC临床应用专家共识[10]指出，阻碍SPC治疗的因素来自医患双方。一是由于医生缺乏使用SPC的医疗经验、对SPC的优势认知不足，以及对SPC相关治疗建议的不信任；二是由于患者对SPC的认知较少。因此，未来仍需要大规模开展医患教育，传递规范化的降压治疗理念，同时也要优化SPC的治疗方案，优先推荐强效、长效、明确降低心血管事件风险的SPC药物。足剂量A+C SPC更胜一筹
目前我国上市的SPC种类繁多，既有传统的固定复方制剂，也有新型的固定复方制剂。培哚普利/氨氯地平SPC含有两种经典的ACEi和CCB成分，其中10 mg精氨酸培哚普利是足剂量ACEi，与8 mg的叔丁胺盐培哚普利是等效剂量，在降低血压、发挥靶器官和心血管保护方面更具优势。培哚普利和氨氯地平两种成分的半衰期均超过30 h[11]，可长效平稳控制24 h血压[12]。一系列研究显示，针对不同血压级别的患者，培哚普利/氨氯地平SPC均能强效降低血压，实现降压目标，血压达标率超过90%[12-14]。培哚普利/氨氯地平这一组合的心血管益处已经被ASCOT、ASCOT-Legacy、EUROPA-CCB等大型临床研究证实，其在降低全因死亡、心血管死亡、总冠脉事件、卒中、新发糖尿病以及肾损伤风险方面均表现出临床优势。ASCOT研究[15]证实氨氯地平±培哚普利联合治疗显著降低心脑血管事件风险；随后ASCOT-Legacy研究[16]结果显示，随访约16年后，氨氯地平±培哚普利仍显著降低心脑血管事件风险，显著降低卒中死亡风险达29%，显著降低未经降脂治疗患者心血管死亡风险21%。
参考文献：[1] Wang Z, Chen Z, Zhang L, et al. Status of Hypertension in China: Results From the China Hypertension Survey, 2012-2015. Circulation. 2018; 137:2344-56.[2] Parati G, Kjeldsen S, Coca A, Cushman WC, Wang J. Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension: A Systematic Review and Meta-Analysis. Hypertension. 2021 Jan 4:HYPERTENSIONAHA12015781.[3] Tsioufis K, Kreutz R, Sykara G, van Vugt J, Hassan T. Impact of single-pill combination therapy on adherence, blood pressure control, and clinical outcomes: a rapid evidence assessment of recent literature. J Hypertens. 2020 Jun;38(6):1016-1028.[4] Rabi DM, McBrien KA, Sapir-Pichhadze R, Nakhla M, Ahmed SB, Dumanski SM, Butalia S, Leung AA, Harris KC, Cloutier L, Zarnke KB, Ruzicka M, Hiremath S, Feldman RD, Tobe SW, Campbell TS, Bacon SL, Nerenberg KA, Dresser GK, Fournier A, Burgess E, Lindsay P, Rabkin SW, Prebtani APH, Grover S, Honos G, Alfonsi JE, Arcand J, Audibert F, Benoit G, Bittman J, Bolli P, Côté AM, Dionne J, Don-Wauchope A, Edwards C, Firoz T, Gabor JY, Gilbert RE, Grégoire JC, Gryn SE, Gupta M, Hannah-Shmouni F, Hegele RA, Herman RJ, Hill MD, Howlett JG, Hundemer GL, Jones C, Kaczorowski J, Khan NA, Kuyper LM, Lamarre-Cliche M, Lavoie KL, Leiter LA, Lewanczuk R, Logan AG, Magee LA, Mangat BK, McFarlane PA, McLean D, Michaud A, Milot A, Moe GW, Penner SB, Pipe A, Poppe AY, Rey E, Roerecke M, Schiffrin EL, Selby P, Sharma M, Shoamanesh A, Sivapalan P, Townsend RR, Tran K, Trudeau L, Tsuyuki RT, Vallée M, Woo V, Bell AD, Daskalopoulou SS. Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2020 May;36(5):596-624.[5]Joint Committee for Guideline Revision. 2018 Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension. J Geriatr Cardiol. 2019 Mar;16(3):182-241.[6] Task Force of the Latin American Society of Hypertension. Guidelines on the management of arterial hypertension and related comorbidities in Latin America. J Hypertens. 2017 Aug;35(8):1529-1545.[7] Tay JC, Sule AA, Chew EK, Tey JS, Lau T, Lee S, Lee SH, Leong CK, Lim ST, Low LP, Oh VM, Phoon KY, Tan KW, Wu A, Yeo LS. Ministry of Health Clinical Practice Guidelines: Hypertension. Singapore Med J. 2018 Jan;59(1):17-27. doi: 10.11622/smedj.2018007. PMID: 29376186.[8]Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71(6):e13-e115.[9] Chen X, Xu SK, Guo QH, Hu Z, Wang HY, Yu J, Li WH, Tang GB, Zhang HF, Li Y, Wang JG. Barriers to blood pressure control in China in a large opportunistic screening. J Clin Hypertens (Greenwich). 2020 May;22(5):835-841.[10] Campana E, Cunha V, Glaveckaite S, Gruev I, Lamirault G, Lehmann E, Masi S, Mfeukeu Kuate L, Mishshenko L, Ona DID, Oo MZ, Tautu OGF, Vachulova A, Vintila AM, Wolf J, Zvartau N, Narkiewicz K, Laurent S. The use of single-pill combinations as first-line treatment for hypertension: translating guidelines into clinical practice. J Hypertens. 2020 Dec;38(12):2369-2377.[11] 美国FDA网站药品说明书：www.fda.gov[12] Karpov YA, Gorbunov VM, Deev AD. Effectiveness of Fixed-Dose Perindopril/Amlodipine on Clinic, Ambulatory and Self-Monitored Blood Pressure and Blood Pressure Variability: An Open-Label, Non Comparative Study in the General Practice. High Blood Press Cardiovasc Prev. 2015 Dec;22(4):417-25.[13] Abdelhady A, Khader S, Sinnuqrut S, Albow A. The Efficacy of Perindopril/Amlodipine in Reaching Blood Pressure Targets: Results of the CONTROL Study. Clin Drug Investig. 2016 May;36(5):357-66.[14] Glezer MG. [Antihypertensive Effect of Switching to a Fixed Perindopril/Amlodipine Combination in Patients Ineffectively Treated by Free Sartan-Containing Combinations. Results of the AVANGARD Study]. Kardiologiia. 2019 Oct 14;59(10):31-38. Russian.[15] Dahlöf B, Sever P S, Poulter N R, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BP[J]. Lancet, 2005, 366(9489):895-906.[16] Gupta A, Mackay J, Whitehouse A, et al. Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial. Lancet. 2018 Sep 29;392(10153):1127-1137.
陈瑞珍 教授复旦大学附属中山医院心内科主任医师，教授，医学博士，博士生导师。上海市心血管病研究所中心实验室副主任，教育部新世纪优秀人才计划入选者，上海市优秀学术带头人。国际心脏研究会会员、欧洲心脏病学会会员、欧洲心力衰竭协会会员、中华医学会心血管病学分会心力衰竭学组委员、ISHR中国转化医学工作委员会委员、中国医疗保健国家交流促进会精准心血管病分会常务委员、中国医师协会中西医结合分会心脏康复专家委员会委员、中国中药协会心血管药物临床研究专业委员会委员、中国心衰中心联盟委员。主要从事内科心血管疾病的临床与基础研究，尤其是对病毒性心肌炎与扩张型心肌病、心力衰竭、高血压等有长期深入的研究。主持国家自然科学基金课题6项，作为负责人或主要PI承担国家及省部级科研课题20余项。在Circulation、Circulation Research、Europe Heart Failure、J Viol、IJC等杂志发表SCI收录论著70余篇，中文核心期刊发表论著100余篇。获国家科技进步二等奖、省部级科技进步奖十余项以及上海市巾帼创新奖、明治乳业生命科学奖、上海市三八红旗手标兵等。- End -