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2016年心血管病學重要臨床進展

2017-02-16 09:35:04崔煒劉德敏耿雪
臨床薈萃 2017年2期
關鍵詞:血脂研究

崔煒,劉德敏,耿雪

(河北醫科大學第二醫院河北省心腦血管病研究所心內一科,河北石家莊050000)

2016年心血管病學重要臨床進展

崔煒,劉德敏,耿雪

(河北醫科大學第二醫院河北省心腦血管病研究所心內一科,河北石家莊050000)

臨床心臟病學在2016年有了重大改變,尤其是在高血壓、心力衰竭、冠心病、降脂治療及心律失常等方面發表了一系列指南。本文就高血壓的控制目標、心力衰竭的藥物治療、冠心病的藥物治療、他汀類藥物的多效性及心律失常的器械治療進行概述。

高血壓;心力衰竭;冠狀動脈疾病;血脂;心律失常;診斷;治療;指南

崔煒,男,醫學博士。河北醫科大學第二醫院副院長,博士研究生導師、教授、主任醫師。現為中國醫師協會心力衰竭專業委員會常委,河北省醫師協會內科學分會主任委員,河北省醫院協會醫療質量管理專業委員會主任委員,臨床薈萃雜志總編輯。自1988年以來,以第一作者或通訊作者在國內外刊物上發表論文500余篇,主編、參編專著15部,獲河北省科技進步二等獎2項、三等獎2項,獲得實用新型專利3項。

2016年心血管領域進展頗多,多家學術組織更新了臨床指南,重要的臨床試驗也層出不窮。本文重點對臨床日常工作有影響的內容進行概述。

1 高血壓

更加嚴格的血壓控制能否更多獲益尚存爭議,血壓控制目標再起波瀾[1-3]。HOPE-3試驗表明,對于不合并心血管疾病的中危高血壓人群,強化降壓并不能獲得明顯益處[4]。對VALUE試驗的后續分析表明,將收縮壓降低到130 mmHg以下并不能獲得進一步明顯益處[5]。Xie等[6]對19502015年間的19項隨機對照試驗計44 989例患者所進行的meta分析表明,在平均3.8年的隨訪期內,強化降壓組的平均血壓水平為133/76 mmHg,非強化降壓組的平均血壓水平為140/81 mmHg。與非強化降壓組相比,強化降壓使主要心血管不良事件發生風險降低14%,心肌梗死風險降低13%,腦卒中風險降低22%,白蛋白尿發生風險降低10%;但是,強化降壓對全因死亡、心血管死亡、終末期腎病及心力衰竭的發生風險沒有顯著影響。嚴重不良事件在強化降壓治療組的發生風險增高35%,嚴重低血壓的發生風險在強化降壓組增加168%。Brunstr?m等[7]對45項計73 738例糖尿病合并高血壓患者進行的meta分析表明,對于基線收縮壓高于140 mmHg的糖尿病患者,降壓治療可顯著降低全因及心血管死亡風險、心肌梗死、腦卒中及終末期腎病風險;但基線收縮壓<140 mmHg的患者,降壓治療則會增加心血管死亡風險。CLARIFY研究對22 672例合并高血壓的穩定性冠心病患者平均5年的隨訪研究表明,合并高血壓的冠心病患者最適血壓大約在130/78 mmHg左右。收縮壓低于120 mmHg或舒張壓低于60 mmHg會明顯增加不良事件風險,呈現出典型的J型曲線現象[8]。2016年發布的歐洲心血管病預防指南也沒有推薦嚴格的血壓控制目標[9]。然而,積極的血壓控制的聲音似乎在重新抬頭[10]。對SPRINT試驗的后續分析表明,即使對于75歲以上可自由活動的老年人,將血壓控制在120 mmHg以下也可以進一步獲益[11]。Eryd等[12]對瑞典全國187 106例2型糖尿病患者的注冊數據進行分析表明,與收縮壓130~139 mmHg組人群相比,較低血壓組(收縮壓110~119 mmHg)的2型糖尿病患者具有較低的心血管事件風險;但較低血壓組的全因死亡風險及心力衰竭風險增加。Ettehad等[13]對發表在19662015年間的123項研究計613 815例受試者所進行的meta分析表明,收縮壓每降低10 mmHg會帶來主要心血管事件風險降低20%、冠心病風險降低17%、腦卒中風險降低27%,并使全因死亡風險降低13%。Thomopoulos等[14]及Verdecchia等[15]的meta分析也支持將收縮壓控制在130 mmHg以下。2016年加拿大高血壓指南建議對于某些具有高危心血管風險的高血壓患者,可以將收縮壓控制在120 mmHg以下[16]。國際高血壓協會(ISH)在2016年發表的科學文告中認為多數高血壓患者的收縮壓應該控制在130 mmHg以下,但不建議控制在120 mmHg以下[17]。

腎交感神經去除術(RDN)治療高血壓的效果仍然存在爭議。Sharp等[18]對英國18個醫學中心的253例接受RDN患者的觀察性研究表明,RDN可有效地降低患者的血壓;有趣的是,與藥物治療相似,RDN降低血壓的幅度與基線血壓呈正相關。DENERHTN試驗表明,RDN能有效地降低患者6個月時的血壓[19]。Rohla等[20]的單中心研究(采用Simplicity RDN導管消融系統)表明,RDN的治療有效(6個月時ABPM平均收縮壓至少降低5 mmHg以上)率為45.6%。新的meta分析也提示RDN可以有效地降低頑固性高血壓患者的血壓水平[21-22]。除降低血壓之外,多項研究提示RDN還有其他額外效應。如Kiuchi等[23]證明RDN可以改善腎臟功能、減少蛋白尿;Donazzan等[24]研究表明RDN可以降低心臟交感神經活性;D?rr等[25]的研究表明RDN可使患者的血壓明顯下降,并伴有血漿miRNA表達增加。但是,Krakoff等[26]的meta分析則表明,RDN雖可降低血壓,但其效果卻不優于藥物治療;Oliveras等[27]對24例頑固性高血壓患者的研究表明,加用螺內酯(50 mg/d)較RDN能更加有效地控制血壓。

2 心力衰竭

心力衰竭的主要治療目標之一是降低再住院率。Donzé等[28]研究表明,HOSPITAL計分系統可以有效地預測心力衰竭患者的30天再住院風險;積分越高,30天內再住院風險越高。Yazdan-Ashoori等[29]證明基于床邊的臨床指標計算的LACE計分系統可以較好地預測心力衰竭患者出院30天死亡或再住院風險,LACE積分≥13分患者出院30天內死亡或再住院風險增加91%。心力衰竭患者非心力衰竭或非心臟原因再住院日益引起重視。Vader等[30]對744例心力衰竭患者的研究發現,出院后早期再住院的原因更多是非心力衰竭原因。首次歐洲心力衰竭調查(EHFS-1)數據表明,非心力衰竭住院的比率高達43%,而心力衰竭作為第一診斷入院者僅40%。出院3個月內,以心力衰竭入院患者的病死率為7%,而非心力衰竭原因住院者也高達5%[31]。Adamson等[32]采用CardioMEMS監測心力衰竭患者的肺動脈壓力,并以此指導治療。結果表明,以肺動脈壓為指導的治療策略可以使出院30天心力衰竭再住院風險降低49%,使全因再住院風險降低58%。

心力衰竭合并心房顫動(房顫)構成了心力衰竭患者中的一個特殊人群,對這樣的一個特殊心力衰竭人群的治療一直缺乏堅實的循證醫學治療證據。Nielsen等[33]進行的大規模前瞻性觀察性研究表明,合并房顫的心力衰竭患者仍然可以從β-受體阻斷劑治療中獲益。在205 174例房顫患者中,39 741例合并心力衰竭。應用β-受體阻斷劑可使1年的全因死亡風險降低25%。Kotecha等[34]對11項試驗計13 833例左心室射血分數減低心力衰竭(HFrEF)患者所進行的meta分析表明,對于竇性心律的HFrEF患者,β-受體阻斷劑的治療獲益不依賴于年齡及性別。

左心室射血分數保存心力衰竭(HFpEF)仍然是研究熱點。2016年歐洲心力衰竭指南對HFpEF的診斷進行了限定。在新指南中,HFpEF的心力衰竭診斷必須有血漿BNP或NT-proBNP水平的升高;而HFrEF診斷則不必滿足這一條件[35]。腦鈉肽(BNP)預測急性失代償心力衰竭的價值發生的價值在HFpEF和HFrEF患者也不相同。BNP在3天內升高超過200 ng/L發生急性失代償性心力衰竭在HFpEF患者中的風險明顯升高(HR=4.0),但對預測HFrEF患者發生急性失代償則沒有價值。此外,短期(3天內)明顯的體重增加(5磅,≈2.27 kg)無論對HFpEF和HFrEF患者均預示急性失代償心力衰竭的發生增加,但輕度體重增加(2磅,≈0.91 kg)在HFpEF患者預示急性失代償心力衰竭發生風險增加[36]。Wan等[37]對ROSE AHF試驗的后續分析表明,低劑量多巴胺(2 μg/kg/min)可以增加HFrEF患者尿量、降低血漿胱抑素-C水平,但對HFpEF患者則可能有不利影響。由于HFpEF患者缺乏有效改善預后的治療方法,因此2016年發表了一些有趣的令人耳目一新的治療方法,包括通過在房間隔放置造口器完成的房間隔造口術可以改善HFpEF患者運動狀態下的血流動力學指標等[38]。

心力衰竭的藥物治療有了新的進展。2016年無論歐洲心臟病學會(ESC)、美國心臟病學會/美國心臟學會(ACC/AHA)還是加拿大心臟病學會均在心力衰竭的藥物治療中增加了LCZ696和伊伐布雷定作為HFrEF的治療用藥[35,39-40]。Meta分析也顯示,對于HFrEF患者,應用LCZ696可以進一步改善患者遠期預后[41]。

心臟再同步化治療(CRT)的適應證在2016年有收緊的趨勢。2016年ESC心力衰竭指南認為對于QRS間期<130 ms的心力衰竭,不建議進行CRT治療,而此前的建議為QRS間期<120 ms不推薦CRT治療[35]。Sharma等[42]對6項研究計1 764例患者所進行的meta分析表明,基線下右心室功能不能預測CRT植入后的反應。Asbach等[43]的研究表明,植入CRT時將右心室電極置于中部室間隔對心功能改善及心電圖QRS波群寬度并無顯著影響,也不增加室性心律失常及埋藏式心律轉變除顫器(ICD)的風險,但似乎可延緩心力衰竭的住院。

Huang等[44]在218例擴張型心肌病終末期心力衰竭患者中發現,血漿BNP水平與預后呈現U型曲線關系。在終末期心力衰竭患者,低水平或正常水平的BNP預示著更加不良的預后。此外,肺臟超聲在肺淤血的評價方面的價值得到了初步確認[35,45]。

3 冠狀動脈疾病

比伐盧定在冠狀動脈介入治療(PCI)術中抗凝的價值得到進一步確認。Shah等[46]對6項試驗計14 095例患者進行的meta分析表明,PCI術中應用比伐盧定抗凝可以使30天全因死亡風險降低19%,使心血管死亡風險降低34%,但對心血管不良事件、心肌梗死、靶血管重建等風險無顯著影響。比伐盧定使急性支架內血栓風險增加231%(RR=3.31,95%CI=1.79~6.10),但使主要出血風險降低37% (出血風險降低主要見于經非橈動脈途徑、使用GPⅡb/Ⅲa受體拮抗劑者及使用氯吡格雷者)。Ng等[47]對REPLACE-2,ACUITY及HORIZONS-AMI等3項試驗的匯總分析表明,比伐盧定在女性患者出血降低的獲益較男性更明顯。Fahrni等[48]進行的meta分析表明,PCI術后持續靜脈輸注比伐盧定(1.75 mg/kg/h)3小時可以消除比伐盧定相關的急性支架內血栓形成風險,同時不增加出血風險。2016年中國PCI術指南也推薦比伐盧定的這種用藥方案[49]。

支架植入術后雙聯抗血小板治療(DAPT)的時程仍然是臨床關注的熱點,多數學者主張應個體化[50]。2016年版的中國PCI指南有限度地支持較短時程的DAPT方案,建議穩定性冠心病患者藥物支架(DES)術后DAPT的時程為6個月,高危出血風險者甚至可短至1~3個月;但對急性冠狀動脈綜合征(ACS)患者仍堅持1年以上的DAPT[49]。2016年ACC/AHA相關指南對此也有相似的推薦[51]。中國的I-LOVE-IT 2試驗結果表明,對于覆膜可降解的雷帕霉素藥物支架,6個月的DAPT治療效果不遜于12個月的DAPT[52]。OPTIDUAL試驗表明,對于植入DES的患者(60%為第2代DES),超過1年的DAPT并不會有更多的獲益[53]。IVUS-XPL試驗也支持6個月的DAPT[54]。但是,Bittl等[55]對10項隨機對照試驗(RCT)共計31 666例植入第二代DES患者所進行的meta分析表明,較短時間的DAPT(3~12個月)較較長時間的DAPT(12~36個月)使全因死亡風險降低17%、主要出血風險降低40%,但使心肌梗死及支架內血栓風險分別增加34%及75%。進一步風險/效益分析表明,較短的DAPT可減少3個死亡及5個出血/1 000人/年,但增加4個心肌梗死及3個支架內血栓/(1 000人·年)。多項meta分析雖支持6個月的DAPT作為標準療程[56-61],但心肌梗死患者及ACS患者可在延長的DAPT中獲益,接受復雜PCI手術、合并糖尿病及外周血管病患者似乎也可從延長的DAPT中獲益[59,62-68]。但如何在臨床選擇延長時間的抗血小板治療策略呢?Yeh等[69]的研究為臨床提供了一種解決思路,并驗證了一套計分系統,如果患者的積分<2分,則不推薦雙聯抗血小板藥物超過1年;如果積分≥2分,則推薦DAPT時間超過1年。這套計分系統值得進一步研究和驗證。

2016年新版中國PCI指南發布,其中幾點需要注意:①ACS患者抗血小板治療時,P2Y12受體拮抗劑優選替格瑞洛;②對PCI術中采用比伐盧定進行抗凝的推薦力度加大,并建議以維持量持續至術后4小時;③不建議PCI術前給予負荷劑量的他汀類藥物;④對于管徑狹窄<90%的穩定性冠心病患者,需要獲得明確的缺血證據方可進行PCI治療;⑤對無復流的患者,除冠脈內給予鈣通道阻斷劑、硝普鈉、腺苷、硝酸酯類藥物外,還可以冠脈內給予替羅非班;⑥對急性支架內血栓的患者,除常規方法外可進行冠狀動脈內溶栓[49]。

β-受體阻斷劑在冠心病治療中的地位趨于降低。Motivala等[70]對NCDR注冊數據的研究表明,在接受PCI的老年(≥65歲)穩定型心絞痛患者,如果沒有心肌梗死病史、沒有心力衰竭或左心室收縮功能減退,長期應用β-受體阻斷劑沒有任何心血管獲益。Puymirat等[71]的多中心前瞻性人群研究表明,對于沒有心力衰竭的心肌梗死患者,雖然早期應用β-受體阻斷劑可以減低30天死亡風險;但1年后停用β-受體阻斷劑并不會增加遠期死亡風險。2015年版歐洲NSTE-ACS診治指南也認為,在現代治療的背景下,長期應用β-受體阻斷劑在沒有左心功能減退或心力衰竭的NSTE-ACS患者的獲益缺乏證據;在NSTE-ACS早期,當左心功能狀態不明時應避免使用β-受體阻斷劑[72]。但對于有心肌梗死病史或心力衰竭者,應用β-受體阻斷劑仍可獲益。Hioki等[73]的研究表明,在接受PCI的心肌梗死患者,即使是KillipⅠ級,長期應用β-受體阻斷劑可以改善患者的預后。BETA-AMI試驗表明,在接受成功急診PCI的KillipⅠ、Ⅱ級的STEMI,早期靜脈給予艾司洛爾有助于減輕心肌損傷[74]。

4 血脂代謝紊亂及治療

2016年中國發布了新的血脂治療指南,其中以下幾點需要臨床關注:①堅持血脂目標治療導向。對于高危人群,低密度脂蛋白膽固醇(LDL-C)的靶目標調至<1.8 mmol/L(70 mg/dL);對于不能達到此目標者,LDL-C應較基線降低50%以上;LDL-C數值在目標值以內者,應進一步下降30%。②傾向于降低LDL-C采用聯合治療策略。首先推薦對國人采用中等強度的他汀類藥物治療,如果不能達標則推薦中等強度的他汀與依折麥布聯合應用[75]。2016年ESC也推出了新的血脂治療指南和心血管病預防指南。與中國血脂治療指南相比,歐洲血脂治療指南及心血管病預防指南中針對血脂治療的指導思想很相似,仍然堅持靶目標導向的治療策略[9,76]。但歐洲血脂治療指南也有些變化:①血脂檢查不再強調空腹血檢測血脂。②推薦了PCSK9抑制劑作為頑固性高脂血癥的治療藥物。③與中國指南不同的是,歐洲指南認為當LDL-C介于達標值之上、正常高限之下時,LDL-C降幅至少應達到50%以上。④為了達標,歐洲指南建議他汀類藥物應使用到最大劑量。⑤對于2型糖尿病患者,將ApoB納入了治療指標[76]。2016年,加拿大也推出了新的血脂治療指南,其特點是全面推薦ApoB作為血脂治療的評價指標,并將達標值確定為<0.8 g/L[77]。

他汀類藥物非降脂效應的臨床意義繼續受到否定。Billings等[78]的研究表明,在心臟外科手術圍手術期應用高強度阿托伐他汀并不能降低圍手術期急性腎損傷發生風險。STICS研究表明,對于接受冠狀動脈搭橋手術(CABG)和(或)主動脈瓣置換術的竇性心律患者,圍手術期應用20mg/d的瑞舒伐他汀并不能降低術后房顫的發生風險及圍手術期心肌損傷風險,反而使圍手術期急性腎損傷發生風險增加[79]。

5 心律失常

新型口服抗凝劑(NOAS)在房顫患者的臨床上應用日趨廣泛。2016年歐洲房顫治療指南優先推薦NOAC做為房顫抗凝的首選藥物,華法令僅用于不能使用NOAC的情況。此外,新指南不推薦采用抗血小板治療用于體循環栓塞的預防。值得提出的是,新指南認為,對于高危卒中患者,即使消融后維持了竇性心律也應接受長期的口服抗凝藥物治療[80]。2016年的加拿大房顫治療指南也在非瓣膜病房顫患者優先推薦使用NOAC進行抗凝治療。加拿大指南的房顫抗凝策略選擇主要基于年齡是否超過65歲及CHADS2計分值,此點和歐美相關指南不同[81]。Munoz等[82]對4項臨床試驗計58 338例房顫患者的meta分析表明,即使在輕-中度腎功能減退的患者,與華法令相比,NOAC仍可進一步降低房顫患者體循環栓塞風險,并降低主要出血風險。Dahal等[83]對11項研究的meta分析表明,在非終末期腎臟病的房顫患者,接受華法令抗凝治療可使體循環栓塞及死亡風險下降,出血風險不增加;但對于終末期腎臟病患者,華法令抗凝治療并不降低體循環栓塞及死亡風險,反而明顯增加出血風險。對接受抗凝治療的房顫患者的主要擔憂是出血,目前預測出血的計分系統不少,但哪種計分系統預測出血的價值更好卻少有研究。Senoo等[84]對AMADEUS試驗進行的后續分析表明,對于接受華法令抗凝的房顫患者,HASBLED計分系統預測出血的價值優于ATRIA及ORBIT系統。但即使HAS-BLED計分系統,其總體預測價值也并不優秀。至于預測房顫患者卒中風險的效能,Aspberg等[85]對瑞典房顫患者的人群研究表明ATRIA計分系統優于CHADS2及CHA2DS2-VASc計分系統。Ruff等[86]對ENGAGE AF-TIMI 48試驗的后續分析表明,引入諸如肌鈣蛋白、NT-proBNP、D-二聚體等生物學標志物可顯著增加CHA2DS2-VASc計分系統對非瓣膜病房顫患者腦卒中的預測價值。

眾所周知,房顫會明顯增加腦卒中的風險,并且一直是房顫治療的主要關注點之一。然而,Odutayo等[87]對104項人群研究計9 686 513例房顫患者的meta分析表明,房顫不但使全因死亡及腦卒中的風險增高,還使心血管死亡、主要心血管不良事件、缺血性心臟病、猝死、心力衰竭、慢性腎臟病及外周血管病風險明顯增加。值得注意的是,在上述所有終點中,絕對和相對風險增加最多的是心力衰竭,而腦卒中是風險增加最低的。包括47個國家在內的大規模房顫人群(n=15 400)的1年隨訪研究表明,病死率高達11%(單純房顫者病死率為6%,合并其它疾病者則高達16%)。在1年隨訪期內,卒中發生率僅為4%。與Odutayo等[88]的研究結果相似,心力衰竭所致死亡高達30%,而腦卒中所致死亡僅占8%。Violi等[89]所完成的meta分析表明,即使進行抗凝治療,房顫患者發生心肌梗死的風險仍明顯增高,特別是那些合并動脈粥樣硬化性疾病的患者尤其明顯。以上研究可能影響房顫治療的重點和關注點,提示對房顫患者不應僅重視腦卒中的預防,更應關注其他心血管終點事件的防控。

Sapp等[90]對259例植入ICD后仍有頑固性室性心動過速(室速)的缺血性心肌病患者進行了研究,發現與進一步強化抗心律失常藥物治療相比,對室速進行射頻消融治療可獲得更好的臨床預后,但并未降低死亡和ICD正確放電風險。Santangeli等[91]對14項研究所做的meta分析表明,胺碘酮及射頻消融術均可有效地治療植入ICD患者的復發性室速,胺碘酮還可以降低不正確放電的風險。然而,無論胺碘酮還是射頻消融手術均不能進一步降低此類患者的病死率,胺碘酮反而有增加病死率的趨勢。

北京阜外醫院團隊采用射頻消融技術消融左心房迷走神經節叢治療頑固性血管迷走性暈厥取得了較好的效果,值得進一步研究[92]。Rivarola等[93]對1例迷走神經介導的嚴重房室傳導阻滯患者進行了心房心內膜下迷走神經消融并獲得成功。

Kwok等[94]對14項觀察性研究計400 750例受試者所做的meta分析表明,房室傳導阻滯會使死亡風險增加24%,使心力衰竭或心功能不全的風險增加39%,使房顫的風險增加45%;但一度房室傳導阻滯不增加心血管死亡,冠心病或心肌梗死,卒中或TIA的風險。Tanboa等[95]對合計40 437例患者所進行的meta分析表明,伊伐布雷定可使房顫的發生風險增加15%以上。

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The year in cardiology 2016

Cui Wei,Liu Demin,Geng Xue

First Department of Cardiology,the Second Hospital of Hebei Medical University and the Institute of Cardiocerebrovascular Disease of Hebei Province,Shijiazhuang 050000,China Corresponding author:Cui Wei,Email:cuiwei21c@163.com

Many guidelines and a lot of progresses in cardiology have been changed in 2016,especially in hypertension,heart failure,coronary artery disease,lipid lowering,and cardiac arrhythmias.This review focuses on the target of hypertension control,drug treatment of chronic heart failure and coronary artery disease,pleiotropic effects of statins in cardiovascular disease,and device treatment for cardiac arrhythmias.

hypertension;heart failure;coronary artery disease;lipid;cardiac arrhythmia;diagnosis;treatment; guideline

R541

A

1004-583X(2017)02-0093-09

10.3969/j.issn.1004-583X.2017.02.001

2017-01-13編輯:武峪峰

崔煒,Email:cuiwei21c@163.com

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