2023+KSH共识文件：难治性高血压（英文版）.pdf

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1、Parketal.Clinical Hypertension https:/doi.org/10.1186/s40885-023-00255-4REVIEWResistant hypertension:consensus document fromtheKorean society ofhypertensionSungha Park1,Jinho Shin2,Sang Hyun Ihm3,4*,Kwang-il Kim5,Hack-Lyoung Kim6,Hyeon Chang Kim7,Eun Mi Lee8,Jang Hoon Lee9,10,Shin Young Ahn11,Eun Jo

2、o Cho12,Ju Han Kim13,Hee-Taik Kang14,Hae-Young Lee15,Sunki Lee16,Woohyeun Kim17 and Jong-Moo Park18 Abstract Although reports vary,the prevalence of true resistant hypertension and apparent treatment-resistant hypertension(aTRH)has been reported to be 10.3%and 14.7%,respectively.As there is a rapid

3、increase in the prevalence of obesity,chronic kidney disease,and diabetes mellitus,factors that are associated with resistant hypertension,the prevalence of resistant hypertension is expected to rise as well.Frequently,patients with aTRH have pseudoresistant hyperten-sion aTRH due to white-coat unco

4、ntrolled hypertension(WUCH),drug underdosing,poor adherence,and inaccurate oce blood pressure(BP)measurements.As the prevalence of WUCH is high among patients with aTRH,the use of out-of-oce BP measurements,both ambulatory blood pressure monitoring(ABPM)and home blood pressure monitoring(HBPM),is es

5、sential to exclude WUCH.Non-adherence is especially problematic,and methods to assess adherence remain limited and often not clinically feasible.Therefore,the use of HBPM and higher utilization of single-pill xed-dose combination treatments should be emphasized to improve drug adherence.In addition,

6、primary aldosteronism and symptomatic obstructive sleep apnea are quite common in patients with hypertension and more so in patients with resistant hypertension.Screening for these diseases is essential,as the treatment of these second-ary causes may help control BP in patients who are otherwise dic

7、ult to treat.Finally,a proper drug regimen com-bined with lifestyle modications is essential to control BP in these patients.Keywords Ambulatory blood pressure monitoring,Home blood pressure monitoring,Hypertension,Refractory hypertension,Resistant hypertensionOpen Access The Author(s)2023.Open Acce

8、ss This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use,sharing,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons

9、licence,and indicate if changes were made.The images or other third party material in this article are included in the articles Creative Commons licence,unless indicated otherwise in a credit line to the material.If material is not included in the articles Creative Commons licence and your intended

10、use is not permitted by statutory regulation or exceeds the permitted use,you will need to obtain permission directly from the copyright holder.To view a copy of this licence,visit http:/creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver(http:/creativecom-mons.

11、org/publicdomain/zero/1.0/)applies to the data made available in this article,unless otherwise stated in a credit line to the data.Clinical HypertensionSungha Park and Jinho Shin contributed equally to this work.*Correspondence:Sang Hyun Ihmlimshcatholic.ac.krFull list of author information is avail

12、able at the end of the articlePage 2 of 19 Parketal.Clinical Hypertension IntroductionHigh blood pressure(BP)is associated with increased cardiovascular complications,regardless of the type of prescribed antihypertensive medications 1.BP reduc-tion at any level has shown a 10%reduction in cardio-vas

13、cular events per 5 mmHg reduction in systolic BP.In addition to population-based strategies for identifying patients with untreated hypertension and introducing antihypertensive therapy,BP reduction to recommended levels is important for reducing cardiovascular risk and optimizing antihypertension t

14、reatment.In Korea,the overall control rate of hypertension is less than half of the hypertensive population,and the control rate in patients treated for hypertension is approximately 70%2.Patients with resistant hypertension(RH)are particularly challenging in terms of the reasons for their reduced r

15、esponse to multiple antihypertensive medica-tions,clinical presentation,specic etiology,prognosis,and management.Understanding the underlying etiol-ogy and pathophysiology of uncontrolled hypertension treated with multiple antihypertensive medications will help achieve a breakthrough in the stagnant

16、 BP control rate 3.Accordingly,the Korean Society of Hypertension has published an expert consensus on the denition,epi-demiology,etiology,diagnosis,and management of RH.Denition ofresistant hypertensionRH is dened as the failure to achieve the target BP despite the use of 3 antihypertensive drugs,c

17、ommonly including dihydropyridine calcium channel blockers(CCBs),renin-angiotensin system(RAS)inhibitors,and diuret-ics,or the need for treatment with 4 antihypertensive medications to achieve the target BP 4,5.Patients who fail to achieve the target BP despite the use of ve or more antihypertensive

18、 medications,ideally including thiazide-like diuretics and spironolactone,are dened as having treatment-refractory hypertension 6,7.e target BP should be in accordance with the current guide-lines.For example,the threshold for diagnosis is 130/80 mmHg according to the American College of Cardiology/

19、American Heart Association guidelines 4.For Korean patients,the threshold may dier based on underly-ing risk factors 5,8.Previous studies included patients who were diagnosed with hypertension based on oce BP as well as patients who would be categorized as hav-ing pseudoresistant hypertension.erefor

20、e,the term“apparent treatment RH”(aTRH)should be used for patients in whom pseudoresistant hypertension has not been ruled out.e causes of pseudoresistant hyper-tension include white-coat uncontrolled hypertension(WUCH),non-adherence,poorly measured oce BP,or undertreatment 4.For an accurate diagnos

21、is of RH,out-of-oce BP monitoring,such as 24-hour ambulatory blood pressure monitoring(ABPM)and/or home blood pressure monitoring(HBPM),should be performed to rule out WUCH.is is essential because WUCH impacts as many as 1/3 of patients with aTRH 9.Moreover,the possibility of non-adherence needs to

22、be ruled out,as it is common,especially with polypharmacy and a higher number of anti-hypertensive medications 10.Finally,Graphical AbstractPage 3 of 19 Parketal.Clinical Hypertension antihypertensive medications,including thiazide-like or thiazide-type diuretics,must be titrated to maximally tol-er

23、ated doses before making a diagnosis.Epidemiology ofresistant hypertensione reported prevalence of RH varies signicantly according to specic studies.In the 2018 AHA scien-tic statement,the prevalence of RH among all patients with hypertension was 12-15%based on population stud-ies and 15-18%for clin

24、ic based reports 4.In a pooled analysis of 3,207,911 patients with hypertension,the prevalence rates of true and aTRH were 10.3%and 14.7%,respectively 11.Age,higher baseline BP,obesity,exces-sive salt ingestion,chronic kidney disease(CKD)and dia-betes mellitus(DM)were associated with a higher risk o

25、f RH 12.e prevalence of RH increases with age.Several factors contribute to the higher risk of RH in older adults 13,14.ey include age-related vascular changes(i.e.,vascular stiness),neurohormone imbalances,multiple comorbidities(including kidney disease,obesity,and dia-betes),poor adherence to medi

26、cation or polypharmacy,and insucient lifestyle modications(especially high-salt diets)13,14.Noubiap et al.analyzed the prevalence of aTRH by region 11.ey found that the prevalence of aTRH did not dier by region,with the prevalence of RH in the Americas,Asia,and Europe being 14.8%,14.7%,and 14.8%,res

27、pectively.e prevalence of treatment RH in cohorts that underwent out-of-oce BP monitor-ing tended to be lower than that reported previously.In a Korean study that recruited 3088 patients with essen-tial hypertension from 247 primary care physicians,the prevalence of RH was 7.9%15.In another study in

28、volving 16,284 Korean patients with hypertension who underwent ABPM at a single tertiary referral hospital,the overall prevalence of RH was 10.1%.Within this group,the prevalence of RH(excluding refractory hyperten-sion)was 9.2%,and refractory hypertension accounted for 0.9%of the cases 16.e prevale

29、nce of RH dened by home BP was recently reported in an analysis of the Japan Morning Surge Home BP(J-HOP)study.Using the average of home BP threshold of 135/85 mmHg and 130/80 mmHg,the prevalence of RH was 10.7%and 12.5%,respectively 17.RH is associated with an adverse prognosis compared with patien

30、ts without RH.In a retrospective cohort of 205,750 patients with incident hypertension over a median follow-up of 3.8 years,RH was associated with an approximately 50%higher risk of cardiovascular eventshazard ration(HR):1.47,95%condence inter-val(CI):1.33-1.62 18.In a post hoc analysis of 14,684 pa

31、tients from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT),1870 patients were dened as having aTRH.e results showed that aTRH was associated with an increased risk of coronary heart disease(HR:1.47,95%CI:1.26-1.71),cardiovascular disease(HR:1.46,95%CI:1.29-1.

32、64)and end stage renal disease(HR:1.95,95%CI:1.26-1.71)19.In a retrospective analysis of 16,284 Korean patients who underwent ABPM,RH was associated with a 62%higher risk of cardiovascular mortality(HR:1.62,95%CI:1.16-2.26)16.Similarly,RH based on home BP measurement is associated with an adverse pr

33、ognosis.In an analy-sis of 4,261 patients with hypertension from the J-HOP study with a median follow-up of 6.2 years,the adjusted HRs of uncontrolled treatment RH were 2.02(1.38-2.94)and 1.81(1.23-2.65)when using a home BP threshold of 135/85 mmHg and 130/80 mmHg,respectively 17.Use of out-of-oce B

34、P monitoring,such as ABPM or HBPM,for the diagnosis and treatment of RH is important,as it can better predict cardiovascular outcomes in patients with RH 20.Evaluation ofetiologyDiagnosis ofresistant hypertensionRH can be diagnosed by ruling out pseudoresistance,which is dened as a lack of BP contro

35、l despite appropri-ate treatment in patients who do not have RH.Several factors,such as improper BP measurement,the“white-coat eect,”medication non-adherence,and treatment inertia,contribute to pseudoresistance.According to current guidelines,accurate BP measurement is the cor-nerstone of RH diagnos

36、is 21,22.e“white-coat eect”should be excluded when using ABPM or HBPM 23.Medication non-adherence is common in patients with aTRH 24.Treatment inertia is one reason why a large subset of patients do not achieve their BP target.Between 2007 and 2010,less than 50%of patients were prescribed an optimal

37、 antihypertensive regimen in the United States 23.erefore,a careful evaluation to exclude these fac-tors should be performed before diagnosing RH.It is also important to rule out the possibility of pseudoresistance due to the white-coat eect in the diagnosis of RH in older adults,as this phenomenon

38、is more common 25.Lifestyle factors contributing resistant hypertension(Table1)ObesityIncreased adiposity is associated with elevated BP 26.Obesity-related hypertension is associated with increased salt sensitivity,increased sympathetic nervous system activity,activation of the renin-angiotensin-ald

39、oster-one system(RAS),and aldosterone secretion by adipose tissue 26,27.In NHANES(National Health and Nutri-tion Examination Survey),body mass index 30 kg/m2 Page 4 of 19 Parketal.Clinical Hypertension doubled the risk to have aTRH 28.However,no cur-rent guidelines recommend the use of specic drugs

40、in patients with obesity.Dietary sodiumDietary sodium increases BP,particularly in certain groups that are more salt-sensitive or have CKD 29.Despite large person-to-person variations in salt sensitiv-ity,vascular dysfunction,arterial stiness,sympathetic activation,impaired renin-angiotensin axis su

41、ppression,mineralocorticoid receptor activation,and immune cell modulation are suggested as possible mechanisms 30,31.One study showed that reducing dietary sodium from 250 mmol(5.75g)/day to 50 mmol(1.15g)/day for 1-week lowered oce systolic BP by 22.7 mmHg(P=0.008)in patients with RH 32.Patients s

42、hould be advised to adhere to the DASH(Dietary Approaches to Stop Hypertension)diet with less than 2 g of sodium/day(5 g of table salt)to eectively lower BP 29.Physical inactivityPhysical inactivity is independently associated with BP elevation and risk of hypertension 33.However,it is uncertain whe

43、ther sedentary life itself is indepen-dently related to RH because of a paucity of data 34.Recently,a small randomized trial(n=50)showed that a thrice-weekly treadmill exercise program for 812 weeks lowered daytime systolic ambulatory BP by 5.9 mmHg(P=0.03)in patients with RH 34.Patients with RH sho

44、uld engage in at least 150 min/week of moderate-intensity aerobic exercise or 75 min/week of vigorous-intensity aerobic exercise.AlcoholRegular alcohol consumption is associated with a BP elevation of 1 mmHg for every 10 g of alcohol consumed(1 standard drink)35.Heavy alcohol use may be asso-ciated

45、with aTRH,since alcohol may interfere with the pharmacologic action of antihypertensive agents 36.SmokingNicotine from cigarettes,vaping uids,and smokeless tobacco increases BP 37.To reduce cardiovascular events,smoking cessation is recommended for patients with RH.Medication-related resistant hyper

46、tensionSome classes of medications can increase BP,includ-ing anticonvulsants,antidepressants,antipsychotics,antiemetics,antineoplastic agent,calcineurin inhibitors,contraceptives,erythropoietin,glucocorticoids,min-eralocorticoids,nonsteroidal anti-inammatory drugs(NSAIDs),glucocorticoids,estrogen-c

47、ontaining oral contraceptives and hormone replacement,sympatho-mimetic amines(pseudoephedrine,ephedrine,cocaine,amphetamine),vascular endothelial growth factor inhibi-tors,erythropoietin-stimulating agents,immunosup-pressive agents(cyclosporine,tacrolimus),anticancer drugs(vascular endothelial growt

48、h factor inhibitors,tyrosine kinase inhibitors and proteasome inhibitors),serotonin-norepinephrine reuptake inhibitors,and dietary supplements(ginseng,licorice)4,38,39.e eect of these drugs on increasing BP varies from per-son to person,ranging from little to no eect to severely elevated BP.As some

49、medications such as NSAIDs,cold medications,and oral contraceptives can be purchased and taken by patients without a prescription,medication reconciliation is an important process in the manage-ment of patients with hypertension 40.PseudopheochromocytomaAfter true pheochromocytoma has been ruled out

50、 as the cause of the sudden increase in BP,pseudopheo-chromocytoma should be considered.Pseudopheo-chromocytoma is a pheochromocytoma-like syndrome characterized by paroxysmal hypertension,abrupt eleva-tion of BP,and the absence of panic at the onset of attack 41.Many patients with pseudopheochromoc