고혈압 어떻게 잘 진단하고, 치료할 것인가?

SPRINT 연구와목표혈압 가천의대심장내과 정욱진

고혈압어떻게잘진단하고, 치료할것인가? 학습성과 2013 한국고혈압학회의진료지침을바탕으로고혈압환자에서의적절한진단과치료를임상에적용할수있다. 구체적학습성과 1. 고혈압환자를새로운진료지침에따라서정확히진단할수있다. 2. 고혈압환자에서합병증예방을위한모니터링방법을활용할수있다. 3. 고혈압환자에서치료의목표를알고적용할수있다. 4. 고혈압환자에서적절한치료약제를선택하거나비약물적치료법을적용할수있다. 5. 특정상황의고혈압환자를치료할수있다.

고혈압의치료목표 일반적치료목표 당뇨병 만성신장질환 노인성고혈압

HOT 연구 : 당뇨에서만 80 mm Hg 이하로낮추는것이심혈관질환예방에효과적 CV Events per 1000 Patient-Years P=.005 for trend 25 24.4 20 18.6 15 11.9 10 5 0 90 mm Hg 85 mm Hg 80 mm Hg HOT=Hypertension Optimal Treatment study. Hansson et al. Lancet. 1998;351:1755-1762.

ACCORD 연구 (2 중 2x2 분획디자인 ) 지질혈압위약군 Fibrate 강력조절표준조절 강력한혈당조절 1383 1374 1178 1193 5128 표준적 혈당조절 1370 1391 1184 1178 5123 2753 2765 2362 2371 10,251 5518 * 94% power for 20% reduction in event rate, assuming standard group rate of 4% / yr and 5.6 yrs follow-up 4733 * N Engl J Med. 2010;362:1575-85

ACCORD BP trial 수축기혈압 Target SBP<120 Target SBP<140 N Engl J Med. 2010;362:1575-85

당뇨병 4,733 명평균 4.7 년추적관찰 Patients with Events (%) 20 15 10 5 ACCORD BP trial 1 차종말점 ( 비치명적심근경색, 비치명적뇌졸중또는심혈관질병에의한사망 ) Target SBP<120 Target SBP<140 HR = 0.88 95% CI (0.73-1.06) 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization N Engl J Med. 2010;362:1575-85

Adverse Events ACCORD BP trial 부작용 Intensive N (%) Standard N (%) P value Serious AE 77 (3.3) 30 (1.3) <0.0001 Hypotension 17 (0.7) 1 (0.04) <0.0001 Syncope 12 (0.5) 5 (0.2) 0.10 Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02 Hyperkalemia 9 (0.4) 1 (0.04) 0.01 Renal Failure 5 (0.2) 1 (0.04) 0.12 egfr ever <30 ml/min/1.73m 2 99 (4.2) 52 (2.2) <0.001 Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93 Dizziness on Standing 217 (44) 188 (40) 0.36 N Engl J Med. 2010;362:1575-85

INVEST : Diabetes and CAD JAMA 2010

목표혈압 ( 당뇨병동반시 ) 2013 ADA : 140/80mmHg 미만 2013 ESH/ESC : 140/85mmHg 미만 2013 KSH : 140/85mmHg 미만 2014 JNC-8 : 140/90mmHg 미만 Diabetes Care 2013;36(1):S11-S66 2013 ESH/ESC, 2013 JNC8 2013 대한고혈압학회진료지침

심장동맥질환과고혈압 심장동맥질환이동반된고혈압환자에서혈압을 < 130/80mmHg 미만으로낮추는것이심혈관질환을추가로낮춘다는증거가없다.

목표혈압 ( 심장동맥질환, 뇌혈관질환 ) 심장동맥질환, 뇌혈관질환의목표혈압 : 140/90mmHg 미만 2013 ESH/ESC guideline 2013 대한고혈압학회진료지침

단백뇨가있는고혈압성만성콩팥병에 강력한혈압조절은효과적 만성신장질환악화, 말기신장질환진단, 사망 1094 명흑인, 평균 8.8~12.2 년추적관찰 Appel LJ et al. N Engl J Med 2010;363:918-929

만성콩팥병이동반된고혈압에서의 치료지침 (KDIGO* 2012) Albumin 뇨목표혈압권장혈압강하제 < 30 mg/day 140/90mmHg 없음 30-300 mg/day 130/80mmHg ACEI or ARB > 300mg/day 130/80mmHg ACEI or ARB 2013 대한고혈압학회진료지침 * Kidney Disease: Improving Global Outcomes Kidney Int 2012;2(Suppl):337-414

노인고혈압의목표혈압 현재까지모든노인고혈압임상연구는수축기혈압 160mmHg 이상인사람들을대상으로진행하였고, 140mmHg 이하로낮췄을때심혈관질환이추가로예방되었다는증거가없다.

노인고혈압진료지침 (ESH/ESC) 1) < 80 세미만인환자는수축기혈압이 160 mmhg 이면우선 150~140 mmhg 으로낮출것이권고되며환자가기립성저혈압등의부작용이없다면 140mmHg 미만까지낮출것을고려할수있음 2) 80 세이상이면서신체적, 정신적으로건강한환자는수축기혈압 160 mmhg 이면수축기혈압을 150~140 mmhg 으로낮추는것이도움이된다.(80 세이상이면서노환이심한고혈압환자에서혈압치료가도움이된다는증거는없다.)

목표혈압 ( 노인고혈압 ) 1. 우선 140~150 mmhg으로조절 2. 140 mmhg미만으로조절 - 80세미만 - 기립성저혈압등부작용없음 - 신체적정신적건강 2013 대한고혈압학회진료지침

JNC 8

목표혈압의요약

수축기혈압목표혈압 수축기혈압 <140 mmhg: 일반적인고혈압 당뇨병 뇌혈관질환 관상동맥질환 노인고혈압 수축기혈압 140~150 mmhg: - 노인고혈압 수축기혈압 < 130mmHg - 알부민뇨가있는만성콩팥병

확장기혈압목표혈압 확장기혈압 < 90mmHg 당뇨병또는알부민뇨를동반한만성콩팥병이외의모든고혈압 확장기혈압 < 85mmHg 당뇨병 확장기혈압 < 80mmHg 알부민뇨가동반된만성신장질환

목표혈압의요약 수축기혈압 <140 mmhg: 당뇨병을포함한모든고혈압 뇌혈관질환 관상동맥질환 만성신장질환 (JNC-8) 확장기혈압 < 90mmHg 당뇨병, 단백뇨가있는만성신장질환이아닌모든고혈압 당뇨병, 만성신장질환 (JNC-8) 수축기혈압 < 150 mmhg: - 노인고혈압 (KSH, ESH/ESC, CHEP, NICE 80 y, JNC-8 60 y) 수축기혈압 < 130mmHg - 단백뇨가있는만성신장질환 (KSH, KDIGO) 확장기혈압 < 85mmHg 당뇨병 (KSH, ESH/ESC) 확장기혈압 < 80mmHg 당뇨병 (ADA) 단백뇨가있는만성신장질환 (KSH, KDIGO)

2015 AHA/ACC/ASH AHA/ACC/ASH, 2015

General target BP for secondary prevention in CAD patients 140/90mmHg lower target BP (<130/80mmHg) - some individuals with CAD - previous MI, stroke or transient ischemic attack or CAD risk equivalents (carotid artery disease, PAD, abdominal aortic aneurysm) AHA/ACC/ASH, 2015

AHA, 2007 AHA/ACC/ASH, 2015 AHA guideline for patients with CAD 2007 2015 140/90mmHg general 140/90mmHg 140/90mmHg elderly(>80) 150/90mmHg High CAD risk, Stable/unstable angina, non- STEMI, STEMI LVD 130/80 mmhg 120/80 mmhg High risk 140/90 mmhg 130/80 mmhg CAD, ACS, HF CAD, Post-MI, stroke, TIA, PAD, carotid artery disease, AAA

목표혈압 ( 관상동맥질환, 뇌혈관질환 ) 상태목표혈압분류 80 세이상노인 <150/90mmHg IIa/B 관상동맥질환 급성관상동맥증후군 심부전 관상동맥질환 급성심근경색후뇌경색또는급성일과성뇌허혈경동맥질환말초동맥질환복부대동맥류 <140/90mmHg <130/80mmHg I/A IIa/C IIa/B IIb/C IIb/C AHA/ACC/ASH Scientific Statement J Am Coll Cardiol 2015;65:1998-2004

비당뇨심혈관질환고위험군의 혈압조절 당뇨와이전의뇌졸중제외 50 세이상 + SBP 130~180mmHg + 증가된심혈관계위험 ( 다음 3 중 1) 1) CKD egfr of 20~60 ml /min/1.73 m2 BSA(MDRD) 2) 10-Y risk of CVD 15% (Framingham risk score); 3) 75 세 SPRINT Research Group. N Engl J Med 2015; 373:2103-2116.

SPS3 Trial Examine effect of more intensive blood pressure treatment than is currently recommended Randomized Controlled Trial Target Systolic BP Intensive Treatment SBP < 120 mmhg (N=4,678) Standard Treatment SBP < 140 mmhg (N=4,683) Primary outcome CVD composite: first occurrence of Myocardial infarction (MI), Acute coronary syndrome (non-mi ACS), Stroke, Acute decompensated heart failure (HF), Cardiovascular disease death The SPRINT Research Group. N Engl J Med 2015;373:2103-16.

Major Inclusion Criteria 50 years old Systolic BP : 130 180 mm Hg At least one additional cardiovascular disease (CVD) risk Clinical or subclinical CVD (excluding stroke) Chronic kidney disease (CKD) (egfr 20 <60ml/min/1.73m 2 ) Framingham Risk Score for 10-year CVD risk 15% Age 75 years Major Exclusion Criteria Stroke Diabetes mellitus Polycystic kidney disease Congestive heart failure (symptoms or EF < 35%) Proteinuria >1g/d CKD with egfr < 20 ml/min/1.73m2 The SPRINT Research Group. N Engl J Med 2015;373:2103-16

SPRINT: Systolic BP During Follow-up Year 1 Mean SBP 136.2 mm Hg Standard Mean SBP 121.4 mm Hg Intensive The SPRINT Research Group. N Engl J Med 2015;373:2103-16

SPRINT: Primary Outcome Primary Outcome: MI, ACS, Stroke, HF, CV Death The SPRINT Research Group. N Engl J Med 2015;373:2103-16

Composite Cardiovascular Events (%/year) All-cause Mortality (%/year) 비당뇨심혈관질환고위험군 철저한혈압조절시심혈관사고를감소시킴 3.26 년만에조기종료 2.5 P<0.001 2.19% 2.5 P=0.003 2.0 2.0 1.5 1.65% 1.5 1.40% 1.03% 1.0 1.0 0.5 0.5 0.0 Intensive <120mmHg Standard <140mmHg 0.0 Intensive <120mmHg 121.5 mmhg (2.8 medications) vs. 134.5mmHg (1.8 Medications) Standard <140mmHg SPRINT Research Group. N Engl J Med 2015; 373:2103-2116.

SPRINT Research Question Examine effect of more intensive high blood pressure treatment than is currently recommended Randomized Controlled Trial Target Systolic BP Intensive Treatment Goal SBP < 120 mm Hg Standard Treatment Goal SBP < 140 mm Hg SPRINT design details available at: ClinicalTrials.gov (NCT01206062) Ambrosius WT et al. Clin. Trials. 2014;11:532-546.

Stroke Major Exclusion Criteria Diabetes mellitus Polycystic kidney disease Congestive heart failure (symptoms or EF < 35%) Proteinuria >1g/d CKD with egfr < 20 ml/min/1.73m 2 (MDRD) Adherence concerns Hypertensive patients under the age of 50

Primary Outcome and Primary Hypothesis Primary outcome CVD composite: first occurrence of Myocardial infarction (MI) Acute coronary syndrome (non MI ACS) Stroke Acute decompensated heart failure (HF) Cardiovascular disease death Primary hypothesis* CVD composite event rate lower in intensive compared to standard treatment *Estimated power of 88.7% to detect a 20% difference based on recruitment of 9,250 participants, 4 6 years of follow up and loss to follow up of 2%/year. N Engl J Med 2015;373(22):2103-2116

SPRINT Research Group. N Engl J Med 2015; 373:2103-2116.

N Engl J Med 2015;373(22):2103-2116 Renal outcome Outcome Intensive treatment Standard treatment HR(95% CI) P Value Patients(%) % per year Patients(%) % per year CKD (N = 1330) (N=1316) Composite renal outcome 50% reduction of egfr 14(1.1) 0.33 15(1.1) 0.36 0.89(0.42-1.87) 0.76 10(0.8) 0.23 11(0.8) 0.26 0.87(0.36-2.07) 0.75 Dialysis 6(0.5) 0.14 10(0.8) 0.24 0.57(0.19-1.54) 0.27 KT 0 0 Incident albuminuria 49/526(9.3) 3.02 59/500(11.8) 3.90 0.72(0.48-1.07) 0.11 W/O CKD (N=3332) (N=3345) 30% reduction in egfr to < 60ml/min 127(3.8) 1.21 37(1.1) 0.35 3.49(2.44-5.10) < 0.001 Incident albuminuria 110/1769(6.2) 2.00 135/1831(7.4) 2.41 0.81(0.63-1.04) 0.10

3020 subjects with recent lacunar infarct Open label: SBP < 130(127mmHg) vs SBP; 130-149(138mmHg) Non significant reduction in stroke(hr: 0.81, 95 % CI: 0.64-1.03, P = 0.08) Composite outcome of stroke, MI or vascular death(hr: 0.84, 0.68-1.04, P = 0.32) Significant reduction of ICH(HR: 0.37, 0.15-0.95, P = 0.03) Lancet 2013;382:507-515

SPS3 Trial A randomized, multicenter trial of a 2 X 2 factorial design, aspirin 325 mg + placebo vs aspirin 325 mg + clopidogrel 75 mg systolic BP 130-149 mmhg vs < 130 mmhg Lacunar stroke, Randomized within 6 months of event Primary outcome: Recurrent stroke -> Antiplatelet study was terminated early due to increase death in dual antiplatelet group Benavente OR, et al. Lancet 2013;382:507-15.

SPS3 Trial 3,020 patients(mean age 63 years), Mean follow-up 3.7 years Mean BP at entry ~145/80mmHg At 1 yr follow-up Average SBP : 138 vs. 127mmHg Benavente OR, et al. Lancet 2013;382:507-15.

SPS3 Trial Ischemic & Hemorrhagic Stroke No statistically significant reduction in stroke Higher Target Group = 2.8% Lower Target Group = 2.3% P = 0.08 Benavente OR, et al. Lancet 2013;382:507-15.

How applicable is SPRINT in the Asia Pacific region? J Hypertens 2003;21:707-761

SPRINT eligible population in Korean, 2008, 30 세이상 : 의료보험공단표본코호트 고혈압환자대상 ( 혈압약복용력 or BP => 140/90 mm Hg) ( 당뇨, 뇌졸증기왕력제외 ) Major risk factor 3개이상, CKD or previous CHD Age < 50 Age => 50 10 yr CV risk SPRINT BP category 10 yr CV risk SPRINT BP category None 1 2 3 4 합계 None 1 2 3 4 합계 < 15% 2944 5482 886 381 123 9816 < 15% 3069 3348 1515 606 146 8684 16.66 31.02 5.01 2.16 0.7 55.54 10.05 10.96 4.96 1.98 0.48 28.43 29.99 55.85 9.03 3.88 1.25 35.34 38.55 17.45 6.98 1.68 63.74 53.3 52.93 47.39 42.27 30.44 30.97 26.26 20.3 16.37 > 15% 1675 4803 788 423 168 7857 > 15% 7014 7463 4255 2379 746 21857 9.48 27.18 4.46 2.39 0.95 44.46 22.97 24.44 13.93 7.79 2.44 71.57 21.32 61.13 10.03 5.38 2.14 32.09 34.14 19.47 10.88 3.41 36.26 46.7 47.07 52.61 57.73 69.56 69.03 73.74 79.7 83.63 합계 4619 10285 1674 804 291 17673 합계 10083 10811 5770 2985 892 30541 26.14 58.2 9.47 4.55 1.65 100 33.01 35.4 18.89 9.77 2.92 100 24.9 %(14843/59444) 우리나라전체 15% 정도 / 투약군의 25% 미국전체 8%/ 투약군의 17% With courtesy from Dr Jin Ho Shin

SBP target can be lowered to below 130mmHg if tolerated for Patients over the age of 50 with previous CHD High risk hypertensives over the age of 50 without previous history of CHD or MI Non frail elderly hypertensives CKD with/without overt proteinuria To prevent acute heart failure, CHD death and mortality 1 additional medication to for 172 subjects to reduce 1 CHD mortality

고혈압조절의목표혈압 1. 일반적인경우목표혈압은 140/90mmHg 이다. 2. 80 세이상의노인환자의경우수축기혈압을우선 150mmHg 미만으로낮추고, 신체적으로건강하거나기립성저혈압이없으면 140mmHg 미만으로낮춘다. 단, 이완기혈압은 60mmHg 이상으로조절한다. 3. 당뇨병은 140/85mmHg 미만으로낮추고, 단백뇨동반만성콩팥병 130/80mmHg 이하로낮춘다. 4. SPRINT 연구의결과 일부 50 세이상의 ( 비당뇨병 ) 심혈관계고위험군에서는 121.4mmHg 까지낮추어심혈관사고감소했으나적용에는더논의가필요한결과이다.