2014.1.18 KSH 개원의 연수강좌, 제주 고혈압 어떻게 치료할 것인가? 박정배 관동의대 제일병원 내과

고혈압 어떻게 치료할 것인가? 생활요법치료

가장 믿을만한 생활요법치료? 알코올 섭취제한(남자; 20-30g/d, 여자; 10-20g/d) 채소, 과일, 저지방유제품의 섭취 권장 체중감량; 체질량 지수 25 kg/m2 미만 유지 허리둘레를 남자 < 102cm, 여자 < 88cm 유지) 5. 운동(중등도 강도, 하루 30분, 일주일 5-7회 권장) 6. 금연

생활요법치료의 효과 2013 대한고혈압학회진료지침

TONE연구: 노인 고혈압 환자에서 염분 제한으로 소변 염분과 합병증 발생 감소 Whelton et al, JAMA 1998 노인 고혈압 환자에서 Sodium 제한과 체중감량의 효과 : TONE 연구 Sodium을 제한한 경우 소변 sodium의 양이 줄었고 합병증의 발생도 유의하게 감소했다. Whelton et al, JAMA 1998

효과적인 생활요법 개선의 효과  monotherapy

고혈압 어떻게 치료할 것인가? 약물 치료

약물선택의 원칙 (1) 약을 처음 투여할 때는 부작용을 피하기 위하여 저용량으로 시작한다. 약효가 24시간 지속되어 1일 1회 복용이 가능한 약을 선택한다. 1일 1회 복용이 가능한 약을 처방할 때는 최저효과/최대효과 비(trough/peak ratio)가 0.5 이상인 약이 좋다. 하루 1회 복용으로 혈압이 조절되지 않으면 2회 이상 나누어 복용할 수 있다. 일차 고혈압약으로 안지오텐신전환효소 억제제, 안지오텐신 수용체 차단제, 베타차단제, 칼슘차단제, 이뇨제 중에서 선택하며 적응증, 금기사항, 환자의 동반질환, 무증상 장기 손상 등을 고려한다.

약물선택의 원칙 (2) 노인에서 베타차단제는 치료 이득에 대한 논란이 있어 특별한 적응증이 있는 경우에만 사용한다. 베타차단제와 이뇨제의 병용투여는 당뇨병의 발생 위험을 증가시키기 때문에 당뇨병 발생의 위험이 높은 환자에게는 주의해야 한다. 혈압이 160/100 mmHg 이상이거나, 목표 혈압 보다 20/10 mmHg 이상 높은 경우는 처음부터 고혈압 약을 병용 투여 할 수 있다. 병용요법은 강압 효과를 상승시키고 부작용을 줄이고, 환자의 약 순응도를 증가시켜, 심혈관 질환과 무증상 장기손상을 방지하는데 도움이 된다.

질환에 따른 추천 고혈압약 2013 대한고혈압학회진료지침

고혈압 약의 적응증과 금기 2013 대한고혈압학회진료지침

고혈압 어떻게 치료할 것인가? 병합 요법

수축기혈압 (Pulse ), 확장기혈압의 결정 (Flow) 인자 Endothelial dysfunction Central artery stiffness 수축기혈압 Pulse wave reflection LV function Peripheral Resistance   Veins Stroke Volume 이완기혈압 Park JB 2009

혈압은 다양한 기전으로 조절된다. Patient 1 Patient 2 Patient 3 Although the endogenous regulation of BP is not completely understood, three regulatory mechanisms have been well-characterized: (1) sympathetic nervous system (SNS), (2) renin-angiotensin system (RAS), and (3) aldosterone release. These different mechanisms do not necessarily work independently of each other; indeed, these homeostatic pathways interact to regulate BP. As such, therapeutic strategies targeting multiple regulatory pathways is of benefit in patients with hypertension that need their BP controlled to target levels. Note: more detailed discussion on the SNS and the RAS is given later (see ‘CCB/ARB: complementary mode of action)’. Sympathetic nervous system Renin-angiotensin system Total body sodium B. Waeber, March 2007,

일차약의 종류 A- ACE억제제 또는 안지오텐신차단제 B- 베타차단제 (알파-베타차단제 포함) C- 칼슘차단제 D- 티아 지드 또는 티아지드 유사 이뇨제 Etc- 알파차단제 및 기타 약제

Number of BP Medications 목표혈압에 도달하는데 필요한 약 개수 UKPDS (<85 mm Hg, diastolic) MDRD (<92 mm Hg, MAP) HOT (<80 mm Hg, diastolic) AASK (<92 mm Hg, MAP) Polypharmacy may be necessary to reach BP goals in hypertension management.45,47,48 RENAAL (<140/90 mm Hg) IDNT (135/85 mm Hg) 1 2 3 4 Number of BP Medications Bakris et al. Am J Kidney Dis. 2000;36:646-661; Bakris et al. Arch Intern Med. 2003;163:1555-1565; Lewis et al. N Engl J Med. 2001;345:851-860. Trial abbreviations: UKPDS = United Kingdom Prospective Diabetes Study; MDRD = Modification of Diet in Renal Disease; HOT = Hypertension Optimal Treatment; AASK = African American Study of Kidney Disease; RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; IDNT = Irbesartan Diabetic Nephropathy Trial. 45. Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. 47. Brenner BM, Cooper ME, de Zeeuw D, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. 48. Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Special report: preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661. 49. Bakris GL, Weir MR, Shanifar S, et al, for the RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy. Results from the RENAAL study. Arch Intern Med. 2003;163:1555-1565. SLIDE 16

병용요법이 용량증가보다 혈압 조절율이 높다. This slide indicates the conclusions from a meta-analysis that aimed to quantify the incremental effect of combining blood pressure-lowering drugs from any two classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over one drug alone and to compare the effects of combining drugs with that of doubling the dose. The analysis included 42 factorial trials (10,968 participants), in which participants were randomly allocated to one drug alone, another drug alone, both drugs together, or a placebo. Reference Wald DS, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med 2009;122:290–300. ‘The extra BP reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug’ Conclusions from a meta-analysis comparing combination antihypertensive therapy with monotherapy in over 11,000 patients from 42 trials Wald et al. Am J Med 2009;122:290–300 Single-pill Combination Scientific Slide Resource Item code: EXF10.202; Release Date: July 2010

혈압과 심혈관 위험에 따른 단일약제-병용요법의 선택 2013 대한고혈압학회진료지침

권장 병용요법 (ESH/ESC) 2013 ESH/ESC guideline 1. Beta-blocker-diuretic combination was as effective as other combinations and more effective than placebo. However, beta-blocker- diuretic combination has more new-onset diabetes in susceptible individuals 2. No RCT results of beta-blocker – CCB combination 3. Two different combination of RAS blockers not recommended 2013 ESH/ESC guideline

권장 병용요법 (굵은선: 우선 권장되는 병용요법, 가는선: 가능한 병용요법) ACE, 안지오텐신전환효소; ARB, 안지오텐신 차단제. 2013 대한고혈압학회진료지침

RAAS Blocker CCB* Diuretic* 레닌-안지오텐신계에 기반을 둔 복합치료 greater BP reduction in many demographic groups complementary effects with other drugs additive efficacy greater BP reductions in many demographic groups complementary effects with other drugs, particularly RAAS blockers 다양한 RAS based Combo제재 중에서 CCB와 HCTZ만 보는 것은 현재 가장 많이 처방되는 두 가지 복합제재이며, 보는 바와 같이 이러 이러 한 benefit이 있기 때문이다. Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) have great potential as foundations for antihypertensive combinations. As noted in JNC 7, renin-angiotensin-aldosterone system (RAAS) inhibition provides benefits beyond blood pressure (BP) lowering.1 Since the benefits of RAAS inhibition have been so clearly demonstrated, a clinician may choose a thiazide diuretic or a calcium channel blocker (CCB) and add a RAAS blocker when combination therapy becomes necessary. Combining a thiazide diuretic with an ARB or ACEI can provide a greater reduction in BP than either drug alone,2 and increased responder rates. 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA. 2003;289:2560–2572. 2. Weir MR. The rationale for combination versus single-entity therapy in hypertension. Am J Hypertens. 1998;11:163S–169S *Versus either drug alone. RAAS=renin-angiotensin-aldosterone system; CCB=calcium channel blocker; BP=blood pressure. Weir MR. Am J Hypertens. 1998;11:163S–169S.

저용량 칼슘차단제(CCB)+안지오텐신수용체차단제(ARB) 와 고용량 단일요법과의 목표혈압 (<140/90 mmHg) 도달률 Patients achieving BP goal (%) N=137 * In addition to the smoother BP variation, CCBARB therapy achieved BP goal (<140/90 mmHg) in a significantly (p<0.05) higher proportion of patients not controlled on low-dose monotherapy (61.6%) than higher-dose CCB (42.8%) and ARB (40.5%) alone. Reference Andreadis EA, et al. High-dose monotherapy vs low-dose combination therapy of calcium channel blockers and angiotensin receptor blockers in mild to moderate hypertension. J Hum Hypertens 2005;19:4916. CCB ARB CCB + ARB *p<0.05 vs CCB and ARB alone Andreadis et al. J Hum Hypertens 2005;19:491–6

ACCOMPLISH: 초반 복합요법(SPC) 의 우수한 목표혈압 조절율 90 81.7 78.5 80 70 60 Control rate (%) 50 40 Baseline Control Rates 37.2 37.9 30 20 10 ACEI / HCTZ N=5733 CCB / ACEI N=5713 P<0.001 at 30 months follow-up Control defined as <140/90 mmHg

저용량 CCBARB이 고용량 단일약보다 혈압변화 (trough-to-peak) 더 우수하다. BP (mmHg) variability 0.950* 0.936 0.935 Together with the physiological rationale for a CCBARB, available data also suggest that the CCBARB is a more attractive therapeutic strategy than high-dose monotherapy in terms of BP control and 24-hour BP profile. This study evaluated the clinical efficacy, specifically the 24-hour BP variability of high-dose monotherapy with CCBs or ARBs versus low-dose CCBARB treatment in stage 1 and 2 newly diagnosed hypertensive patients with inadequate BP control (>140/90 mmHg) after conventional low-dose monotherapy. The CCBs evaluated were amlodipine, felodipine and lacidipine; ARBs included in the study were valsartan, irbesartan, candesartan, losartan and telmisartan. From the 137 patients who were not controlled by low-dose monotherapy, 35 received a higher dose of CCBs; 42 received a higher dose of ARBs; and 60 received low-dose CCBARB therapy. The results revealed that low-dose CCBARB therapy was characterised by lower variability compared with both high-dose treatment groups. The mean trough-to-peak ratio for SBP was significantly higher for dual CCBARB therapy compared with high-dose CCB or ARB therapies (p<0.05). *p<0.05 vs CCB and ARB alone Values in boxes represent trough-to-peak ratio Andreadis et al. J Hum Hypertens 2005;19:491–6 Reference Andreadis EA, et al. High-dose monotherapy vs low-dose combination therapy of calcium channel blockers and angiotensin receptor blockers in mild to moderate hypertension. J Hum Hypertens 2005;19:4916.

Single-pill combo 가 free-combination 보다 21% 더 약물 순응도가 좋다. Cohort study of general practice research data (N=755) 100 Single-pill combination therapy 80 Co-administration of two pills 60 Patients fully compliant (%) 40 20 21% 17% This was a retrospective cohort study of individuals aged >20 years, who were newly treated with an ACE inhibitor (n=7,837) or a thiazide diuretic (n=4,906) during the study period January 1998–September 2003. Data were obtained from a general practice research database, Integrated Primary Care Information, in the Netherlands. Individuals were identified who, having started with an ACE inhibitor or a thiazide diuretic, subsequently continued with a two-pill (n=297) or a single-pill (n=458) combination therapy. Compliance was defined as a percentage of days covered with treatment greater than 80%. Persistence was defined as the duration of continuous therapy. Additionally, patients with a gap of more than 6 months between prescriptions were considered to be non-persistent. As shown on the slide, more patients (21%) receiving SPC therapy than receiving separate pills were fully compliant. 3 6 9 12 15 18 21 24 27 Months since start of therapy Patients on free combination had a higher odds ratio (OR) of being non-compliant than patients on SPC: OR 2.09 (95% CI: 1.69, 2.59) Sturkenboom et al. J Hypertens 2005;23(Suppl 2):S236 Reference Sturkenboom M, et al. Association between adherence and goal attainment in antihypertensive therapy. J Hypertens 2005;23(Suppl. 2):S236.

Overall 63% of new patients received combination therapy 한국에서의 복합치료 처방빈도 Overall 63% of new patients received combination therapy ▼ 59% 63% 66% 64% 65% ▼ 신환에서 BP Goal 에 도달하기 위해서 2개이상의 항고혈압복용하는 환자가 63%였다. Total [N=130] Cardio [N=40] Endo [N=30] Nephro Neuro [Base = all, N=( ), Unit =weighted % of pts] [Base = all, N=( ), Unit =weighted % of pts] Source : market research June, 2008

Global survey of current practice in management of hypertension Chalmers J, Arima H, Harrap S, Touyz R, Park JB, 2013 J Hypertens Number of Countries / 31 RAS/CCB RAS/D CCB/D CCB/BB D/BB Hypertensive Patients 27 22 5 6 3 Type 2 Diabetes 26 12 1

사람이 늙어가면 혈압도 늙어간다. 53세 132/88mmHg 63세 140/90mmHg 73세 154/86mmHg 어떻게 할 것인가? 63세 140/90mmHg 73세 154/86mmHg 83세 162/84mmg 93세 168/80mmHg 남자, 172cm. 76kg.

2014년 춘계고혈압 국제학회 날짜; 2014년 5월 9일-10일(금-토) 장소: 서울 여의도 콘라드(CONRAD) 호텔 Theme: Guide Hypertension Well

ISH 2016 Seoul The 26th International Society of Hypertension Biennial Scientific Meeting ISH 2016 Seoul September 24(Sat) – 29(Thu), 2016 COEX, Seoul, Korea