Paul Drawz, MD, MHS, MSDivision of Renal Diseases and Hypertension

October 4, 2012

Hypertension Update:JNC 8 and Beyond

I have the following financial relationships to disclose: Grant/Research support from: NIDDK

I will discuss the following off label use and/or investigational use in my presentation: Renal nerve ablation

Disclosure informationPaul Drawz

Grand Rounds – October 4, 2012

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

1973: Task Force I National High Blood Pressure Education Program:

Report to the Hypertension Information and Education Committee. Task Force I. Database. Recommendations for a National High Blood Pressure Program Database for Effective Antihypertensive Therapy. DHEW Publication No (NIH) 75–593, September 1 1973

History of JNC

Year Group Pages References BP target1973 Task Force I ? ? ?1977 JNC (1) 7 1 DBP <901980 JNC (2) 6 14 DBP <901984 JNC (3) 13 40 DBP <901988 JNC (4) 16 54 < 140/901993 JNC V 30 117 < 140/901

1997 JNC VI 34 254 < 140/902

2003 JNC VII 48 386 < 140/903

From Task Force I to JNC VII

1. Consider <130/852. <130/85 in CKD, <125/75 with >1g proteinuria/day; <130/85 in diabetics3. <130/80 in diabetics and those with renal disease

Projected Pages/Referencesfor JNC 8

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

Treating hypertension reduces cardiovascular disease

Lower BP targets reduce cardiovascular disease “Intense” BP targets do not improve outcomes

BP Targets – Overview

Placebo(n=70)

Active tx(n=73)

Deaths 4 0Adverse events* 23 2Total 27 2

P < 0.001

* Retinopathy, doubling of BUN, dissecting aortic aneurysm, SAH, CHF, DBP >140mmHg, MI VA CSG, JAMA, 1967.

10,940 participants Age 30 to 69yr Screening DBP ≥95mmHg, randomization DBP ≥90mmHg

Stepped Care – antihypertensive therapy Goal DBP ≤90mmHg

Referred Care – referred to usual sources of care DBP at year 1: 87.6 vs. 94.0 DBP at year 4: 84.6 vs. 89.7

Hypertension Detection and Follow-Up Program (HDFP)

HDFP Cooperative Group, JAMA 1979, p2562.

All-cause mortality (Rate per 100, SC vs. RC) Overall: 6.4 vs. 7.7 DBP 90-104: 5.9 vs. 7.4 DBP 105-114: 6.7 vs. 7.7 DBP ≥115: 9.0 vs. 9.7

Hypertension Detection and Follow-Up Program (HDFP)

HDFP Cooperative Group, JAMA 1979, p2562.

Systolic Hypertension in the Elderly Study (SHEP)

4736 men and women with SBP >= 160 and DBP <90 Randomized

Placebo Active treatment (chlorthalidone plus atenolol/reserpine as

needed) Target BP <160 for those with bl SBP >180 Others: target drop 20mmHg for those with bl <180

Follow up: 5 years Outcome

34% reduction in major CVD rate

Curb JD et al, JAMA, 1996, pg 1886.

1148 subjects – type 2 DM Randomized Tight BP control (< 150/85 mmHg) Less tight control (< 180/105 mmHg)

Achieved BP 144/82 mmHg and 154/87 mmHg Tight BP control reduced risk: Stroke – 44% Deaths related to diabetes – 32% Heart failure – 56% Deterioration in retinopathy – 34%

UKPDS 38Lowering BP reduces adverse outcomes

UK Prospective Diabetes Study Group, BMJ, 1998, pg 703.

19,193 patients with DBP 100-115mmHg Targeted BP <90mmHg, <85mmHg, <80mmHg Achieved 144/85, 141/83, 140/81 No difference Major cardiovascular events Stroke Mortality (cardiovascular or all-cause)

Target <80mmHg: Decreased MI

HOT study

Hansson L, Lancet, 1998, p1755.

BP target studies in CKD MDRD AASK

ACCORD

What about intense lowering?

Usual BP – MAP 107 mmHg (140/90) Low BP – MAP 92 mmHg (125/75) Study 1 – 585 subjects GFR 25 to 55 Mean decline in GFR (ml/min/3yrs)

12.3 in usual vs. 10.8 in low BP target (P = 0.18)

Study 2 – 255 subjects GFR 13 to 24 Mean decline in GFR (ml/min/yr)

4.2 in usual vs. 3.7 in low BP target (P = 0.28)

Lowering BP doesn’t slow progression of CKD – MDRD

Klahr S, NEJM, 1994, pg 877.

d

Klahr S, NEJM, 1994, pg 877.

Effect of low BP target depends on baseline level of proteinuria

n = 32n = 63n = 136n = 54n = 104n = 420

● Low BP target● Usual BP target

●●

●

●

● ●

MDRD – long term outcomes

Sarnak MJ, Ann Int Med, 2005, pg 342.

Kidney failure Kidney failure or all-cause mortality

0 24 48 72 96 120Follow-up, mo

0 24 48 72 96 120 144Follow-up, mo

Usual BP Usual BP

Low BP Low BP

African American, non-DM, GFR 20-65 Randomized

Usual MAP (102 to 107 mmHg) Low MAP (92 mmHg)

Achieved BP 141/85 vs. 128/78 GFR decline (ml/min/1.73m2/yr)

Usual: 1.95 Low: 2.21 (P = 0.24)

No difference in 50% decline GFR, death, ESRD or composite

Lowering BP doesn’t slow progression of CKD – AASK

Wright JT Jr, JAMA, 2002, pg 2421.

AASK – Doubling of Cr, ESRD or DeathAccording to Baseline Proteinuria Status

Appel LJ, NEJM, 2010, pg 918.

4,733 participants with type 2 DM SBP target <120mmHg vs. <140mmHg Achieved SBP 119mmHg vs. 134mmHg

ACCORD, NEJM, 2010, p1575.

Outcome Intense Standard HR P valuePrimary* 1.87 %/yr 2.09 %/yr 0.88 (0.73-1.06) 0.20Stroke 0.32 %/yr 0.53 %/yr 0.59 (0.39-0.89) 0.01Death 1.28 %/yr 1.19 %/yr 1.07 (0.85-1.35) 0.55eGFR <30 4.2 % 2.2 % <0.001Macroalbuminuria 6.6 % 8.7 % 0.009

* Nonfatal MI, nonfatal stroke, or death from CV causes.

Year Group BP target1973 Task Force I ?1977 JNC (1) DBP <901980 JNC (2) DBP <901984 JNC (3) DBP <901988 JNC (4) < 140/901993 JNC V < 140/901

1997 JNC VI < 140/902

2003 JNC VII < 140/903

From Task Force I to JNC VII

a. Except in those with >1g proteinuriab. Except among diabetics

1967 VA: tx > placebo (DBP 115-129)1970 VA: tx > placebo (DBP 90-114)

1979 HDFP: SC (goal <90) > RC

1994 MDRD: 125/75 = 140/90a

1996 SHEP: active (goal <160) > placebo

1998 UKPDS: 150/85 > 180/1051998 HOT: no difference DBP 90, 85, 80b

2002 AASK: 125/75 = 140/90

1. Consider <130/852. <130/85 in CKD, <125/75 with >1g proteinuria/day; <130/85 in diabetics3. <130/80 in diabetics and those with renal disease

2005 MDRD: long-term follow up2010 AASK: proteinuria subgroup2010 ACCORD: SBP 120 = 140

What will they be: < 140/90 mmHg Diabetes: < 130/80 mmHg CKD: < 140/90 mmHg

Significant proteinuria: < 125/75 mmHg

What should they be: < 150/90 mmHg (B) Diabetes: < 150/85 mmHg (B/C) CKD: < 140/90 mmHg (C)

Significant proteinuria: < 125/75 mmHg (B/C)

JNC 8 BP Targets

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

* ALLHAT investigators

**

**

33,357 participants Chlorthalidone vs. amlodipine vs. lisinopril (vs. terazosin) SBP during f/u: chlorthal < amlodipine ≤ lisinopril Primary outcome – fatal CHD or non-fatal MI

Chlorthalidone = amlodipine = lisinopril Secondary outcomes

Heart failure reduced with chlorthal vs. amlodipine/lisinopril Stroke, combined CVD, HF, coronary revascularization

reduced with chlorthalidone vs. lisinopril Greater benefit to chlorthalidone in blacks vs. non-blacks

ALLHAT

ALLHAT, JAMA, 2002, p2981.

11,506 participants Benazepril-amlodipine vs. benazepril-HCTZ Achieved SBP 131.6 vs. 132.5 (P<0.001) Primary outcome – death from CV causes, nonfatal

MI, nonfatal stroke, angina, resuscitation from cardiac arrest, coronary revascularization 9.6% vs. 11.8% (HR 0.80 (0.72 to 0.90))

ACCOMPLISH

Jamerson K, NEJM, 2008, p2417.

First-line drugs for hypertension2009 Cochrane Review

Drug All-cause mortalityCardiovascular

eventsThiazides 0.89 (0.83, 0.96) 0.70 (0.66, 0.76)

Low-dose thiazide 0.89 (0.82, 0.97) 0.70 (0.64, 0.76)High-dose thiazide 0.90 (0.76, 1.05) 0.72 (0.63, 0.82)

Beta-blocker 0.96 (0.86, 1.07) 0.89 (0.81, 0.98)ACEI 0.83 (0.72, 0.95) 0.76 (0.67, 0.85)CCB 0.86 (0.68, 1.09) 0.71 (0.57, 0.87)

Wright JM, Cochrane, 2009.

Beta-blockers in the treatment of hypertension Compared to: Diuretics ACEI ARB CCB

Outcomes All-cause mortality Major cardiovascular events

Beta-blockers for hypertension2012 Cochrane Review

Wiysonge CS, Cochrane, 2012.

Outcome Comparator HR (95% CI)All-cause mortality Placebo 0.99 (0.88, 1.11)

Diuretic 1.04 (0.91, 1.19)CCB 1.07 (1.00, 1.14)RAS inhibitor 1.10 (0.98, 1.24)

Cardiovascular disease Placebo 0.88 (0.79, 0.97)Diuretic 1.13 (0.99, 1.28)CCB 1.18 (1.08, 1.29)ACEI 0.81 (0.63, 1.04)ARB 1.16 (1.04, 1.30)ACEI/ARB 1.00 (0.72, 1.38)

Beta-blockers for hypertension2012 Cochrane Review

Wiysonge CS, Cochrane, 2012.

Assuming absence of “compelling indications” Most classes of antihypertensive medications are

appropriate Blacks – consider diuretics Beta-blockers may not be appropriate, especially in

the elderly

JNC 8 – Initial treatment

Age modifies beta-blocker effect

Bangalore S, JACC, 2008, p1062.

OutcomeNo.

studiesBBn/N

Comparisonn/N

RR(95% CI) P value RR (95% CI)

HeterogeneityChi2 P value

ELDERLY (>= 60 y)

Death 6 3429/43709 3304/43501 1.03 (0.99-1.08) 0.146 7.46 0.281

CV Death 6 1707/43709 1619/43501 1.05 (0.98-1.12) 0.145 12.90 0.053

MI 6 1469/43709 1425/43501 1.03 (0.96-1.10) 0.459 12.09 0.063

Stroke 6 1608/43709 1346/43501 1.19 (1.11-1.28) <0.0001 10.39 0.109

YOUNG (<60 y)

Death 3 345/9148 360/9164 0.98 (0.85-1.13) 0.745 0.80 0.669

CV Death 3 176/9148 169/9164 1.06 (0.86-1.31) 0.567 4.26 0.119

MI 3 341/9148 341/9164 1.01 (0.88-1.17) 0.846 1.52 0.402

Stroke 3 198/9148 255/9164 0.78 (0.65-0.94) 0.009 0.23 0.893

0.75 1 1.25BB better BB worse

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

Traditionally clinic based Alternative/newer measures Home Ambulatory

Central blood pressure Pulse wave velocity

Measurement of BP

Clinic and home BP to categorize patients Normotensive White-coat hypertension Masked hypertension Sustained hypertension

Increased risk for events with masked and sustained hypertension

White-coat at increased risk for development of sustained hypertension

White-coat and Masked Hypertension

Bobrie G, JAMA 2004.Fagard RH, J Htn 2007.

Adjusted HR for CV events1.18 (0.67 – 2.10)2.06 (1.22 – 3.47)1.96 (1.27 – 3.02)

Ambulatory Blood Pressure Monitoring (ABPM)

10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10Time (h)

Sleep Wakening

Meta-analysis Hypertensive population (n = 23,856) General population (n = 9,641)

Evaluated predictive ability of daytime BP, nighttime BP, night-to-day BP ratio, and nondipping Total mortality Cardiovascular events

Nighttime BP Predicts Cardiovascular disease

Hansen TW, Hypertension, 2011, pg 3.

Ambulatory BP and CV diseaseHypertensive patients

Hansen TW, Hypertension, 2011, pg 3.

AdjustedTotal mortalityNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Cardiovascular eventsNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Fully AdjustedTotal mortalityNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Cardiovascular eventsNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Ambulatory BP and CV diseasePopulation based cohorts

Hansen TW, Hypertension, 2011, pg 3.

AdjustedTotal mortalityNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Cardiovascular eventsNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Fully AdjustedTotal mortalityNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

Cardiovascular eventsNighttime (+ 10 mmHg)Daytime (+ 10 mmHg)Night-to-day ratio (+ 0.1)Nondipping (0, 1)

32 patients with CKD (eGFR < 90) Night/day ABP > 0.9 (nondippers) Normal daytime ABP (< 135/85) At least 1 antihypertensive in AM

Shifted ≥1 antihypertensive to the evening ABPM at baseline and 8 weeks Nighttime SBP decreased

114 to 107 (P < 0.001) Dipping restored in 87.5% No change in daytime or 24hr SBP/DBP

Nighttime BP is modifiable in patients with CKD

Minutolo R, AJKD, 2007, pg 908.

MAPEC study – 2156 subjects Randomized All antihypertensives in morning ≥ 1 antihypertensive in evening

48hr ABPM at baseline and annually

Chronotherapy – purposeful timing of medications throughout the day

Hermida RC, Chronobiology Int, 2010, pg 1629.

PM dosing (at final evaluation) Lower sleep SBP (111 vs. 116, P < 0.001) Increased dippers (66% vs 38%, P < 0.001) Lower 48hr SBP (120.8 vs 122.1, P = 0.029)

Primary outcome (CVD morbidity and mortality) HR 0.39 (0.29 to 0.51, P < 0.001)

Major CV events HR 0.33 (0.19 to 0.55, P < 0.001)

Decreased deaths (12 vs 28, P = 0.008)

MAPEC Study – results

Hermida RC, Chronobiology Int, 2010, pg 1629.

Treatment of hypertension lowers: Clinic BP more than ambulatory BP Nighttime BP more than daytime BP

For every 10mmHg decrease in clinic SBP 24hr Ambulatory SBP decreases 4.2mmHg Nighttime SBP decreases 3.3mmHg

Clinic vs. nighttime BPExplanation for negative “target” BP study results?

Mancia G, 2004, J HTN, p435.

Ambulatory Blood Pressure Monitoring Evaluate white-coat hypertension Further research necessary

Treat masked hypertension? Target ambulatory/nighttime BP?

JNC 8 – ABPM

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

Copyright © The American College of Cardiology. All rights reserved.

Renal Sympathetic Nervous System

J Am Coll Cardiol Intv. 2012;5(3):249-258. doi:10.1016/j.jcin.2011.12.011

The Renal SNSNTS = solitary tract nucleusPVN = paraventricular nucleusRVLM = rostral ventrolateral medulla.

Figure Legend:

Proof of principal study Resistant hypertension Catheter based renal sympathetic denervation Follow up for 1 year

Renal nerve ablation

Krum H, Lancet 2009.Krum H, Circ 2011.

Renal nerve ablation lowers BP

Krum H, Lancet 2009.

Renal nerve ablation lowers BP in CKD

Hering D et al. JASN doi:10.1681/ASN.2011111062

©2012 by American Society of Nephrology

History: JNC 1 through 7 What to expect Target BP Initial treatment Ambulatory blood pressure monitoring

Novel new treatment

Outline

Thank you.

Cleveland VAMC 1085 subjects with hypertension

Nighttime SBP measured on the day of or day before discharge

Adjusted HR for 10mmHg increase in nighttime SBP: 1.12 (1.03 to 1.23) – Death/ESRD/50% decline 1.26 (1.08 to 1.47) – 50% decline in GFR 1.30 (0.94 to 1.80) – ESRD

Hospital nighttime BP predicts adverse outcomes

Drawz PE, Ren Fail, 2010.

Lowering nighttime BP associated with decreased urinary protein excretion 32 CKD subjects – 1 antihypertensive at night

24hr protein excretion 235 to 167mg (P < 0.001) Nondippers (valsartan in AM vs PM)

Albuminuria lowered (vs baseline) by PM dosing only 200 untreated, non-proteinuric hypertensives

Valsartan 160mg in AM vs PM UAE lower with PM dosing (25 vs 17 mg/d, P = 0.014)

Lowering nighttime BP reduces proteinuria

Hermida RC, J Htn, 2005, p1913.Hermida RC, HTN, 2005, p960.Minutolo R, AJKD, 2007, p908.