Session 3B JNC on Hypertension Alan Cementina MD

JNC 8

Update on Hypertension

Guidelines

Alan Cementina, MD

Associate Clinical Professor

Family Medicine Center at Asylum Hill

DISCLOSURE

I have not had nor do I currently have any

financial relationships with the manufacturers of

health care products.

I will not discuss any pharmaceuticals, medical

procedures, or devices that are investigational or

unapproved for their stated use by the FDA.

JNC 8?

JNC Late

JNC Wait

JNC.

Not!

NHLBI adopts new collaborative

partnership model for clinical practice

guidelines development

Gary H. Gibbons, M.D. - June 19, 2013

In June 2012, the NHLBAC recommended that the Institute transition to a

new model in accordance with the best practice standards established by

the IOM, in which the Institute focuses its primary effort on the generation

of high-quality systematic evidentiary reviews and supports the

development of clinical practice guidelines through partnerships with

professional societies and other organizations.

GOALS

Identify Highlights of JNC7.

Understand evidence influencing

recommendations for new BP goals.

Understand evidence influencing the

recommendations for choice of first line

therapy.

Identify concerns about Beta-Blockers.

Be aware of the role of spirinolactone.

Measuring BP

Seated quietly for 5 min in chair.

Feet on floor, arm supported at heart level.

No caffeine, exercise or smoking for 30min.

Cuff bladder encircle at least 80% arm circ.

At least 2 measurements and average.

Measuring BP

Inflate 20-30mmHg above pulse extinction.

Deflate at rate of 2mmHg/sec.

SBP = onset of 1st Karotkoff sound.

DBP = disappearance of Karotkoff sounds.

Study drug

Add on drug

BP achieved

Population

End Points

Psaty B, JAMA, 1997, 277(9)

Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial

JAMA 2002;288:2981-97

33,357 pts age >55 with stage 1-2 HTN and 1

other CHD risk factor.

Randomized, double-blind, active-controlled

clinical trial.

Randomized to amlodipine or lisinopril, v.

chlorthalidone. (doxazosin)

Goal BP

Copyright restrictions may apply.

The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, JAMA 2002;288:2981-2997.

Cumulative Event Rates for All-Cause Mortality, Stroke, Combined Coronary Heart Disease, Combined Cardiovascular Disease, Heart Failure, and Hospitalized Plus Fatal Heart Failure by

Treatment Group

A

L

C

JNC7 Summary

Lowering SBP as close to 120 mmHg as is feasible is the single most important goal.

Traditional agents (thiazide diuretics) are the most cost effective choice for initial Rx.

Few of your patients will be adequately treated using whatever you choose first.

Certain drug classes confer particular benefit for selected patients with specific co-morbid conditions.

JNC7 Summary

ACEI/ARB should be included for patients

with DM.

ACEI/ARB/BB/HCTZ should be included for

patients with CAD.

ACEI/ARB/BB/AA/diuretic should be used

for patients with impaired LV systolic function.

CCB not recommended in HF.

2013

Is a BP

Antihypertensive Therapy in the Elderly

HYVET Hypertension in the Very Elderly Trial

NEJM 2008; 358: 1887-98.

3,485 patients from Europe, China*, Australasia, and Tunisia aged 80 and older with SBP 160 mmHg

Randomized to indapamide SR (Lozol) 1.5 mg vs placebo

After 3 mo, perindopril (Aceon) 2/4 mg could be added

Target BP 150/80 mmHg

Primary endpoint = fatal or nonfatal stroke

* 95% of patients from Eastern Europe or China

NEJM 2008; 358: 1887-98

Benazepril plus HCTZ or amlodipine

Journal of Hypertension 2009, 27:13601369

ONTARGET

Composite of CV

death, MI, stroke or

hospitalization for

heart failure.

Telmisartan, Ramipril, or both in high risk patients

ACCORD BP

NEJM 2010; 362: 1575-85.

4733 pts with type 2 DM at high CV risk.

Randomized to SBP

Am J Cardiol 2007;99[suppl]:44i55i

N Engl J Med 2010;362:1575-85.

N Engl J Med 2010;362:1575-85.

Event rate

in the

Standard

Rx group

was 50%

lower than

expected

Summary of Recent Studies Evaluating

Goal BP

2008 HYVET Low risk > 80y/o: SBP

2013

Are all thiazide diuretics equivalent?

Are they still the best choice for

initial therapy?

Chlorthalidone vs HCTZ Estimated Dosing

Equivalence based on Estimated Equivalent

BP Reduction

6.5

12

20

28

6.4

18

3.8

24

18

23

0

5

10

15

20

25

30

3 6 12.5 25 50 100 200

HCTZ Chlor.

Red

ucti

on

in

SB

P (

mm

Hg

)

Carter BL, Ernst ME, Cohen JD. Hypertension 2004;43:4-9.

50 mg HCTZ ~ 25 to 37.5 mg

chlorthalidone

We conducted a literature search

from 1960 to 2003 to identify

studies that evaluated the

pharmacokinetic and blood

pressurelowering effects of these 2 agents.

Major U.S. Diuretic Trials

VA Cooper (3) HCTZ 50-100 mg

PHS trial Chlorothiazide 500-1000 mg

HDFP Chlorthalidone 50-100 mg

MRFIT HCTZ 50-100mg(BID) or

Chlorthalidone 50-100 mg

EWPHBPE HCTZ 25-50 mg

MRC HCTZ 25-50 mg

SHEP Chlorthalidone 25-50 mg

TOMHS Chlorthalidone 15-30 mg

ALLHAT Chlorthalidone 12.5-25 mg

Outcomes in Diuretic Trials

HDFP

MRFIT

SHEP

TOMHS

ALLHAT

VA II (beat placebo, with help)

MRFIT (lost to chlorthalidone)

EWPHBPE (beat or tied placebo)

HAPPHY (tied b-blockers)

MAPPHY (lost to metoprolol)

MRC-E (beat placebo, atenolol)

MIDAS (tied CCB)

INSIGHT (tied nifedipine)

PATS (beat placebo)

ANBP-2 (lost to, or tied with, enalapril)**

ACCOMPLISH (lost in combo with benazepril to amlodipine/benazepril)**

Chlorthalidone Hydrochlorothiazide

**12.5-25 mg HCTZ

dosing

No comparator proven

superior

ACCOMPLISH

NEJM 2008; 359: 2417-28.

11,506 pts with HTN at high CV risk.

Randomized to benazepril + amlodiopine or benazepril + HCTZ.

Primary endpoint: composite of CV death, non-fatal MI, non-fatal stroke, hospitalization for angina, resuscitation after SCA and coronary revascularization.

3 year mean follow up

n engl j med 359;23

Perspective on ACCOMPLISH A typical drug company study (Novartis)

Selection of an inferior comparator (HCTZ) at suboptimal dose (used the excuse that it is the most commonly prescribed agent and dose)

Comparison is essentially amlodipine vs HCTZ Amlodipine t1/2 = 38-50 hrs

Benazepril t1/2 = 8-12 hrs, trough:peak 0.4 (>0.5 recommended by FDA)

HCTZ t1/2 = 8-15 hrs

Other important points: Heart failure not included in primary composite

Predict ABPM substudy will yield revealing results (e.g. HOPE substudy) Likely that nighttime control better in amlodipine group (only need to see 4-6 mmHg

diff based on epi studies to explain 20% diff in outcome)

Office BP overestimates response to HCTZ (Finkielman Am J Hypertens 2005;18:398-402)

Findings will likely be overemphasized to demote importance of diuretic-based regimens

Ernst ME, Carter BL, Basile JN. All thiazide-like diuretics are not chlorthalidone:

Putting the ACCOMPLISH study into perspective. Journal of Clinical

Hypertension 2009;11:5-10

2013

Are all Beta-Blockers Equivalent?

JACC, 2006;47 (suppl):361A

ATENOLOL

2013

What drug to add in resistant HTN

after ACE/ARB, BB, CB and

Thiazide Diuretic?

Resistant HTN

Failure to reach goal BP taking

at least 3 drugs, one of which is a

diuretic.

JNC 7, 2003

Options for Treatment of Resistant

Hypertension

Identify and treat secondary causes.

Centrally acting alpha agonists.

Direct vasodilators.

Aldosterone antagonists (ENaC).

Renal artery denervation.

The Role of Spironolactone in Resistant HTN

At least 5 studies from 2002 to 2007.

Patient populations poorly characterized.

Differed with respect to both nature and number of baseline therapies.

1 study did not attempt to characterize primary hyperaldosteronism.

All but 1 study were open and not controlled.

None assessed hard clinical endpoints.

Low-dose Spironolactone in

Resistant Hypertension

Lane, et. al., Journal of Hypertension 2007; 25: 891-894.

Open observational study, 25-50mg of spirinolactone added to ACE-I/ARB + (3 drugs)

N = 119, after 11 dropout due to side effects (no trend), 6 mo follow up.

Excluded hyper-aldosterone, renal HTN, CKD, CHF.

21.7 mmHg drop in SBP*

8.5 mmHg drop in DBP*

0.3 mmol/L rise in K+

2 patients with K+ above 6.0 mmol/L

48 (31%) achieved target BP of

Inhibition of Epithelial Sodium

Channel in Blacks with HTN

Saha, et. al., Hypertension 2005; 46: 481-487.

Prospective randomized placebo-controlled

doubled-blind trial.

2-by-2 factorial design: amiloride 10mg,

spironolactone 25mg, both or placebo added to

diuretic and CCB.

N=98, 9 wk follow up, excluded if PRA

elevated.

-4.6mmHg, P=0.006

-1.8mmHg, P=0.07

Hypertension. 2005;46:481-487

No hyperkalemia

JNC 8?

Hypothetical JNC 8

Recommendations

Goal BP likely to be refined (relaxed) for population subgroups,

particularly for those >80 and those with DM.

Chlorthalidone recommended over HCTZ, but pre-eminence as

first line therapy might be challenged.

Reduced role for Beta-Blockers as initial therapy (still pre-

eminent for HFrEF and CAD), particularly atenolol.

Recommendation for low dose aldosterone antagonist as add-on

therapy in resistant HTN.

Introduction of renal artery sympathetic denervation.

? Delineation of role for ambulatory/home BP monitoring.

Documents

Session 3B JNC on Hypertension Alan Cementina MD