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.

2003

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 <140/90. Mean follow-up 4.9 years.

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

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

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 <140/90 a universal goal for all patients?

Is SBP<120 ideal?

Antihypertensive Therapy in the Elderly

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

NEJM 2008; 358: 1887-98

Benazepril plus HCTZ or amlodipine

ONTARGET
Telmisartan, Ramipril, or both in high risk patients
Composite of CV death, MI, stroke or hospitalization for heart failure.

Journal of Hypertension 2009, 27:13601369

ACCORD BP

NEJM 2010; 362: 1575-85. 4733 pts with type 2 DM at high CV risk. Randomized to SBP <120mmHg or SBP <140mmHg. Primary endpoint: nonfatal MI, nonfatal stroke, or CV death. 4.7 yr mean follow up.

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

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

Event rate in the Standard Rx group was 50% lower than expected

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

Summary of Recent Studies Evaluating Goal BP

2008 HYVET

Low risk > 80y/o: SBP<150 is still beneficial High risk 68.4y/o: SBP<130 no better than <140 High risk 66.4y/o: SBP =130 is optimal

2008 ACCOMPLISH

2009 ONTARGET

2010 ACCORD BP

High risk Diabetics 62.2y/o: SPB<120 no better than <140

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

30
Reduction in SBP (mmHg)

25 20 18 15 10 5 0 3 6 12.5 25 50 3.8 12 6.4 6.5

23 18

24 20

28

100

200

HCTZ

Chlor.

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.

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

Major U.S. Diuretic Trials

VA Cooper (3) PHS trial HDFP MRFIT
EWPHBPE MRC SHEP TOMHS ALLHAT

HCTZ 50-100 mg Chlorothiazide 500-1000 mg Chlorthalidone 50-100 mg HCTZ 50-100mg(BID) or Chlorthalidone 50-100 mg HCTZ 25-50 mg HCTZ 25-50 mg Chlorthalidone 25-50 mg Chlorthalidone 15-30 mg Chlorthalidone 12.5-25 mg

Outcomes in Diuretic Trials

Chlorthalidone

Hydrochlorothiazide

HDFP MRFIT SHEP TOMHS ALLHAT

No comparator proven superior

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)**

**12.5-25 mg HCTZ dosing

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, nonfatal MI, non-fatal stroke, hospitalization for angina, resuscitation after SCA and coronary revascularization. 3 year mean follow up

n engl j med 359;23

n engl j med 359;23

n engl j med 359;23

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

Perspective on ACCOMPLISH
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 Heart failure not included in primary composite Predict ABPM substudy will yield revealing results (e.g. HOPE substudy)

Other important points:

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 diureticbased 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?

ATENOLOL

JACC, 2006;47 (suppl):361A

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 <140/90
* Likely overestimated.

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

No hyperkalemia

Hypertension. 2005;46:481-487

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 preeminent 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.