ba md wed 03 0805 saseen hypertension - cleveland … controlled if treated guidelines for...

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Hypertension Pharmacotherapy

Joseph Saseen, Pharm.D., FCCP, BCPSProfessor

University of ColoradoAnschutz Medical Campus

School of Pharmacy and Medicine

American Heart Association (AHA)Heart Disease and Stroke Statistics—2011 Update

82.6 Million Americans have Cardiovascular Disease

Rogers VL, et al. Circulation. 2011;123.* Total cholesterol ≥240 mg/dL

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National Health and Nutrition Examination Survey (NHANES) in the U.S.

Hypertension 2007;49:69-75. JAMA 2010;303:2043-2050.

72.3% Controlled if Treated

Guidelines for Hypertension

● 2003 - The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

● 2007 - American Heart Association Scientific Statement (AHA)

● 2011 - American Heart Association Scientific Statement (AHA)

JNC 8 (to be release in 2012)

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Guidelines for Hypertension

http://www.nhlbi.nih.gov/guidelines/cvd_adult/background.htm

JNC7: Blood Pressure Classification

Hypertension 2003;42:1206–1252

Blood Pressure Classification

Systolic BP

(mm Hg)

Diastolic BP

(mm Hg)Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 hypertension

140-159 or 90-99

Stage 2 hypertension

≥160 or ≥100

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Polling Question…

● Lower is better with regard to BP goals, with regard to reducing risk of CV events.

True

False

2003: The 7th Report of the Joint National Committee on Prevention, Detection,

Evaluation, and Treatment of High Blood Pressure (JNC7)

Primary Goal: CV morbidity & mortality

Blood Pressure Goals:

● <140/90 mm Hg for most patients

● <130/80 mm Hg for Diabetes or Chronic Kidney Disease

Hypertension 2003;42:1206–1252.

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2007 AHA Scientific Statement:Treatment of Hypertension in the

Prevention and Management of Ischemic Heart Disease

Circulation. 2007;115:2761-2788.

CAD, coronary artery disease

● High CAD defined by AHA as:– diabetes,

– chronic kidney disease,

– CAD equivalent (carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm), or

– 10-year Framingham risk score ≥10%

AHA: Evidence-Base for BP GoalsBoth < 140/90 or <130/80 mm Hg

● Classification of Recommendation: IIa–Weight of evidence/opinion is in favor of

usefulness/efficacy

● Level of Evidence: B–Data derived from a single randomized trial or

nonrandomized studies

Circulation. 2007;115:2761-2788.

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Current Controversy: BP Goals lower than < 140/90 mm Hg

● A 2009 Cochrane analysis:– 7 trials (22,089 subjects)

comparing different diastolic BP targets were included

– Did not demonstrate that more aggressive lowering of BP reduced mortality or morbidity better than the standard < 140/90 mm Hg

Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD004349.

JAMA 2009:302(10): 1047-1048.

Systolic Blood Pressure Intervention Trial (SPRINT)

Sponsored by National Heart, Lung, and Blood Institute (NHLBI)

● Two-arm, multicenter, randomized clinical trial:– Intensive Control: SBP <120 mm Hg

– Standard BP: SBP <140 mm Hg

● 9250 patient with hypertension, ≥ 55 yrs, and at least one additional CV risk factor followed for 4-6 years

● Patients with serious comorbidities are excluded (eg, diabetes, prior stroke, left ventricular dysfunction)

● Primary outcome: First occurrence of MI, acute coronary syndrome, stroke, heart failure, or CVD death

● Anticipated completion in December 2018http://www.clinicaltrials.gov/ct2/show/NCT01206062?term=sprint&rank=2

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AHA/ACCF Guideline: 2011 UpdateSecondary Prevention and Risk Reduction

Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease

● Blood pressure control–Goal: 140/90 mm Hg

–Patients with blood pressure ≥140/90 mm Hg should be treated, as tolerated, with blood pressure medication, treating initially with beta-blockers and/or ACE inhibitors, with addition of other drugs as needed to achieve goal blood pressure.(Level of Evidence: A)

Circulation. 2011;124:2458-2473

Is Lower Better in CKD:<130/80 mm Hg vs. <140/90 mm Hg

● Systematic Review; 3 trials (MDRD, AASK, REIN-2) with 2272 participants

● Trials did not show that a lower BP target of <125/75 to 130/80 mm Hg is more beneficial than a target of less than 140/90 mm Hg

● Lower-quality evidence suggested that a low target may be beneficial in subgroups with proteinuria greater than 300 to 1000 mg/day

Upadhyay A, et al. Ann Intern Med; published online March 14, 2011

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Reflective Question…

A BP goal of <130/80 mm Hg is recommended in patients with diabetes. Is this an evidence

based recommendation?

Hypertension Optimal Treatment (HOT) Trial: Major Cardiovascular Events at 4 yrs

All Patients n=18,790; p=NS

Lancet. 1998;351:1755-1762.

Patients with Diabetesn=1501; p=0.005

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The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial

● Randomized, open-label, multi-center trial

● Intensive (SBP <120 mm Hg) vs. standard (SBP < 140 mm Hg) BP lowering

● 4733 patients with hypertension and:–Stable type 2 diabetes and high CVD risk

–40-79 years if established clinical CVD, or 55-79 years if ≥ 2 CV risks or subclinical CVD

● Primary Outcome: nonfatal MI, nonfatal stroke or CV death

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

ACCORD-BP

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

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ACCORD-BP: Results

Intensive Events (%/yr)

StandardEvents (%/yr) HR (95% CI) P

Primary Outcome 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

Pre-specified Secondary Outcomes

Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55

CV Death 60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25

Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03

Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

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

ACCORD-BP: Adverse EventsIntensive

N (%)Standard

N (%)P

Serious Adverse Events 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

eGFR ever <30 mL/min/1.73m2 99 (4.2) 52 (2.2) <0.001

Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93

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

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JNC 7 Algorithm

Drug(s) for the compelling indications

Other drugs (diuretics, ACEI,

ARB, BB, CCB) as needed.

Stage 1 HypertensionThiazide-type

diuretics for most. May consider

ACEI, ARB, BB, CCB,

or combination.

Stage 2 Hypertension

2-drug combination for most (usually

thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Initial Drug Choices

With Compelling Indications

Without Compelling Indications

Hypertension 2003;42:1206–1252.

AHA Scientific Statement

Circulation. 2007;115:2761-2788.

AreaSpecific Drug Indications

General CAD Prevention

Monotherapy or combination therapy:

● ACEI (or ARB),

● CCB,

● or thiazide diuretic first-lineHigh CAD risk1

CAD2 Beta-blocker with ACEI or ARB

LVDACEI or ARB and beta-blocker and aldosterone antagonist and diuretic

CAD, coronary artery disease; LVD, left ventricular dysfunction (aka. systolic heart failure)

1= diabetes, chronic kidney disease, CAD equivalent (carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm), or 10-year Framingham risk score ≥10%

2= stable angina, unstable angina/NSTEMI, or STEMI

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Polling Question…

● The reason that beta-blockers are no longer first-line for most patients with hypertension is because they cause too many side effects (e.g., erectile dysfunction, fatigue).

True

False

A Cochrane Collaboration (2007):Beta-Blockers for Hypertension

● 13 randomized trials in 91,561 patients

Atenolol used 75% of the time

CochraneDatabase of Systematic Reviews 2007, Issue 1. Art.No.:CD002003.

Beta-blocker vs.

Relative Risk (95% CI)

CV Disease Stroke Death

Placebo0.88*

(0.79-0.97)

0.80* (0.66–0.96)

0.99 (0.88-1.11)

Thiazide1.13

(0.99-1.13)

1.17 (0.65–2.09)

1.04 (0.91-1.19)

ACEI/ARB1.00

(0.72-1.38)

1.30*(1.11-1.53)

1.10 (0.98-1.24)

CCB1.18*

(1.08-1.29)

1.24*(1.11-1.40)

1.07(1.00-1.14)

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Comparison of Beta-BlockersDaily

Frequencyt½ (hr) Lipid

SolubilityCardio-

selectivityAlpha

Blockade

Atenolol (generic)

1-2 6-7 Low Yes No

Metoprolol Tartrate

2 3-7

Moderate to High

Yes NoMetoprolol

Succinate (Toprol XL®)

1 n/a

Carvedilol (Coreg®)

2 6-10High No Yes

Carvedilol (Coreg® CR)

1 n/a

Beta-Blocker After MI

● Systematic review of 82 randomized controlled trials, that evaluated mortality

● Long term use:–23% mortality reduction (RR 0.77; 69-0.85)

However: “Most evidence was for propranolol, timolol, metoprolol, whereas atenolol, which is commonly used, is inadequately evaluated for

long term use”

BMJ 1999;318:1730-1737.

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Antihypertensive Pharmacotherapy

● Traditional First-Line Agents– Angiotensin Converting

Enzyme Inhibitor (ACEi)

– Angiotensin Receptor Blocker (ARB)

– Beta-Blocker

– Calcium Channel Blocker (CCB)

– Diuretic (typically a thiazide)

● Alternative Agents– Aldosterone Antagonist (e.g.,

spironolactone)

– Alpha Antagonist (i.e., terazosin)

– Centrally Acting Alpha Agonist (i.e., clonidine)

– Direct Arterial Vasodilator (i.e., hydralazine)

– Direct Renin Inhibitor (i.e., aliskiren)

– Loop Diuretic

– Rauwolfia Alkaloid (i.e., reserpine)

ANGIOTENSIN II

ANGIOTENSINOGEN

ANGIOTENSIN I

Vasoconstriction Aldosterone

synthesis

Sodium/Water Reabsorption

Blood Pressure

Glomerulus

Juxtaglomerular Cells

Efferent Arteriole

Afferent Arteriole

Nep

hro

n

SympatheticNerves

MaculaDensa

Renin

Converting Enzyme

AdrenalCortex

Kidney Intestine CNS Peripheral Nervous System Vascular Smooth Muscle

Heart

Contractility

Cardiac Output

Total Peripheral Resistance

Vasopressin

Sympathetic Discharge

BloodVolume

Renin Secretion

Macula densa signal Renal artery pressure/blood flow

Sympathetic stimulation

DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill Companies, Inc; 2008.

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Diuretics● Thiazide-type preferred

● Very inexpensive

● Long-term effects from decreasing peripheral vascular resistance

● Dose-dependent metabolic side effect (e.g., hypokalemia, hyperglycemia)

● Potassium sparing drugs minimize hyopkalemia but do not enhance BP lowering

Beta-Blockers

● Cardioselective agents are preferred

● Most are generic

● Decrease contractility, decrease heart rate, decrease adrenergic stimulation to lower BP

● Dose-dependent side effects (e.g., exercise intolerance, fatigue, heart block)

● Little to no role for ISA type beta-blockers

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ACE Inhibitors

● Generic and inexpensive

● All available in fixed-dose combinations with HCTZ

● Slightly less effective in African Americans when used as monotherapy

● Most side effect (e.g., cough, angioedema) are not dose dependent

● Contraindicated in:

–Pregnancy, bilateral renal artery stenosis, history of angioedema,

ARBs

● Losartan is the only generic (valsartan, irbesartan in 2012)

● All available in fixed-dose combinations with HCTZ, some in three-drug combinations with amlodipine and HCTZ

● Slightly less effective in African Americans when used as monotherapy

● Fewest side effects of all major antihypertensive classes

● Contraindicated in:

– Pregnancy, bilateral renal artery stenosis

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Calcium Channel BlockersDihydropyridines

– Amlodipine

– Felodipine

– Nifedipine

● Potent vasodilators

● Most common CCBs used in hypertension

● Dose dependent side effects (e.g., peripheral edema)

● Most are generic

Non-Dihydropyridines– Diltiazem

– Verapamil

● Moderate vasodilators that lower heart rate

● Dose dependent side effects (e.g., brady-cardia, constipation)

● Most are generic and extended release formulations

Combination Regimens

● Mean # of antihypertensive agents needed:–≥ 2 if goal BP is < 140/90 mm Hg

–≥ 3 if goal BP is < 130/80 mm Hg

● A diuretic is usually additive with other agents

● Many fixed-dose combinations:– Traditional: thiazide/ACEI, thiazide/ARB,

thiazide /beta-blocker, CCB/ACEI

– Newer: ARB/CCB, ARB/CCB/thiazide

● Fixed-dose combinations may decrease pill burden and costs

DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill Companies, Inc; 2008.

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Compliance, Safety, and Effectiveness of Fixed-Dose Combinations of Antihypertensive Agents

● Meta-analysis of 15 studies (n=32,331):

Fixed-Dose vs. Free Drug Combinations

P-value

Compliance 21% higher with fixed-dose 0.02

Persistence with therapy

54% better with fixed-dose (trend) 0.08

Hypertension. 2010;55:399-407.

New Antihypertensive Drugs:Fixed Dose Combination Products

Two-Drug Combinations ● Telmisartan + Amlodipine

(Twynsta)

● Amlodipine + Valsartan (Exforge)

● Amlodipine + Olmesartan (AZOR)

● Aliskiren + HCTZ (Tekturna HCT)

● Aliskiren + Amlodipine (Tekamlo)

● Aliskiren + Valsartan (Valturna)

● Azilsartan + Chlorthalidone (Edarbychlor)

Three-Drug Combinations● Amlodipine + Valsartan +

HCTZ (Exforge HCT)

● Amlodipine + Olmesartan + HCTZ (Tribenzor)

● Aliskiren + Amlodipine + HCTZ (Amturnide)

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New Evidenceand

Clinical Controversies

Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic

Hypertension (ACCOMPLISH) trial

● Randomized, double-blind, controlled trial

● 11,506 patients with hypertension and:–Age ≥ 60 years; 55-59 years eligible if ≥ 2 CV

diseases or target organ damage

–SBP ≥ 160 mm Hg or on BP medication

–Evidence of CV disease, kidney disease, or target organ damage

● 1° endpoint: CV morbidity or mortality

N Engl J Med 2008;359:2417-28.

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ACCOMPLISH Study DesignRandomization

Amlodipine/Benazepril 5/20 mg

Benazepril/HCTZ 20/12.5 mg


Benazepril/HCTZ 40/12.5 mg


Benazepril/HCTZ 40/25 mg

ForcedTitration

Free add-on other agentsN Engl J Med 2008;359:2417-28.

ACCOMPLISH: Results

● Study terminated early after a mean of 3 years

● BP Lowering:

Benazepril/ Amlodipine

Benazepril/ HCTZ

BP “control”(<140/90 mm Hg)

75.4% 72.4%

Mean BP* (mm Hg)

131.6/73.3 132.5/74.4

N Engl J Med 2008;359:2417-28.40

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ACCOMPLISH: Primary Endpoint Results

(n=7,640)P=0.004

N Engl J Med 2008;359:2417-28.

(n=11,506)P<0.001

(n=4,560)P=0.002

Polling Question

Is it proven that high adherence with antihypertensive medications reduces risk of CV events compared with low adherence?

Yes

No

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Adherence and CV Events● 18,806 newly diagnosed hypertensive patients ≥

35 yrs. of age (mean age 62 yrs.)

● Adherence categorized by dispensing count

Circulation. 2009;120:1598-1605.

Adherence and CV Events

● Association with First Acute CV Event

Multivariate analysis adjusted for age, gender, use of antithrombotics, 5 concurrent medications, presence of diabetes mellitus,

dyslipidemia, prior hospitalization, and weighted by the inverse estimated propensity scores. Time-dependent covariates included adherence to AHT, use of combination AHT, antithrombotics, 5 concurrent medications, presence of peripheral vascular diseases, diabetes mellitus, and dyslipidemia.

Circulation. 2009;120:1598-1605.

AdherenceHazard Ratio

(95% CI) P-value

Low 1.00 -

Intermediate0.86

(0.71-1.03)0.11

High0.62

(0.40-0.96)0.03

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How are an ACE inhibitor, ARB, and direct renin

inhibitor (DRI) different from each other?

Vascular Resistance

Renin

Angiotensin II AT1 receptor

Angiotensinogen

Angiotensin I

Aldosterone synthesis

SodiumRetention

Nitric Oxide

Bradykinin

Inactive Products

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Ongoing Telmisartan Alone and in Combination With Ramipril (ONTARGET)

● 25,620 patients

● Randomized, double-blind trial

● Combination vs. ramipril:– Hypotension:

• 4.8 vs. 1.7% (p<0.001)

– Renal dysfunction:• 13.5 vs. 10.2%

(p<0.001)

P=ns

N Engl J Med. 2008;358:1547-1559.

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December 20, 2011: Novartis announces termination of the ALTITUDE study

● Study overview:–Patients with type 2 diabetes & renal

impairment randomized, double-blind, to aliskiren or placebo added to standard of care treatment (ACE inhibitor or ARB)

● Trial terminated based on independent data monitoring committee recommendation–Increased incidence of non-fatal stroke, renal

complications, hyperkalemia and hypotension in the aliskiren trial arm after 18-24 months.

www.Novartis.com

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Polling Question…Which of the following doses of hydrochlorothiazide is the most appropriate to use in patients with hypertension?

12.5 mg daily

25 mg daily

50 mg daily

Antihypertensive Efficacy of Hydrochlorothiazide as Evaluated by

Ambulatory Blood Pressure Monitoring

● Evaluated the antihypertensive efficacy of hydrochlorothiazide (HCTZ) by 24-hour ambulatory BP monitoring (ABPM)

● Meta-analysis of randomized trials

● Trials included:–14 studies of HCTZ 12.5 to 25 mg daily (n=1,234)

–5 studies of HCTZ 50 mg daily (n=229)

J Am Coll Cardiol 2011;57:590–600.

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Comparative 24-hr ABPM Efficacy


Compared with HCTZ dose 12.5 to 25 mg, p<0.001 for other antihypertensive drugs

Dose Response with HCTZ


p<0.0001 for 50 mg versus 12.5 or 25 mg on SBP (p=NS for all other comparisons)

4 Studies(n=129)

9 Studies(n=503)

5 Studies(n=123)

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Polling Question…

● Hydrochlorothiazide and chlorthalidone are equally effective in the treatment of hypertension.

True

False

A Tale of Two Thiazides

Chlorthalidone Hydrochlorothiazide● Thiazide-like diuretic

● Not frequently used in U.S.

● Used in all the major landmark clinical trials

● 50-60 hr half life

● Undisputed BP lowering efficacy; twice as potent as HCTZ in 24-hr BP lowering

● Preferred over HCTZ in resistant hypertension

● Thiazide-type diuretic

● Frequently used in the U.S.

● Not used in most major landmark clinical trials

● 9-10 hr half life

● Questionable 24-hr BP lowering efficacy with 12.5 to 25 mg

● Easily available in most fixed dose combination products

N Engl J Med 2009;361:2153-64. J Am Coll Cardiol 2011;57:590–600.

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Chlorthalidone vs. HCTZ: CV Events

● Retrospective observational cohort study from the Multiple Risk Factor Intervention Trial

● 12,866 primary prevention men 35-57 yrs; initial therapy with chlorthalidone (n=2392) or HCTZ (n=4049) started at 50 or 100 mg daily

Hypertension 2011;57:689-694.

CV EventsAdjust HR (95% CI) P-value

Chlorthalidone 0.51 (0.43-0.61) <0.0001

HCTZ 0.64 (0.55-0.75) <0.0001

Chlorthalidone vs. HCTZ 0.79 (0.68-0.92) 0.0016

Resistant Hypertension

● Defined as:– Not at goal BP on 3 or more agents

– Patient requiring 4 or more agents, even if at goal BP

● Treatment Strategies:– Rule out secondary causes and non-adherence

– Assure appropriate diuretic therapy• Preferentially use chlorthalidone instead of

hydrochlorothiazide

• An aldosterone antagonist (e.g., spironolactone) as add-on therapy is highly effective

• Consider a loop diuretic if CrCl < 30 mL/min

– Optimize combinations, prudently use alternate agents

Calhoun DA, et al. Circulation. 2008;117:e510-526

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Antihypertensive Use in Patients with Resistant Hypertension Prescribed 4 or

More Agents

● 140,126 patients hypertension on ≥4 antihypertensive agents between May 1, 2008 and June 30, 2009

Hypertension. 2011;58:1008-1013


Should hypertension be treated differently in very

elderly patients ( 80 years)?

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Circulation 2011, 123:2434-2506

Principles of Hypertension Treatment•Target SBP ≤140 mm Hg in patients aged 55-79•Target SBP ≤140 mm Hg in patients aged ≥80+•Achieved values <140 mm Hg for those aged ≤79 are appropriate;•But for those aged ≥80, 140 to 145 mm Hg, if tolerated, can be acceptable

Lifestyle Modifications

Not at Target Blood Pressure

Initial Drug Choices

Without Compelling Indication With Compelling Indication

Not at Target Blood Pressure

Optimize dosages or add additional drugs until goal BP is achieved. Refer to a clinical hypertension specialist if unable to achieve control.

Compelling Indication•Heart Failure

•Post myocardial infarction•CAD or High CVD risk

•Angina Pectoris•Aortopathy/Aortic Aneurysm

•Diabetes•Chronic Kidney Disease

•Recurrent Stroke Prevention•Early Dementia

Initial Therapy Options*•Thiaz, BB, ACEI, ARB, CCB,

Aldo Ant.•BB, ACEI, Aldo Ant, ARB

•Thiaz, BB, ACEi, CCB•BB, CCB

•BB, ARB, ACEi, Thiaz, CCB•ACEi, ARB, CCB, Thiaz, BB

•ACEI, ARB•Thiaz, ACEi, ARB, CCB•Blood Pressure control*Combination Therapy

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Initiation of Antihypertensive Drug Therapy in the Elderly

● Initial drug should be started at the lowest dose and gradually increased, depending on BP response, to the maximum tolerated dose– If BP response is inadequate after reaching “full dose”,

add a second drug from another class

– If response is inadequate after reaching “full doses” of 2 drugs, add a third drug from another class

● When BP is 20/10 mm Hg above goal, therapy should be initiated with 2 drugs. However, treatment must be individualized.– Orthostatic hypotension (SBP decrease of > 20 mm Hg

after 3 minutes of standing) may occurCirculation 2011, 123:2434-2506

Hypertension in the Very Elderly Trial (HYVET)

● 3845 patients age 80 years or older with hypertension

● Randomized, double-blind, to:– Placebo or

– Perindopril +/-Indapamide

● Trial stopped early after 1.8 years

P=0.06 P=0.02

N Engl J Med 2008;358:1887-98.

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70

80

90

100

110

120

130

140

150

160

170

180

0 1 2 3 4 5

Blo

od P

ress

ure

(m

mH

g)

Follow-up (years)

Placebo

Indapamide SR +/-perindopril

15 mmHg

6 mmHg

N Engl J Med 2008;358:1887-98.

Target BP = 150/80 mm Hg

HYVET – Results

BP goals in Patients ≥ 80yrs

● Data suggest SBP of 150 mm Hg as the diagnostic criterion for hypertension and the treatment target

● When SBP <150 mm Hg is readily and safely obtained with 1 or 2 drugs, further treatment intensification to <140 mm Hg could be considered

● The lowest safely achieved SBP ≥150 mm Hg is acceptable for patients under 3 circumstances:1) despite taking a regimen of 4 well-selected and appropriately

dosed drugs, goal has not been achieved;

2) prescribed therapy is causing unacceptable side effects

3) in attempting to reach the SBP target, the DBP is being reduced to a potentially dangerous level <65 mm Hg

Circulation 2011, 123:2434-2506

33

BP and outcomes in very old hypertensive CAD patients: an INVEST substudy

(Am J Med. 2010;123:719 –26)

Circulation 2011, 123:2434-2506

Renal Disease and Hypertension

Stage 5CKD

Stage 4 CKDHypertensive

Nephrosclerosis

DiabeticNephropathy

Stage 3 CKD

Micro-albuminuria

Proteinuria(>1 gm/d)

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Effect of Inhibitors of the Renin-Angiotensin System and Other Antihypertensive Drugs

on Renal Outcomes

Systematic review and meta-analysis

● ACEi or ARB vs. other antihypertensive drugs – Doubling serum creat. RR = 0·71 (0·49–1·04)

– ESRD RR = 0·87 (0·75–0·99)

● Placebo-controlled trials of ACEi or ARBs showed greater benefits than comparative trials, but were accompanied by BP reductions

Lancet 2005; 366: 2026–33

Effect of Combination ACEi and ARB for Proteinuria in CKD

● 49 studies including 6181 patients

● The combination of ARB with ACEi further reduced proteinuria more than either alone:–Ratio of means (95% CI) over 5 to 12 months:

• ACEi + ARB vs. ARB 0.75 (0.61 to 0.92)

• ACEi + ARB vs. ACEi 0.82 (0.67 to 1.01)

Ann Intern Med. 2008;148:30-48.

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ACCOMPLISH: Renal Outcomes

● Pre-specified secondary analysis– CKD progression defined as doubling of serum

creatinine or end-stage renal• Benazepril/amlodipine 113 (2·0%)

• Benazepril/HCTZ 215 (3·7%) p<0·0001

● 1093 patients had CKD at baseline:– CV and total mortality higher than in non-CKD

– About half had diabetes; did not influence results

– CKD progression slower in benazepril/amlodipine than benazepril/HCTZ (p=0.001)

Lancet 2010; 375: 1173–81

The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8)

● Staring with evidence models and a set of prioritized critical questions important for clinical practice

● Critical questions are being answered by conducting systematic reviews of the scientific evidence using a rigorous and standardized approached

Status Report on the NHLBI-Sponsored CVD Prevention Guidelines presented in

November 2011 at the AHA Meeting

http://www.nhlbi.nih.gov/guidelines/cvd_adult/background.htm

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Evidence-Based Clinical Practice Guidelines for CVD PreventionEvidence-Based Clinical Practice Guidelines for CVD Prevention

How the Process Has Evolved

Strictly evidence-based

Focus only on randomized controlled trials assessing important health outcomes (no use of intermediate/surrogate measures)

Every included study is rated for quality by two independent reviewers using standardized tools

Evidence statements graded for quality using prespecified criteria

Separate grading for recommendations

Independent methodology team to ensure objectivity of the review

Initial set of recommendations focused on 3 key questions

71


Rationale for the Questions

Interest in assessing the evidence to support 140/90 mm Hg as a treatment threshold or goal

Should the treatment threshold / goal be lower in populations with diabetes, chronic kidney disease, coronary artery disease, stroke, and other co-morbidities or characteristics?

Should the treatment threshold / goal be different in older adults?

Use of different treatment thresholds and goals is confusing

Is there evidence that treatment to lower BP with a particular drug or drug class improves outcomes compared to another?

72

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Question 1

Among adults with hypertension, does initiating antihypertensive pharmacological therapy at specific BP thresholds improve health outcomes?− When to initiate drug treatment?

73


Question 2

Among adults, does treatment with antihypertensive pharmacological therapy to a specified BP goal lead to improvements in health outcomes?− How low should you go?

74

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Question 3

In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes? − How do you get there?

75


Inclusion/Exclusion Criteria

Randomized Controlled Trials

RCTs are subject to less bias and represent the gold standard for determining efficacy and effectiveness1

Search dates: 1966 to present

Minimum one-year follow-up period

Studies with sample sizes less than 100 excluded

1 Institute of Medicine. 2011. Finding What Works In Health Care. Standards For Systematic Reviews. Washington, DC: The National Academies Press.

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Populations Included

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Evidence-Based Clinical Practice Guidelines for CVD Prevention

Articles Screened = 2662

Good = 15

Included = 101

Total Abstracted = 66

Excluded = 2561

(Did not meet prespecified

inclusion criteria)Poor = 35Fair = 51

Question 3: In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative

benefits and harms on specific health outcomes?

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Next Steps

Evidence statements and recommendations (in progress)

Draft report (in progress)

Review of the draft report by:

Other federal agencies (CDC, CMS, AHRQ, HRSA, VA, etc.)

Invited organizations and individuals

Public

Revisions based on comments received

Final report

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Predictions for the JNC 8

● Role of beta-blockers will be second-line or for patients with a compelling indication

● Goal SBP of <140 mm Hg for all, with lower goal on an individual basis

● Address HCTZ vs. chlorthalidone

● ACEI or ARB with CCB might be the preferred first-combination therapy

● Tailored recommendations for the “Very Elderly”

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Pirates of the Caribbean: The Curse of the Black Pearl

● Philosophy of Guidelines

the code is more what you'd call "guidelines" than actual rules

http://www.imdb.com/title/tt0325980/quotes

Conclusions

ba md wed 03 0805 saseen hypertension - cleveland … controlled if treated guidelines for...

Documents