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θεραπευτικά διλήμματα

Ευάγγελος Φραγκούλης, MD, MScΓενικός/ Οικογενειακός Ιατρός

Αν. Αρχίατρος ΕΔΟΕΑΠΓεν. Γραμματέας Ελληνικής Ένωσης Γενικής Ιατρικής

Μέλος Δ.Σ. ΕΛΕΓΕΙΑ

28ο Πανελλήνιο Συνέδριο Γενικής Ιατρικής, Ρόδος 2016

Health impact of chronic diseases

Preventing Chronic diseases. A vital investment. WHO 2005

Blood pressure predicts CV mortality

Prospective Studies Collaboration, Lancet 2002

CV benefits of treating HTN

Hebert et al, Archives Int Med 1993

Chronic Diseases can be prevented and controlled

Preventing Chronic diseases. A vital investment. WHO 2005

Awareness, treatment, control…

CDC/NHNS, National Health and Nutrition Examination Survey, 2011-2012

USPSTF Draft Statement, January, 2015:

• “The USPSTF recommends screening for HTN in adults ≥18y old.

• Ambulatory BP monitoring is recommended to confirm high BP before the diagnosis of HTN, except in cases for which immediate initiation of therapy is necessary…

• Good quality evidence suggest that confirmation of hypertension using home BP monitoring may be acceptable…

• More research is needed on the best home BP monitoring protocols for follow-up of elevated office BP measurements…”

www.uspreventiveservicestaskforce.org/page/Document/RecommendationStatementDraft

BP measurement methods

• Office (attended, OBPM)– Oscillometric (electronic) – preferred method– Auscultatory (mercury, aneroid)

• Office Automated (unattended, AOBP) – Oscillometric (electronic)

• Ambulatory blood pressure monitoring (ABPM)

• Home blood pressure monitoring (HBPM)

For information on blood pressure measurement devices:• http://www.dableducational.org/sphygmomanometers.html• http://www.bhsoc.org/bp-monitors/bp-monitors/

2015

BP measurement methods

Office (attended, OBPM)Oscillometric (electronic) Auscultatory (mercury, aneroid) Preferred

http://www.dableducational.org/sphygmomanometers.htmlhttp://www.bhsoc.org/bp-monitors/bp-monitors/

2015

Auscultatory OBPM is inaccurate!

• In the real world, the accuracy of auscultatory OBPM can be adversely affected by provider, patient and device factors such as:– too rapid deflation of the cuff – digit preference with rounding off of readings to 0 or 5– also, mercury sphygmomanometers are being phased out and

aneroid devices are less likely to remain calibrated

• Consequence: Routine auscultatory OBPMs are 9/6 mm Hg higher than standardized research BPs (primarily using oscillometric devices)

Myers MG, et al. Can Fam Physician 2014;60:127-32.

Auscultatory OBPM is inaccurate! ↓ BP 10/7 mm Hg

Myers et al, Hypertension 2010;55:195-200

correct BP measurement technique

Δ BP (mm Hg) if not done

Rest ≥ 5 min, quiet ↑ 12/6

Seated, back supported ↑6/8

Cuff at midsternal level ↑ ↓2/inch

Correct cuff size ↑ 6 18/4 13 if too small‐ ‐↓7/5 if too large

Bladder center over artery ↑ 3 5/2 3‐ ‐Deflate 2 mm Hg/sec ↓SBP/↑ DBP

No talking during measurement ↑ 17/13

J Clin Hypertens 2012;14:751 Hypertension 2005; 45:142 J Gen Int Med 2012; 27:623 J Hypertens 2005; 23:697 Can J Card 2014; 30:485

2015

Keys to accurate OBPM

• Use standardized measurement techniques and validated equipment

• Measurement using electronic (oscillometric) upper arm devices is preferred over auscultation

• The first reading should be discarded and the latter two averaged.

http://www.dableducational.org/sphygmomanometers.htm

2015

BP measurement methodsOffice Automated (unattended, AOBP)

Oscillometric (electronic)http://www.dableducational.org/sphygmomanometers.html

• Consider unattended AOBP devices taking 3 6 measurements ‐automatically, isolated patient

• ↑ accuracy and reproducibility / ↓white coat effect‐

Mean Office, Home, Ambulatory Blood Pressures: Equivalence Numbers

Description Blood Pressure mmHg

Home BP 135 / 85

Daytime Ambulatory BP 135 / 85

24-hour Ambulatory BP 130 / 80

Automated office BP 135 / 85

An office blood pressure of 140/90 mmHg is comparable to:

2015

Criteria for the diagnosis of hypertension and recommendations for follow-up: overview

Measurement using electronic (oscillometric) upper arm devices is preferred over auscultationABPM: Ambulatory Blood Pressure MeasurementAOBP: Automated Office Blood PressureHBPM: Home Blood Pressure measurementOBPM: Office Blood Pressure measurement

2015

Out of office assessment is the preferred means of diagnosing hypertension

Clinic BP as alternate method

Hypertension: clinical management of primary hypertension in adults [clinical guideline 127] NICE 2011

If the clinic blood pressure is 140/90 mmHg or higher, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension.

2015

Out-of-office BP Measurements

• ABPM has better predictive ability than OBPM and is the recommended out-of-office measurement method.

• HBPM has better predictive ability than OBPM and is recommended if ABPM is not tolerated, not readily available or due to patient preference.

• Identifies white coat hypertension (as well as diagnosing masked hypertension)

2015

Out-of-office BP measurements are more highly correlated with BP-related risk

Mule et al. J Cardiovasc Risk 2002;9:123-9.

SBP

DBP

2015

Only relying on office pressures misses out on white coat and masked hypertension

Manual Office BP mmHg

Ambu

lato

ry B

P m

mHg True

Hypertension

Normotension White Coat Hypertension

Masked Hypertension

200

180

160

140

120

100100 120 140 160 180 200

135

From Pickering et al. Hypertension 2002;40:795-796

2015

The prognosis of white coat and masked hypertension

0

5

10

15

20

25

30

35

Normal23/685

White coat24/656

Uncontrolled41/462

Masked236/3125

CV e

vent

s per

100

0 pa

tient

-yea

r

CV Events

Okhubo et al. J. Am. Coll. Cardiol. 2005;46;508-515

2015

2015

Advantages of Home Blood Pressure Measurement

• More rapid confirmation of the diagnosis of hypertension

• Improved ability to predict cardiovascular prognosis

• Improved blood pressure control

• Can be used to assess patients for white coat hypertension and masked hypertension

• Improved adherence to drug therapy

2015

Suggested Protocol for Home Measurement of Blood Pressure for the diagnosis of hypertension

• Home BP measurement should be encouraged to increase patient involvement in care

• Home blood pressure values should be based on:– Two measures separated by one minute,– Morning and evening,

– For an initial 7-day period. • First day home BP values should not be considered.• The following 6 days blood pressure readings should be

averaged.• Average BP≥ 135/85 mmHg should be considered elevated

2015

2015

2015

Home Measurement: Doing it Right

EQUIPMENT• Validated device• Arm cuffs only (unless massive obesity)• Ensure the cuff size is appropriate: Correct cuff size for mid arm circumference‐ – < 33 cm regular cuff – 33 43 cm ‐ large adult or self adjusting‐ – > 43 cm wrist cuff (if wrist < 22 cm)

2015

Home Measurement: Doing it RightPreparation

DO• Read and carefully follow the

instructions provided with the device

• Relax in a comfortable chair with back support for 5 minutes

• Sit quietly without talking or distractions (e.g. TV)

DON’T• Measure if stressed, cold, in pain or

if your bowel or bladder are uncomfortable

• Measure within 1 hour of heavy physical activity

• Measure within 30 minutes of smoking or drinking coffee

2015

Home Measurement of BP: Confirm Contradictory Home Measurement Readings

If office BP measurement is elevated and home BP is normal or vice versa

Repeat home monitoring or perform 24-hour ambulatoryblood pressure monitoring

2015

How to?• Use validated devices• How to interpret?

– Mean daytime ambulatory blood pressure >135/85 mmHgis considered elevated.

– Mean 24 h ambulatory blood pressure >130/80 mmHg is considered elevated.

A drop in nocturnal BP of <10% is associated with increased risk of CV events

Ambulatory BP Monitoring

2015

2015

Assessment of the Overall Cardiovascular RiskSearch for target organ damage

• Cerebrovascular disease– transient ischemic attack– ischemic or hemorrhagic stroke– vascular dementia

• Hypertensive retinopathy• Left ventricular dysfunction• Left ventricular hypertrophy• Coronary artery disease

– myocardial infarction– angina pectoris– congestive heart failure

• Chronic kidney disease– hypertensive nephropathy

(GFR < 60 ml/min/1.73 m2)– albuminuria

• Peripheral artery disease– intermittent claudication– ankle brachial index < 0.9

Άνδρας, καπνιστής, με Σακχ. Διαβήτη τύπου2 και χειρουργηθείσα περιφερική αγγειακή νόσο –

Δείκτης Καρδιαγγειακού Κινδύνου 2 ?

2015

The Role of Echocardiography

• Echocardiography is useful for: – Assessment of left ventricular dysfunction and the presence of

left ventricular hypertrophy

• Echocardiography is not useful for routine evaluation of hypertensive patients

2015

Assessment for Renovascular Hypertension

Patients presenting with two or more of the following clinical clues listed below suggesting renovascular hypertension should be investigated.

I. Sudden onset or worsening of hypertension and age >55 or <30 years

II. The presence of an abdominal bruitIII. Hypertension resistant to 3 or more drugsIV. A rise in creatinine of 30% or more associated with use of an

angiotensin converting enzyme inhibitor or angiotensin II receptor blocker

V. Other atherosclerotic vascular disease, particularly in patients who smoke or have dyslipidemia

VI. Recurrent pulmonary edema associated with hypertensive surges

2015

Assessment for Renovascular Hypertension

The following tests are recommended, when available, to screen for renal vascular disease:• captopril-enhanced radioisotope renal scan*• doppler sonography• magnetic resonance angiography• CT-angiography (for those with normal renal function)

* captopril-enhanced radioisotope renal scan is not recommended for those with glomerular filtration rates <60 mL/min

2015

Screening for Hyperaldosteronism

Should be considered for patients with the following characteristics:

– Spontaneous hypokalemia (<3.5 mmol/L).– Profound diuretic-induced hypokalemia (<3.0 mmol/L). – Hypertension refractory to treatment with 3 or more drugs.– Incidental adrenal adenomas.

2015

Screening for Hyperaldosteronism

Screening for hyperaldosteronism should include plasma aldosterone and renin activity (or renin concentration)

– measured in morning samples.– taken from patients in a sitting position after resting at least 15

minutes.

• Aldosterone antagonists/ ARBs/ beta-blockers and clonidine should be discontinued prior to testing.

• A positive screening test should lead to referral or further testing.

2015

Screening for Pheochromocytoma

• Should be considered for patients with the following characteristics:– Paroxysmal and/or severe sustained hypertension refractory to usual

antihypertensive therapy;– Hypertension and symptoms suggestive of catecholamine excess (two

or more of headaches, palpitations, sweating, etc); – Hypertension triggered by beta-blockers, monoamine oxidase

inhibitors, micturition, or changes in abdominal pressure; – Incidentally discovered adrenal mass; – Multiple endocrine neoplasia (MEN) 2A or 2B; von Recklinghausen’s

neurofibromatosis, or von Hippel-Lindau disease.

2015

Screening for Pheochromocytoma

• Screening for pheochromocytoma should include a 24 hour urine for metanephrines and creatinine.

• Assessment of urinary VMA is inadequate.

• A normal plasma metanephrine level can be used to exclude pheochromocytoma in low risk patients but the test is performed by few laboratories.

Exogenous potentially modifiable factors that can induce/aggravate hypertension

Prescription Drugs:• NSAIDs, including coxibs• Corticosteroids and anabolic steroids• Oral contraceptive and sex hormones• Vasoconstricting/sympathomimetic decongestants• Calcineurin inhibitors (cyclosporin, tacrolimus)• Erythropoietin and analogues• Antidepressants: Monoamine oxidase inhibitors (MAOIs), SNRIs, SSRIs• Midodrine

Other:• Licorice root• Stimulants including cocaine• Salt• Excessive alcohol use

Θεραπευτικά διλλήματα…

How low it’s too low?

Hypertension guidelines – clear as mud TheHeart.org

“The multitude of guidelines from respected professional bodies and

individuals have caused needless confusion bordering on

chaos.”

Editorial, J Clin Hypertens 2014; 16:251

Παράγοντες κινδύνου για χρόνια νοσήματα

Preventing Chronic diseases. A vital investment. WHO 2005

Lifestyle modifications

2013 AHA/ACC/CDC. An Effective Approach to High Blood Pressure

DASH: Dietary Approaches to Stop Hypertension

• DASH dietary pattern description:• higher in vegetables, fruits, and low-fat dairy

products• higher in whole grains, poultry, fish, and nuts• low in sweets, sugar-sweetened beverages, and

red meats• low in saturated fat, total fat, and cholesterol• high in K, Mg, Ca• rich in protein and fiber

Diuretic selection according to e-GFR

• e-GFR <30ml/min (↑Na) Furosemide Monitor Creatinine/K carefully!

• e-GFR >30 ml/min HCTZ

Eur Heart J 2013; 34:1175

JNC 8 restricted to answering 3 questions

• Does starting drugs at specific BP thresholds improve outcomes? [When to start therapy?]

• Does titrating drugs to a specific BP goal improve outcome? [How low should I go?]

• Do various BP drugs or drug classes differ in benefits and harms on specific outcome? [What drug do I use?]

James et al. JAMA 2014

Comparing current HTN guidelines2014 JNC-8 2013 ESH/ESC

General BPgoal

140/90 140/90

BP goal(elderly)

150/90 (>60yrs)

150/90 (>80yrs)

BP goal DM 140/90 140/85

BP goal CKD 140/90 140/90130/90 w/ proteinuria

Initial drugchoice

TZD, ACE/ARB, CCB TZD, ACE/ARB, CCB, BB

James et al. JAMA 2014

HYVET trialbenefit of target < 150/90 in very elderly

Beckett et al. NEJM 2008

↓ 34% CV events

↓ 39% stroke death

↓ 21% total mortality

VALISH trial no benefit of target < 140/90 in elderly

• Strict Control- SBP < 140 mmHg• Moderate Control- SBP: 140-150 mmHg

• No difference in primary outcome of sudden death, CVA, MI, cardiac death, renal dysfunction

Ogihara et al. Hypertension 2010

JATOS trialJapanese Trial to Assess Optimal SBP

• Randomized to SBP<140 vs. SBP: 140-160

• Achieved BP: 136/75 vs. 146/78

• No difference in CV events or renal failure (p=0.99)

JATOS Study Group. Hypertens Res 2008;31:2115-27

4416 patients aged 65-85 (average age of 74)

ACCORD Trial intensive HTN Tx in DM

• Target SBP < 120 mmHg (Mean SBP 119 mmHg) vs Target SBP < 140 mmHg (Mean SBP 133.5 mmHg)

• No difference in composite primary outcome: nonfatal MI, nonfatal stroke, or CV death

ACCORD Study Group. NEJM 2010

ACCORD Trial

The ACCORD Study Group. NEJM 2010

ALLHATComparison of HTN regimens

• No difference in primary outcome combined fatal CHD ornonfatal MI

ALLHAT Study Group. JAMA 2002

Systolic Blood Pressure Intervention Trial (SPRINT)

Principal Results

Paul K. Whelton, MB, MD, MSc

Chair, SPRINT Steering Committee Tulane University School of Public Health and Tropical Medicine,

and School of Medicine For the SPRINT Research Group

SPRINT- Research question

Major Inclusion Criteria• ≥50 years old

• Systolic blood pressure : 130 – 180 mm Hg (treated or untreated)

• Additional cardiovascular disease (CVD) risk

– Clinical or subclinical CVD (excluding stroke)

– Chronic kidney disease (CKD), defined as eGFR 20 – <60 ml/min/1.73m2

– Framingham Risk Score for 10-year CVD risk ≥ 15%

– Age ≥ 75 years

At least one

Major Exclusion Criteria• Stroke

• Diabetes mellitus

• Polycystic kidney disease

• Congestive heart failure (symptoms or EF < 35%)

• Proteinuria >1g/d

• CKD with eGFR < 20 mL/min/1.73m2 (MDRD)

• Adherence concerns

Demographic and Baseline Characteristics

Systolic BP During Follow-up

Decision to Stop BP Intervention

• On August 20th, 2015, NHLBI Director accepted DSMB recommendation to inform SPRINT investigators and participants of CVD results

• Concurrently, decision made to stop BP intervention

• This presentation based on adjudicated events that occurred through August 20th, 2015• Median follow-up = 3.26 years

• Data for some secondary non-CVD outcomes (e.g. dementia and cognitive impairment) being collected at final close-out visit and this process will be completed in 2016

SPRINT Primary Outcome Cumulative Hazard

SPRINT Primary Outcome and its ComponentsEvent Rates and Hazard Ratios

Primary Outcome Experience in the Six Pre-specified Subgroups of Interest

All-cause MortalityCumulative Hazard

Serious Adverse Events* (SAE) During Follow-up

Summary and Conclusions• SPRINT examined effects of more intensive antihypertensive therapy than currently

recommended

• Participants were US adults ≥50 years with hypertension and additional risk for CVD

• Rapid and sustained difference in SBP achieved between the two treatment arms

• Trial stopped early, due to benefit, after median follow-up of 3.26 years

• Incidence of primary outcome (composite of CVD events) 25% lower in Intensive compared to Standard Group and all-cause mortality reduced by 27%.

• Treatment effect similar in all six pre-specified groups of interest.

• The “number needed to treat” to prevent primary outcome event or death 61 and 90, respectively

Summary and Conclusions• In participants with CKD at baseline, no differences in renal outcomes

• In participants without CKD at baseline, incidence of eGFR reduction ≥ 30% more common in Intensive Group

• No overall difference in serious adverse events (SAEs) between treatment groups

• SAEs associated with hypotension, syncope, electrolyte abnormalities, and hospital discharge reports of acute kidney injury or acute renal failure more common in Intensive Group

• Overall, benefits of more intensive BP lowering exceeded the potential for harm

Resistant hypertension

defined as blood pressure that remains above goal in spite of:• the concurrent use of 3 antihypertensive agents of different

classes • ideally, one of the 3 agents should be a diuretic and • all agents should be prescribed at optimal dose amounts.

• good blood pressure technique to confirm persistently elevated blood pressure levels

• Pseudoresistance- poor medication adherence or white coat hypertension

Calhoun et al, Circulation 2008