Evaluation and Treatment of Hypertensive Patients

Herbert L. Muncie, Jr., M.D.

Proper technique to measure Blood Pressure (JNC VII)

       Sitting, back supported, arm at level of heart Feet on floor, legs uncrossed Rest at least five minutes Proper cuff size (> 80% of arm with bladder) Inflate & palpate radial pulse to approximate BP – deflate cuff Inflate 20-30 mm above palpable systolic Measure Korotkoff I (onset sounds - systolic) and V (disappearance sounds - diastolic)

WatchBP Office

Question

A 58 year old African American female with three separate BP readings averaging 164/92. According to JNC VII, what is her BP classification?

a) Normal b) Prehypertension c) Stage 1 hypertension d) Stage 2 hypertension

Classification of Blood Pressure – JNC VII

Normal Stage 2 Systolic < 120 Prehypertension 120-139 Hypertension Stage 1 140-159 > 160 And Or Or Or Diastolic < 80 80-89 90-99 > 100 Highest value (systolic or diastolic) determines Stage

Treat Prehypertension?

  It is not a disease category (JNC VII) Treatment with ARB (candesartan) for 4 years  Relative risk reduction of developing Stage 1 hypertension 15.6%  Patients with prehypertension are not candidates for drug therapy (JNC VII)

Lifetime Risk

 For men or women who are normotensive at age 55 or 65 and  Who survive to age 80 - 85  90% will develop hypertension

Tests after Initial Diagnosis

  Secondary causes?

 Electrolytes, calcium  Target organ damage?

    ECG Urinalysis CBC BUN & creatinine Other cardiovascular risk factor?

 Lipid profile, glucose

Whom to consider evaluating for 2

o

causes

   Onset of hypertension before age 30 or after age 55    Initial diastolic BP is > 110 mm Patient with unexplained hypokalemia Patient with resistant or difficult to control BP especially if initially good control Signs of Cushing’s disease Signs or symptoms of pheochromocytoma

Pheochromocytoma

 Measure plasma free metanephrine (99% sensitive, 89% specific)  < 61 ng/L excludes diagnosis   > 236 ng/L confirms diagnosis If 62 - 235 ng/L more testing required  24 hour urine metanephrine alone highly sensitive and specific, but often incomplete collection

Renal artery stenosis

  Abdominal bruit suggestive often absent If high index of suspicion & normal renal function [Hartman 2009]   MRA CTA  If high index of suspicion & diminished renal function   MRA Duplex Doppler ultrasonography

Primary hyperaldosteronism

 Screen with plasma aldosterone/renin ratio (cutoff > 25)  β-blockers & DHCCBs stop for 2 weeks  Spironolactone & loop diuretics stop for 6 weeks  Plasma aldosterone should be > 20 ng/dL to make the diagnosis (Nl – 2 – 16 ng/dL – supine)  Renin – nl 12 – 79 mu/dL (supine)

Cushing Syndrome

 24 hr urine free cortisol useful screening (cutoff > 90 mcg/day)   Sensitivity 41 – 70% Specificity – almost 100%  Overnight dexamethasone suppression test equally sensitive, less specific  1 mg dexamethasone midnight – plasma cortisol next morning (cutoff > 100 nmol)

What if you find a 2

o

Cause?

 Renal artery stenosis   For atherosclerotic etiology   Medical therapy is cornerstone [Dworkin 2009] Stenting no better than medical but more complications  May be helpful with recurrent CHF or pulmonary edema For fibromuscular dysplasia – balloon angioplasty is worthwhile

White coat hypertension

 White coat hypertension  Elevated office BP but normal outside office  Normal would be either 24-hour BP with mean < 125/79 or home BP < 132/82  If out of office BP consistently < 130/80 & no evidence of target organ damage  24 hour monitoring or drug therapy can be avoided (JNC VII)  Increased risk of progressing to sustained hypertension [Mancia 2009]

Masked hypertension

 Masked hypertension  Normal office BP but elevated outside office  Suspect if patient with normal office BP has cardiovascular event   Increased risk of cardiovascular events  Pharmacotherapy is indicated Deserves “an aggressive diagnostic & therapeutic approach” [Messerli 2007]

Mrs. Jones

  Mrs. Jones is a 58 year old white female treated for hypertension for the past 6 years. Her BP today in the office is 168/94.

a) b) Which number should you focus on in deciding on modifying treatment?

Systolic BP Diastolic BP

Treatment of Patients > 50 y.o.

 Patients > 50 years old achieve diastolic goal when systolic goal achieved  Focus on systolic control for patients > 50 years old because:   Systolic BP continues to rise with age Diastolic BP levels off around age 50 & will remain at that level or fall after age 50

Non-pharmacologic Therapy

  Weight reduction alone reduces BP Regardless of weight - DASH diet helpful in lowering BP  Increase potassium (6-8 fruits or vegetables a day)  Increase fiber with whole grains (breads, cereals)   Increase calcium intake (low fat dairy) Decrease salt (DASH-low Na)  No added salt

Non-pharmacologic Therapy

 Stage 1 can be treated with lifestyle only (JNC VII)  For one year if no other risk factors   For 6 months with other risk factors You do not have to start medication immediately with Stage 1 (BP < 160/100)

Audience Question

Patients who successfully lose 3 - 9% of their body weight with lifestyle changes can expect to see their average BP decrease how many mm?

a) 3 b) 5 c) 7 d) 10

Weight loss & BP - EBM

  Dieting to lose weight may lower BP in overweight people but the effects are modest & dieting may not be effective alone Cochrane Review  18 randomized trials found weight loss of 3-9%  Associated with decreases of roughly 3 mmHg systolic & diastolic  http://www.chochrane.org/reviews/en/ab000484.html

Lifestyle changes

  Combining intensive lifestyle counseling & physician feedback was not successful long term (18 month) in achieving BP control [Svetkey 2009]  Some early success (6 months) faded over time Dietary choices influence control success  Salt restriction is central especially in those   requiring intensive pharmacotherapy Increase fresh fruits & vegtables Maximum 1 restaurant meal/week

Question

A 50 yo African American male with BP 155/95 (avg.) requires initiating drug therapy. What would be your initial choice of medication class for this patient?

a) b) c) d) e) Thiazide diuretic Calcium channel blocker (CCB) Beta blocker Angiotensin-converting enzyme inhibitor (ACE) Angiotensin receptor blocker (ARB)

Initial Therapy

 JNC VII – a thiazide-type diuretic should be initial therapy unless compelling indication  Most patients with Stage 1 will experience better BP control & lower CVD risk when taking a thiazide-type diuretic  Most patients with Stage 2 disease will experience better BP control & lower CVD risk when taking a multidrug regimen that includes a thiazide-type diuretic

Initial Therapy

 No treatment alters the natural progression of the disease  BP will continue to rise as the patient ages regardless of which medications are used  Therefore, every patient will eventually need for more than one medication to control their BP

Initial Therapy

  Dr. Chobanian (Chair JNC VII) now suggests flexibility in choice of initial drug [Chobanian 2009] – he suggests  Stage 1 – ACE, ARB, CCB or diuretic  Stage 2 – two of those 4 drugs to start With exception of β-blockers after an MI & CCBs effect on CVA risk, all drugs lowered CVD events for a given reduction in BP [Law 2009]

Initial Therapy

 To increase drug persistence & compliance with therapy [Friedman 2010]  Choose medications that will lower BP with few complications & is taken less often   Persistence is lower with more side effects Compliance is lower in males, lower SES groups & in urban environments

Question

A 50 yo African American male with BP 155/95 (avg.) requires initiating drug therapy. What would I choose?

a) b) c) d) e) Thiazide diuretic Calcium channel blocker (CCB) Beta blocker Angiotensin-converting enzyme inhibitor (ACE) Angiotensin receptor blocker (ARB)

STITCH Therapy

 Simplified Treatment Intervention to Control Hypertension (STITCH)  STITCH vs Canadian Hypertension Education Program guideline (CHEP)  CHEP is similar to JNC VII approach

STITCH Treatment

 Initiate therapy with ½ tablet of low dose combination - diuretic & ACEI or ARB  Increase that combination to highest dose tolerated  Then add CCB & increase to highest tolerated dose  Then add non-first-line agents  Alpha-blocker   Beta-blocker Spironolactone

STITCH Therapy

 At 6 months [Feldman 2009]  64.7% controlled on STITCH  52.7% controlled on CHEP (P = 0.03)

Pharmacologic Efficacy

 Average reduction in BP for major classes of drugs  At standard dosage - 9.1 mm (SBP)/5.5 mm (DBP) drop  With half standard dosage 7.1 mm (SBP)/4.4 mm (DBP)  When BP > 20 (SBP) or 10 mm (DBP) above goal (Stage 2) start two medications initially

Question

A 52 year old African American female has not achieved BP control on diuretics. You add an ACE inhibitor to the regimen. You order electrolytes, BUN and creatinine in 1 week. Her creatinine increased from 0.9 baseline to 1.14 mg/dL, a 26.7% increase. What should you do about her ACEI?

a.

b.

c.

d.

Discontinue the ACEI & add a different class Reduce the ACEI dose 50% Reduce the ACEI dose 25% Make no change in the ACEI dosage

Initiating Therapy – Change in Renal Function

 After initiating treatment, common to get decline in renal function  If ≤ 30% non-progressive increase in creatinine  Represents a functional response (reduced intraglomerular pressure) & no change in treatment required  This response is associated with long-term renal protection  If > 30% increase in creatinine, D/C medication & choose another class

Question

A 52 year old African American female has not achieved BP control on diuretics. You add an ACE inhibitor to the regimen. You order electrolytes, BUN and creatinine in 1 week. Her creatinine increased from 0.9 baseline to 1.14 mg/dL, a 26.7% increase. What should you do about her ACEI?

a.

b.

c.

d.

Discontinue the ACEI & add a different class Reduce the ACEI dose 50% Reduce the ACEI dose 25% Make no change in the ACEI dosage

Diuretic - Classes

 Thiazide  Hydrochlorothiazide (HCTZ) dosage best if ≤ 25 mg & preferably 12.5 mg  Outcome benefits have not been established for these dosages of HCTZ  Increasing to 50 mg minimally lowers BP further but significantly increases side effects  Hyponatremia & hypokalemia more common in women  12 combinations with HCTZ available

Diuretic - Classes

 Thiazide  Chlorthalidone 25 mg provided better 24 hr BP control than HCTZ 50 mg  Milligram for milligram twice as potent as HCTZ  Outcome data available regarding reduced CV events  Only 2 combinations available  Chlorthalidone/clonidine (Clorpres

®

) – 15/0.1,0.2, 0.3

 Atenolol/chlorthalidone (Tenoretic

®

) – 25/50, 25/100

Diuretic - Classes

 Loop  If only treating hypertension - use loop diuretics only with renal insufficiency (CrCl < 30 - 40 ml/min)  Discontinue thiazides at this CrCl – not effective  Dosage frequency for BP treatment   Furosemide (Lasix

®

) – BID  QD dosage may lead to reactive Na + renin/angiotensin system retention mediated by Torsemide (Demadex

®

) – QD

Diuretic - Classes

 Potassium sparing  Combined with thiazide - reduces risk sudden death and hypokalemia  Do not combine with continuous K + supplements or give with renal insufficiency  Increased risk hyperkalemia  Especially with ACE or ARB combination  Should be stopped temporarily if diarrhea or vomiting occurs

Selective aldosterone receptor antagonist

    Eplerenone (Inspra

®

) first approved in new class Primary focus in heart failure Add-on to anti-hypertensive Rx Side effects   Hyperkalemia Contraindicated with hyperkalemia, creatinine > 1.8 men, > 2.0 women, or creatinine clearance < 50 ml  Caution in use with ACE or ARB

Diuretics – diabetes & hyperlipidemia?

 Diuretics can raise glucose & lipid levels short-term  However, no long-term adverse effects in diabetics  Fasting glucose increases in older adults regardless antihypertensive drug  Diuretics may be safely used in patients with diabetes or hyperlipidemia

Beta-Blockers

  Available evidence does not support their use as 1 st    line treatment alone Weak effect in reducing CVA Absent effect on CAD [Wiysonge - Cochrane 2007] Lower heart rate with beta-blocker therapy associated with increased risk CV events & death Compelling indications (JNC VII)  Heart failure    Chronic stable angina Post MI Tachyarrhythmia

Beta-Blockers

 Side effects  Increased risk developing type 2 DM     Decreased exercise tolerance Increased risk of Raynaud’s phenomenon Increased insomnia & risk of delirium Abrupt withdrawal can precipitate myocardial ischemia in at risk patients

Beta-Blockers & Diabetes

  In diabetics beta-blockers blunt heart rate & BP response to hypoglycemia  However, no increase in severe hypoglycemia in Type 1 or Type 2 DM  Do not worsen glycemic control when used with ACE/ARB Carvedilol (Coreg ® ) & nebivolol (Bystolic ® ) have neutral or even favorable effect on CHO & lipid metabolism

Angiotensin-Converting Enzyme (ACE) Inhibitors

  Compelling indications (JNC VII)    Heart failure Post MI - systolic dysfunction Diabetics with proteinuria Reduce cardiovascular & all-cause mortality  As effectively as diuretics, β-blocker or CCB [SOR-A]  Diabetics may retain sodium  Add diuretic to enhance response

ACE Inhibitors

 Side effects   Cough (5-15%) women 2x men’s risk Angioedema (0.1-0.2%) – African Americans   and Asians 3 - 4 x risk increase Hyperkalemia with renal insufficiency If patient has bilateral renal artery stenosis  Can cause renal insufficiency  Measure creatinine initially & one week after  starting ACE If > 30% increase in creatinine or hyperkalemia 1 st 2 months – D/C ACE

Angiotensin Receptor Blocker (ARB)

 Three trials found ARBs effective in reducing CV events (LIFE, SCOPE, VALUE)  But not as effectively as ACE  Reduce the risk end-stage renal disease in diabetics  No evidence reduce mortality in diabetics with renal disease  Reserve for patients who cannot tolerate ACE

Angiotensin Receptor Blocker (ARB)

 Low incidence of dizziness or other side effects  Cough not a problem  Caution with renal insufficiency or K + supplements

Angiotensin Receptor Blocker (ARB)

     Less effective if high salt intake Measure serum creatinine initially & 1 week after starting drug Can worsen renal failure Not proven to improve survival post MI ACE & ARB should not be used in pregnancy

Combining ACE & ARB

 CHARM-Added trial found combination reduced CV events & mortality in patients with heart failure  However, in patients without heart failure  Combination lowered BP without CV benefit over ACE alone (ONTARGET)  But did increase hypotension, syncope & renal dysfunction

Ca-Channel Blockers (CCB)

 More effective in African Americans than diuretic or ACE as initial therapy  ALLHAT – if African American cannot take diuretic – CCB preferred initial drug  Greater risk CVA, CHD, CVD, angioedema with ACE  Combination of benazepril/amlodipine was more effective slowing progression of renal disease than benazepril/HCTZ (ACCOMPLISH trial)

Ca-Channel Blocker Risks

 CCB & diuretics are associated with best stroke prevention  Could be due to less visit-to-visit variability  Caution combining non-dihydropyridine CCB (diltiazem; verapamil) with beta blocker   Potential additive negative inotropic effect Can cause heart failure or complete heart block

Direct Renin Inhibitor

 Aliskiren (Tekturna ® )  Monotherapy or combined  Modestly lowers BP  High fat meals decrease absorption  Older hypertensive medications should be considered 1 st (Medical Letter 2007)

Alpha Adrenergic Blockers

   Peripheral sympatholytics Do not produce tachycardia & palpitations Not initial drug of choice  Associated with increased risk of MI

Alpha Adrenergic Blockers

 Side effects  Marked hypotension especially with first dose  Careful in elderly, volume depleted patients, or in patients taking other antihypertensive drugs   Start with lowest dose at bedtime Not recommended for patients with CHF regardless of BP status  May benefit males with BPH symptoms

JNC VII Compelling Indications

Compelling Indic. Diuretic BB

CHF

X X

Post MI

X

High CAD Risk

X X

Diabetes Mellitus

X X

Chronic Kidney Disease Recurrent CVA Prevention

X ACEI ARB CCB AlDO ANT X X X X X X X X X X X X X

Treatment Goal

 For most patients goal BP is < 140/90  Does a lower target (< 135/85) reduce risk?

 Cochrane review found lower targets did not change mortality, MI, CVA, CHF, major cardiovascular events or ESRD [Arguedas 2009]  In the very old (> age 80) with CAD, a suggestion of increased risk of adverse outcomes with SBP < 140 & DBP < 70 [Denardo 2010]

Treatment Goal

 For diabetics or patients with CKD • • ADA/AHA Goal BP is < 130/80 INVEST trial of diabetics with CAD found tight BP control did not improve CVD outcomes over usual control   Was associated with increase in all-cause mortality Emphasis should focus on maintaining SBP between 130 – 139 mm Hg for these patients

Question

Your 52 y.o. African American female patient with a 6 year history of hypertension comes in for a routine office visit. No symptoms. BP 142/92. No change in therapy. When would you want to see her again for follow-up?

a) b) c) d) Two (2) weeks One (1) month Three (3) months Six (6) months

Monitoring Treatment

 No evidence based guidelines address the frequency of monitoring treatment [Keenan 2009]  Monitoring at short intervals increases probability of false positives due to within person variability  Longer intervals (years) increase probability observed increase is real

Monitoring Treatment

 Chance of detecting a true increase in BP is better if:  Abnormal BP is signal for repeat readings at short intervals  Using calibrated sphygmomanometer  Set times to measure BP in relation to drug therapy  Taking mean of several measurements  Or perhaps self-monitoring

Monitoring Treatment

 What is the significance of visit-to-visit (V2V) variability, maximum SBP and episodic hypertension?

 V2V & maximum SBP are strong predictors of stroke, independent of mean SBP (Rothwell 2010)  Interindividual variation is reduced with CCB & non-loop diuretics but increased with ACE, ARB and β-blockers  Does not yet prove a causal link

Telemonitoring & self titration

 Using automated BP measurement with information sent to the office, patients on 2 meds without control [McManus 2010]  Having patients request additional medicine if their BP remained uncontrolled for two consecutive months resulted in lower SBP difference of 3.7 mm (95% CI 0.8 – 6.6)

Combinations of Medications

 Beyond studies of 2 drug combinations, little data on the efficacy of 3 or more drugs   Advice largely empiric and/or anecdotal Triple therapy amlodipine/valsartan/HCTZ (Tribenzor ® ) better BP control than dual therapy [Calhoun 2009]  ASCOT study found ACE & DHPCCB better than B blocker with diuretic  In reducing CV mortality  In reducing new onset DM  In reducing incidence of fatal & nonfatal CVA

Combination therapy

  Maximal dosage of one drug increases risk of side effects Using ½ standard dose resulted in decrease of side effects  81% for CCBs (pedal edema)  80% for thiazides (hypokalemia)  27% for beta blockers (bradycardia/fatigue)  0 % for ACE/ARB (which are not dose related)

Combination therapy

 Therefore, use lower dosages of two drugs [Wald 2009]  Combining drugs from 2 classes will get 5 times greater reduction in BP than doubling one drug  If appropriate consider fixed dose combinations   May improve compliance May reduce total costs

Some Combinations

  Everything is combined with HCTZ Amlodipine & benazepril (Lotrel ® )  Slowed nephropathy more than benazepril & HCTZ [Bakris 2010]  Amlodipine & an ARB    With olmesartan (Azor ® ) With telmisartan (Twynsta ® ) With valsartan (Exforge ® )

Persistence?

 Do patients continue to take their medication?

 As many as 25% of patients stop taking their medications by 6 months  Many variables influence this rate (side effects, cost, patient’s understanding, physician’s ability to explain, etc.)  One new variable is modification of dosage or drug before the end of the 1 st prescription – more persistent if adjusted [Tamblyn R 2010]

Caution in Elderly

 What appears as refractory BP control may be sclerotic arteries – ‘pseudo hypertension’  If radial artery palpable when brachial artery is occluded with cuff (Osler maneuver)  Measure intra-arterial pressure

Hypertension and Elderly

  Criteria for diagnosis unchanged due to age Treatment reduced incidence CVA, CAD, CHF and death from all causes  Treatment initially proven beneficial up to age 80  Treatment after age 80 is now proven beneficial

Hypertension and Elderly

 Aggressiveness of treatment influenced by patient's physiologic age and life expectancy  Life expectancy should be at least as long as time required to see a clinically meaningful decrease in:  Stroke - 3 years  CHF - 4.5 years  Heart attack - 7 years

Isolated Systolic Hypertension



Treatment recommendations:

 Diuretics  Long-acting dihydropyridine CCBs  Strong evidence treatment helpful if > 160 mm  Evidence less strong for 140 - 159 mm  In oldest old males (> 85 yo) higher systolic BP associated with lower mortality

Resistant Hypertension

 BP remains above goal in spite of at least 3 medications at optimal dose  Ideally one of which should be a diuretic  Patients controlled on 4 or more medications should be considered resistant to treatment

Resistant Hypertension Treatment

     Restrict salt intake Increase dose of diuretic  If CrCl is below 30-50 ml/min use loop diuretic Add aldosterone antagonist  Since up to 20% - raised aldosterone/renin ratio Consider evaluating for 2 o causes Future treatment?

 Radiofrequency ablation renal sympathetic nerve  23 mm drop in systolic BP in 89% patients

Incidental Hypertension

 Elevated BP found incidentally during visit  No consensus on how to evaluate or treat in the acute care setting  VA Cooperative Trial (1967) – 143 patients with DBP 115 -130  No adverse outcomes vs placebo initial 3 mo  Close follow-up and perhaps treatment is all that is required

Incidental Hypertension

 Prospective randomized trial of 64 asymptomatic patients with DBP 116 -139  Oral clonidine load vs placebo then maintenance oral clonidine  No clinical difference in BP at 7 days  No evidence demonstrating improved morbidity or mortality with acute treatment of BP in ED

Key Points – Lessons from clinical trials

    BP is the key driver of benefit from medications Drugs that deliver less effective BP control have never produced superior clinical outcomes The choice of initial treatment defines the initial BP response to treatment & the longer term quality of BP control usually requiring fewer add-on drugs Patients with treated hypertension remain at higher risk of CVD

Key Points – Lessons from clinical trials

  If after formal estimate of global risk, their risk of CVD is high, offer statin & ASA therapy Treatment of pre-hypertension with lifestyle changes might prevent development of severe hypertension, target organ damage & diminish risk of dementia

What Questions do you have?