HypertensionHypertensionManagement of the Management of the

“Difficult Patient”“Difficult Patient”

Clay A. Block, M.D.Clay A. Block, M.D.

12-6-200412-6-2004

What is the “difficult patient”?

The “Difficult Patient”The “Difficult Patient”

Resistant HypertensionResistant Hypertension

Intolerant of Multiple MedicinesIntolerant of Multiple Medicines

Definition of HypertensionDefinition of Hypertension

Normal<= 120/80Normal<= 120/80

Prehypertensive 120-139/80-89Prehypertensive 120-139/80-89

Stage 1 Htn 140-159/90-99Stage 1 Htn 140-159/90-99

Stage 2 Htn >= 160/100Stage 2 Htn >= 160/100

Resistant HypertensionResistant Hypertension

Failure to reach goal BP in a patient Failure to reach goal BP in a patient adhering to full doses of an adhering to full doses of an appropriate three drug regimen that appropriate three drug regimen that includes a diureticincludes a diuretic

What are the goals of therapy?What are the goals of therapy?

<140/90 for patients without diabetes or <140/90 for patients without diabetes or renal diseaserenal disease– Most patients who achieve their systolic goal Most patients who achieve their systolic goal

will also achieve their diastolic goalwill also achieve their diastolic goal

<130/80 for patients with diabetes or <130/80 for patients with diabetes or renal diseaserenal disease

(JNC 7)(JNC 7)

What is the Benefit?What is the Benefit?

Stroke Incidence Reduction 35-40%Stroke Incidence Reduction 35-40%

Heart Failure Reduction > 50%Heart Failure Reduction > 50%

Myocardial Infarction Reduction 20-Myocardial Infarction Reduction 20-25%25%

What is the Benefit?What is the Benefit?

Number Needed to Treat to Prevent 1 Number Needed to Treat to Prevent 1 Death Over 10 Years by Lowering Death Over 10 Years by Lowering Systolic Pressure by 12 mmHg in Systolic Pressure by 12 mmHg in Stage 1 Hypertension: Stage 1 Hypertension: 1111

In the Presence of CV Disease or In the Presence of CV Disease or Target Organ Damage the NNT falls Target Organ Damage the NNT falls to to 99

Approach to the Patient With Approach to the Patient With Potentially Resistant HtnPotentially Resistant Htn

Review DiagnosisReview Diagnosis Review GoalsReview Goals Get on Same Page:Get on Same Page:

– Most Patients Will Require Multiple Most Patients Will Require Multiple Agents to Achieve ControlAgents to Achieve Control

– All Medicines Have Side Effects and All Medicines Have Side Effects and CostsCosts

– Don’t Forget Lifestyle Modification and Don’t Forget Lifestyle Modification and Nonpharmacologic Approaches Nonpharmacologic Approaches

Approach to Resistant Approach to Resistant HypertensionHypertension

Establish “true resistance”Establish “true resistance”

– Measure BP accuratelyMeasure BP accurately

– Consider “White Coat Hypertension”Consider “White Coat Hypertension”

– Consider “pseudoresistance”Consider “pseudoresistance”

– Consider secondary causesConsider secondary causes

Accurate BP MeasurementAccurate BP Measurement

““Persons should be seated quietly for 5 Persons should be seated quietly for 5 minutes with feet on the floor and the arm minutes with feet on the floor and the arm supported at heart level”supported at heart level”

Cuff must be appropriately sized (cuff Cuff must be appropriately sized (cuff bladder must encircle 80% of the arm)bladder must encircle 80% of the arm)

Check both arms and a leg (or palpate Check both arms and a leg (or palpate pulses carefully)pulses carefully)

Caffeine and Tobacco can transiently raise Caffeine and Tobacco can transiently raise BP substantiallyBP substantially

Approach to Resistant Approach to Resistant HypertensionHypertension

Establish “true resistance”Establish “true resistance”

– Measure BP accuratelyMeasure BP accurately

– Consider “White Coat Hypertension” (WCH)Consider “White Coat Hypertension” (WCH)

– Consider “pseudoresistance”Consider “pseudoresistance”

– Consider secondary causesConsider secondary causes

'White-coat hypertension' needs 'White-coat hypertension' needs attention attention

Q.My doctor wants to start both me Q.My doctor wants to start both me and my husband on blood-pressure and my husband on blood-pressure pills, and his blood pressure is only pills, and his blood pressure is only 145/95. And my blood pressure is fine 145/95. And my blood pressure is fine at home and only high in my doctor's at home and only high in my doctor's office — isn't this just "white-coat office — isn't this just "white-coat hypertension"? We don't have hypertension"? We don't have headaches, tiredness, dizziness or headaches, tiredness, dizziness or anythinganything– 2002 Honolulu Newspaper Column2002 Honolulu Newspaper Column

White Coat HypertensionWhite Coat Hypertension

20-30% of Apparently Resistant 20-30% of Apparently Resistant Hypertension May be due to “White-Coat Hypertension May be due to “White-Coat Hypertension”Hypertension”

Patients with WCH have an increased risk Patients with WCH have an increased risk of CV events and often have some degree of CV events and often have some degree of end organ damageof end organ damage

Use home or ambulatory monitoring to Use home or ambulatory monitoring to sort outsort out

Home and Ambulatory BP Home and Ambulatory BP Monitoring (ABPM)Monitoring (ABPM)

Often lower than office readingsOften lower than office readings Useful to “calibrate” home monitorsUseful to “calibrate” home monitors Nocturnal Dip (10-20% fall during the Nocturnal Dip (10-20% fall during the

night) is physiologically important night) is physiologically important (Dippers vs. Non-Dippers)(Dippers vs. Non-Dippers)

Can identify “windows of poor Can identify “windows of poor control” or windows of low BP and control” or windows of low BP and correlate with perceived symptomscorrelate with perceived symptoms

Dippers vs. Non-DippersDippers vs. Non-Dippers

More LVHMore LVH More silent cerebrovascular diseaseMore silent cerebrovascular disease More albuminuriaMore albuminuria More progression of CKDMore progression of CKD More CV mortalityMore CV mortality

Additional Information From Additional Information From Ambulatory MonitoringAmbulatory Monitoring

Heart rate: For each 10% less Heart rate: For each 10% less reduction in heart rate, reduction in heart rate, cardiovascular mortality increases by cardiovascular mortality increases by 30% (J Htn 16, 1335-1343, 1998)30% (J Htn 16, 1335-1343, 1998)

Increase in average 24 hour pulse Increase in average 24 hour pulse pressure of >= 53 mmHg confers pressure of >= 53 mmHg confers high riskhigh risk

Why and When ABPMWhy and When ABPM

Suspected WCHSuspected WCH

Excessive VariabilityExcessive Variability

Apparent Drug ResistanceApparent Drug Resistance

Symptoms Suggesting Hypotensive Symptoms Suggesting Hypotensive EpisodesEpisodes

Explanation of ABPM plots

An Example of “White Coat Hypertension”

Approach to Resistant Approach to Resistant HypertensionHypertension

Establish “true resistance”Establish “true resistance”

– Measure BP accuratelyMeasure BP accurately

– Consider “White Coat Hypertension”Consider “White Coat Hypertension”

– Consider “pseudoresistance”Consider “pseudoresistance”

– Consider secondary causesConsider secondary causes

PseudoresistancePseudoresistance PseudohypertensionPseudohypertension Non-adherence may account for up to 50% of Non-adherence may account for up to 50% of

resistant casesresistant cases Inadequate RegimenInadequate Regimen

– Especially inadequate diuretic componentEspecially inadequate diuretic component Interfering medicines and substances also need Interfering medicines and substances also need

to be consideredto be considered– NSAIDsNSAIDs– Excessive Alcohol, Caffeine, or TobaccoExcessive Alcohol, Caffeine, or Tobacco– Excessive Salt IntakeExcessive Salt Intake– Drugs of AbuseDrugs of Abuse– Oral contraceptivesOral contraceptives

Critical Importance of Adequate Critical Importance of Adequate Diuretic TherapyDiuretic Therapy

23/32 patients referred for 23/32 patients referred for management of “resistant management of “resistant hypertension” had evidence of hypertension” had evidence of expanded extracellular volume by expanded extracellular volume by nuclear studynuclear study– None had clinical evidence of expanded None had clinical evidence of expanded

extracellular volumeextracellular volume– All were already on diuretic therapyAll were already on diuretic therapy

Am J Med Sci 1989; 298: 361-365Am J Med Sci 1989; 298: 361-365

Critical Importance of Adequate Critical Importance of Adequate Diuretic TherapyDiuretic Therapy

Control improved in patients treated Control improved in patients treated with potent thiazide diuretics with potent thiazide diuretics (indapamide, metolazone, or larger (indapamide, metolazone, or larger doses of hctz, etc.) or given multiple doses of hctz, etc.) or given multiple daily doses of loop diureticsdaily doses of loop diuretics

Patients with co-existent renal Patients with co-existent renal disease may require more intensive disease may require more intensive diuretic therapydiuretic therapy

PseudohypertensionPseudohypertension

Calcification of the arteries resulting Calcification of the arteries resulting in failure of the BP cuff to compress in failure of the BP cuff to compress and occlude flow and occlude flow

Suspect if:Suspect if:– severe hypertension by cuff but no end severe hypertension by cuff but no end

organ injuryorgan injury– Antihypertensive rx results in sx of Antihypertensive rx results in sx of

Hypoperfusion/hypotension without Hypoperfusion/hypotension without measurable hypotensionmeasurable hypotension

– Pipe stem calcification on x-rayPipe stem calcification on x-ray

PseudohypertensionPseudohypertension

Osler’s Maneuver (the radial artery Osler’s Maneuver (the radial artery remains palpable due to calcification and remains palpable due to calcification and thickening despite inflation of cuff above thickening despite inflation of cuff above systolic pressure)systolic pressure)– Poorly reproduciblePoorly reproducible

““Dynamap”-like devices may be more Dynamap”-like devices may be more accurate in this settingaccurate in this setting

Direct Intra-arterial measurement is the Direct Intra-arterial measurement is the only definitive way to establish the only definitive way to establish the diagnosis, but this is uncommonly donediagnosis, but this is uncommonly done

The Importance of AdherenceThe Importance of Adherence

Only 1/2 to 2/3 of patients take at Only 1/2 to 2/3 of patients take at least 75% of prescribed least 75% of prescribed antihypertensive medicinesantihypertensive medicines– Of those taking < 75%, only 37% Of those taking < 75%, only 37%

achieved BP goalachieved BP goal– Of those taking >= 75%, 81% achieved Of those taking >= 75%, 81% achieved

goalgoal

Arch Int Med 1987; 147:1393-1396Arch Int Med 1987; 147:1393-1396

The Importance of AdherenceThe Importance of Adherence

In a more recent BMJ study, the same In a more recent BMJ study, the same rate of adherence was found in both rate of adherence was found in both responsive and resistant patients responsive and resistant patients (82%)(82%)

BMJ 2001; 323:142BMJ 2001; 323:142

Techniques to Improve AdherenceTechniques to Improve Adherence

Education of the patientEducation of the patient– Increases awareness but less effect on Increases awareness but less effect on

behaviorbehavior Minimize the number of pillsMinimize the number of pills

– Combination pills (acei/diuretic, Combination pills (acei/diuretic, arb/diuretic, arb/ca-blocker, etc.)arb/diuretic, arb/ca-blocker, etc.)

Increase the frequency of visitsIncrease the frequency of visits– Use of care managersUse of care managers

Approach to Resistant Approach to Resistant HypertensionHypertension

Establish “true resistance”Establish “true resistance”

– Measure BP accuratelyMeasure BP accurately

– Consider “White Coat Hypertension”Consider “White Coat Hypertension”

– Consider “pseudoresistance”Consider “pseudoresistance”

– Consider secondary causesConsider secondary causes

Important Secondary Causes of Important Secondary Causes of HypertensionHypertension

Obstructive Sleep ApneaObstructive Sleep Apnea Obesity (Metabolic Syndrome)Obesity (Metabolic Syndrome) EndocrinopathiesEndocrinopathies

– HyperaldosteronismHyperaldosteronism, thyroid , thyroid problems, pheochromocytomaproblems, pheochromocytoma

Kidney DiseaseKidney Disease– Renal Insufficiency and Renal Artery Renal Insufficiency and Renal Artery

StenosisStenosis

Drug Resistant Htn

Logan

J Htn 2001

Stroke or TIA

Basetti

Sleep, 1999

CHF

Javaheri

Circ 1999

All Htn

Nieto

JAMA 2000

CAD

Shafer

Card 1999

Sleep Apnea and HypertensionSleep Apnea and Hypertension

Clear dose response between Clear dose response between severity of OSA and the incidence of severity of OSA and the incidence of hypertensionhypertension– May relate to the “Non-dipping”May relate to the “Non-dipping”

Clear improvement in hypertension Clear improvement in hypertension of approximately 10mmHg with of approximately 10mmHg with effective CPAP therapy (and no effect effective CPAP therapy (and no effect with ineffective CPAP)with ineffective CPAP)

Obesity and the Metabolic Obesity and the Metabolic SyndromeSyndrome

According to the Framingham Heart Study, According to the Framingham Heart Study, 65-78% of the risk for hypertension 65-78% of the risk for hypertension can be related to obesitycan be related to obesity

Obesity is linked to:Obesity is linked to:– OSAOSA– Insulin resistanceInsulin resistance– Resistance to antihypertensive effect of Resistance to antihypertensive effect of

medicinesmedicines– Activation of the RAAS and the SNSActivation of the RAAS and the SNS

Table 1. Forms of primary aldosteronism

Aldosterone-producing adenoma (APA)

Bilateral idiopathic hyperplasia (IHA)

Primary (unilateral) adrenal hyperplasia

Aldosterone-producing adrenocortical carcinoma

Familial hyperaldosteronism (FH)

 Glucocorticoid-remediable aldosteronism (FH type I)

 FH type II (APA or IHA)

Table 2. Prevalence of unrecognized primary aldosteronism in patients with hypertension

Author (Ref.) Country No. screened Prevalence

Gordon et al. (21 ) Australia 199 8.5%

Kumar et al. (22 ) India 103 8.7%

Kreze et al. (23 ) Slovakia 115 13.0%

Lim et al. (24 ) United Kingdom 465 9.2%

Loh et al. (25 ) Singapore 350 4.6%

Fardella et al. (26 ) Chile 305 9.5%

Schwartz et al. (27 )

United States 117 12.0%

Rossi et al. (10 ) Italy 1,046 6.3%

Renal Artery StenosisRenal Artery Stenosis

Krijnen, P. et. al. Ann Intern Med 1998;129:705-711

Associations of Clinical Characteristics with Renal Artery Stenosis

Diagnosis of Renal Artery StenosisDiagnosis of Renal Artery Stenosis

Clinical FeaturesClinical Features– Severe hypertension, resistance, flash Severe hypertension, resistance, flash

pulmonary edema, cad/cvd/pvod, pulmonary edema, cad/cvd/pvod, abdominal bruits, hypokalemia, high abdominal bruits, hypokalemia, high renin level, marked clinical response to renin level, marked clinical response to angiotensin blockade, ARF angiotensin blockade, ARF

Imaging OptionsImaging Options– Duplex ultrasound, MRA, CT Duplex ultrasound, MRA, CT

angiographyangiography

Diagnostic Tests for Renal Artery Stenosis in Patients Suspected of Having Diagnostic Tests for Renal Artery Stenosis in Patients Suspected of Having Renovascular Hypertension: A Meta-Analysis Renovascular Hypertension: A Meta-Analysis

G. Boudewijn C. Vasbinder, MD; Patricia J. Nelemans, MD, PhD; Alfons G.H. Kesse G. Boudewijn C. Vasbinder, MD; Patricia J. Nelemans, MD, PhD; Alfons G.H. Kessels, MD, MSc; Abraham A. Kroon, MD, PhD; Peter W. de Leeuw, MD, PhD; and Jos M.ls, MD, MSc; Abraham A. Kroon, MD, PhD; Peter W. de Leeuw, MD, PhD; and Jos M.A. van Engelshoven, MD, PhD A. van Engelshoven, MD, PhD

18 September 2001 | Volume 135 Issue 6 | Pages 401-41118 September 2001 | Volume 135 Issue 6 | Pages 401-411

Our meta-analysis indicates that CTA and gadolinium-Our meta-analysis indicates that CTA and gadolinium-enhanced MRA are superior to the other studied enhanced MRA are superior to the other studied diagnostic tests for the detection of diagnostic tests for the detection of renalrenal arteryartery stenosisstenosis. Careful selection based on clinical evaluation, . Careful selection based on clinical evaluation, which can increase the pretest probability to 20% to which can increase the pretest probability to 20% to 40%, is a prerequisite for cost-effective use of these 40%, is a prerequisite for cost-effective use of these tests in the work-up strategy for patients with possible tests in the work-up strategy for patients with possible renovascular hypertension Because only a limited renovascular hypertension Because only a limited number of published studies on CTA and gadolinium-number of published studies on CTA and gadolinium-enhanced MRA could be included in our meta-analysis, enhanced MRA could be included in our meta-analysis, further research is recommended. further research is recommended.

What is the definition of RAS?What is the definition of RAS?

Stenosis is considered >=50% luminal narrowingStenosis is considered >=50% luminal narrowing

Clinically relevant (also called “critical”) stenosis Clinically relevant (also called “critical”) stenosis is not well defined (50-70% by some is not well defined (50-70% by some pharmacologic studies vs. 80% by renal vein pharmacologic studies vs. 80% by renal vein reninrenin

Response to intervention does not correlate well Response to intervention does not correlate well with pre or post treatment degree of stenosiswith pre or post treatment degree of stenosis

What is the natural history of RAS?What is the natural history of RAS?

RAS is part of a systemic disease that RAS is part of a systemic disease that effects the entire vascular tree and both effects the entire vascular tree and both kidneyskidneys

Patients are at greater risk for CV events Patients are at greater risk for CV events than of ESRDthan of ESRD

Angiographic progression occurs in 49% Angiographic progression occurs in 49% and occlusion occurs 14%and occlusion occurs 14%

Renal atrophy over two years was 11.7% Renal atrophy over two years was 11.7% vs. 20.8% for stenoses <60% and >=60% vs. 20.8% for stenoses <60% and >=60% respectivelyrespectively

Goals of Management of RAS Goals of Management of RAS

Prevention of clinical events such as Prevention of clinical events such as stroke, MI, chf, or renal failurestroke, MI, chf, or renal failure

Surrogate markers or goals are:Surrogate markers or goals are:– Improvement or normalization of BPImprovement or normalization of BP– Restoration of renal artery patencyRestoration of renal artery patency

November 2003 • Volume 42 • Number 5 Controversies in nephrology

Stable patients with atherosclerotic renal artery stenosis should be treated first with medical management

Medical Therapy vs. Medical Therapy vs. RevascularizationRevascularization

Medical therapies such as Medical therapies such as antihypertensives, antiplatelet agents and antihypertensives, antiplatelet agents and lipid lowering agents will not restore lipid lowering agents will not restore patency, may or may not improve BP, but patency, may or may not improve BP, but have proven efficacy in the reduction of have proven efficacy in the reduction of CV events and deathCV events and death

Renal artery revascularization can restore Renal artery revascularization can restore patency, has at best a modest effect on BP patency, has at best a modest effect on BP , and has no clearly documented effect in , and has no clearly documented effect in the prevention of renal failure or CV the prevention of renal failure or CV eventsevents

The Role for Inhibition of the RAASThe Role for Inhibition of the RAAS

108 patients at high risk for severe RAS 108 patients at high risk for severe RAS were treated with ACEI with diureticswere treated with ACEI with diuretics– 44 with bilateral stenosis44 with bilateral stenosis– 29 with a solitary functioning kidney29 with a solitary functioning kidney– 20 with unilateral stenosis20 with unilateral stenosis

57 developed >=20% rise in creatinine 57 developed >=20% rise in creatinine between 4 days and 4 weeks (about half between 4 days and 4 weeks (about half early)early)– All recovered to baseline after stopping the All recovered to baseline after stopping the

ACEIACEI– KI 1998; 53:986-993KI 1998; 53:986-993

Predictors of Poor Response to Predictors of Poor Response to RevascularizationRevascularization

Elevated Resistive Indices that are Elevated Resistive Indices that are indicative of glomerulosclerosis and indicative of glomerulosclerosis and interstitial fibrosisinterstitial fibrosis

Advancing AgeAdvancing Age Small kidney sizeSmall kidney size

Complications of renal artery Complications of renal artery revascularizationrevascularization

Serious complications excluding Serious complications excluding hematomas occurred in 11% of renal hematomas occurred in 11% of renal artery stent proceduresartery stent procedures

9.5% incidence of clinical 9.5% incidence of clinical atheroembolic eventsatheroembolic events

~5% incidence of ARF~5% incidence of ARF 5 fatalities in a meta-analysis of 644 5 fatalities in a meta-analysis of 644

patientspatients

Role for RevascularizationRole for Revascularization

Resistant hypertensionResistant hypertension Patients intolerant of ACEI or ARB Patients intolerant of ACEI or ARB

with severe hypertension (more than with severe hypertension (more than 20% increase in serum creatinine)20% increase in serum creatinine)

Patients with rapidly declining renal Patients with rapidly declining renal function (1/3 may benefit)function (1/3 may benefit)

Recurrent or intractable pulmonary Recurrent or intractable pulmonary edemaedema

SummarySummary

Establish Dx, risks and benefitsEstablish Dx, risks and benefits Eliminate interference and optimize Eliminate interference and optimize

lifestyle, adherence and regimen lifestyle, adherence and regimen Consider secondary causesConsider secondary causes See frequently and modify regimen See frequently and modify regimen

ReferencesReferences The Seventh Report of the The Seventh Report of the

Joint National Committee Joint National Committee on Prevention, Detection, on Prevention, Detection, Evaluation, and Treatment Evaluation, and Treatment of High Blood Pressureof High Blood Pressure

European Society of European Society of Hypertension Newsletter Hypertension Newsletter 2003; 4, No. 152003; 4, No. 15

Minireview: Primary Minireview: Primary Aldosteronism-Changing Aldosteronism-Changing Concepts in Diagnosis and Concepts in Diagnosis and Treatment. Endo Treatment. Endo 144(6):2208-2213144(6):2208-2213

Obesity, Sleep Apnea, and Obesity, Sleep Apnea, and Hypertension. Hypertension. Hypertension Dec Hypertension Dec 2003:1067-10742003:1067-1074

Clinical Usefulness of Clinical Usefulness of Ambulatory Blood Pressure Ambulatory Blood Pressure Monitoring. J Am Soc Neph Monitoring. J Am Soc Neph 15: S30-S33, 200415: S30-S33, 2004

Mayo Clinic Proceedings Mayo Clinic Proceedings March 2000. 278-284March 2000. 278-284