Refractory Hypertension: Four Cases Paul R. Chelminski, MD, MPH, FACP Associate Professor of Medicine Associate Residency Program Director.

Refractory Hypertension:Refractory Hypertension:Four CasesFour Cases

Paul R. Chelminski, MD, MPH, FACPPaul R. Chelminski, MD, MPH, FACP

Associate Professor of MedicineAssociate Professor of Medicine

Associate Residency Program DirectorAssociate Residency Program Director

ObjectivesObjectives

1.Review JNC-7 Guidelines 1.Review JNC-7 Guidelines

2.Understand common barriers to achieving 2.Understand common barriers to achieving blood pressure control blood pressure control

3.Review some causes of secondary 3.Review some causes of secondary hypertension.hypertension.

4.Review recent advances in our 4.Review recent advances in our understanding of the HTN managementunderstanding of the HTN management

JNC-7* HighlightsJNC-7* Highlights

CVD risk doubles with each 20/10mmHg CVD risk doubles with each 20/10mmHg increment over 115/75increment over 115/75

SBP more important CV risk factorSBP more important CV risk factor Two or more agents usually requiredTwo or more agents usually required Thiazides are first choice and first lineThiazides are first choice and first line Consider 2 agents if BP >20/10 above goalConsider 2 agents if BP >20/10 above goal TargetsTargets

– 140/90140/90– 130/80 if diabetic or CKD130/80 if diabetic or CKD

*Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure, 7th Report http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf.

HTN ClassificationHTN Classification

Meds: Compelling IndicationsMeds: Compelling Indications

HTN Control: Clinical ImpactHTN Control: Clinical Impact

Decreased CVD IncidenceDecreased CVD Incidence– Stroke:35-40%Stroke:35-40%– MI: 20-25%MI: 20-25%– CHF: >50%CHF: >50%

12mmHg BP reduction over 10 yrs will 12mmHg BP reduction over 10 yrs will prevent one death in every 11 patientsprevent one death in every 11 patients

NNT is 9 patients with underlying CVD or NNT is 9 patients with underlying CVD or target organ damage target organ damage

BP Control in Clinical SettingsBP Control in Clinical Settings

>70% non-diabetic & diabetic patients with >70% non-diabetic & diabetic patients with sub-optimal controlsub-optimal control

91% adherent to regimens91% adherent to regimens 70% taking fewer than 3 antihypertensives70% taking fewer than 3 antihypertensives ““Therapeutic Inertia”:Therapeutic Inertia”:

– 45% did not have therapy intensified at first f/u 45% did not have therapy intensified at first f/u visitvisit

– 36% had no change at 236% had no change at 2ndnd f/u visit f/u visit

Challenges to Improving Challenges to Improving Blood Pressure ControlBlood Pressure Control

Four Cases of Refractory Four Cases of Refractory

HypertensionHypertension

Barriers to HTN controlBarriers to HTN control

CostCost Medication side effectsMedication side effects Lack of gratifying response to therapy Lack of gratifying response to therapy

(patient does not feel better)(patient does not feel better) Need for lifestyle changesNeed for lifestyle changes Tedium: titration- requiring multiple visits & Tedium: titration- requiring multiple visits &

close monitoring by MD & patient close monitoring by MD & patient

Case 1Case 1

Visit 1Visit 1 61 yo female with HTN, hyperparathyroidism, 61 yo female with HTN, hyperparathyroidism,

h/o DVTh/o DVT Presents with “pins & needles” in LE’sPresents with “pins & needles” in LE’s MedsMeds

– coumadin, Sensiparcoumadin, Sensipar– amlodipine, lisinopril, furosemide, HCTZ, metoprololamlodipine, lisinopril, furosemide, HCTZ, metoprolol

Social Hx: non-smoker,uninsuredSocial Hx: non-smoker,uninsured BP 194/129 (re-check, 172/111); ?non-BP 194/129 (re-check, 172/111); ?non-

adherence to one medication; recent SBP’s adherence to one medication; recent SBP’s ~140~140

Labs: Na 145, K 3.7, Cr 0.8, Ca 11.7, B12 465Labs: Na 145, K 3.7, Cr 0.8, Ca 11.7, B12 465 Dispo: Restart meds & f/u 4 daysDispo: Restart meds & f/u 4 days

Case 1Case 1

Visit 2Visit 2 c/o Fatiguec/o Fatigue Patient confirms medicationsPatient confirms medications BP 204/132 (re-check, 210/135)BP 204/132 (re-check, 210/135) Receives clonidine in clinic & admitted for Receives clonidine in clinic & admitted for

hypertensive urgency & management of hypertensive urgency & management of hypercalcemiahypercalcemia

Case 1Case 1

Hospitalization & Visit 3Hospitalization & Visit 3 Hydrated with decrease in Ca++Hydrated with decrease in Ca++ Source of HTN identified: non-adherence d/t Source of HTN identified: non-adherence d/t

inability to afford medsinability to afford meds D/C Meds: lisinopril, metoprolol, furosemide D/C Meds: lisinopril, metoprolol, furosemide

(Walmart $4drugs to rescue)(Walmart $4drugs to rescue) BP at f/u 147/101BP at f/u 147/101 Amlodipine addedAmlodipine added

Obstacles to Optimizing HTN Obstacles to Optimizing HTN ManagementManagement

AdherenceAdherence– CostCost– Literacy!Literacy!

Clinical UncertaintyClinical Uncertainty– 50% doctors don’t intervene due to uncertainty about 50% doctors don’t intervene due to uncertainty about

accuracy of triage BP (home blood pressures lower)accuracy of triage BP (home blood pressures lower) Competing Medical DemandsCompeting Medical Demands

– Trial evidence conflicting about influence of multiple Trial evidence conflicting about influence of multiple comorbididitiescomorbididities

Time constraintsTime constraints– Largely unstudiedLargely unstudied

Case 2Case 2

54 yo female with HTN, diabetes, 54 yo female with HTN, diabetes, hypercholesterolemiahypercholesterolemia

BP Meds: amlodipine, lisinopril, HCTZ BP Meds: amlodipine, lisinopril, HCTZ spironolactonespironolactone

BP 7/09: 166/83; A1c 9.0%: Substitute BP 7/09: 166/83; A1c 9.0%: Substitute chlorthalidone for HCTZchlorthalidone for HCTZ

BP 1/09: 164/68; A1c: 7.3%: ?Non-BP 1/09: 164/68; A1c: 7.3%: ?Non-adherence to one medadherence to one med

Case 2Case 2

Social Hx: No tobacco; no ETOH; h/o Social Hx: No tobacco; no ETOH; h/o cocaine use but denies current.cocaine use but denies current.

Drugs That Cause HTNDrugs That Cause HTN

Drugs of abuse Drugs of abuse – Cocaine, methamphetamineCocaine, methamphetamine– AlcoholAlcohol

OTC decongestantsOTC decongestants PrescriptionPrescription

– Venlafaxine/SNRIsVenlafaxine/SNRIs– Estrogens/OCP’sEstrogens/OCP’s– CorticosteroidsCorticosteroids– NamendaNamenda– ErythropoietinErythropoietin– Tacrolimus/CyclosporinTacrolimus/Cyclosporin

Case 3Case 3

62 yo male with HTN, palpitations, myalgias62 yo male with HTN, palpitations, myalgias Meds: felodipine (5mg), atenolol (100mg), Meds: felodipine (5mg), atenolol (100mg),

benazepril (20mg), minoxidil (10mg prn elevated benazepril (20mg), minoxidil (10mg prn elevated BP), KCL 80mEq/dBP), KCL 80mEq/d

Social: no tobacco; retired farmerSocial: no tobacco; retired farmer ROS: no CP, no SOB/DOE, no syncopeROS: no CP, no SOB/DOE, no syncope BP 182/99, P 64. +S4 gallopBP 182/99, P 64. +S4 gallop Labs: K+ 2.8; aldo 90, renin <0.2 (ratio=450)Labs: K+ 2.8; aldo 90, renin <0.2 (ratio=450)

Case 3Case 3

Dx: HyperaldosteronismDx: Hyperaldosteronism Etiology: Adrenal adenoma (rare malignancy), Etiology: Adrenal adenoma (rare malignancy),

adrenal hyperplasiaadrenal hyperplasia W/U: W/U:

– Aldo/Renin: Ratio >30 suggests primary Aldo/Renin: Ratio >30 suggests primary hyperaldosteronismhyperaldosteronism

– MRI of abdomenMRI of abdomen RxRx

– Medical: spironolactoneMedical: spironolactone– ?Surgery?Surgery

Case 3: DenouementCase 3: Denouement

Spironolactone, 100mg bid startedSpironolactone, 100mg bid started Orthostasis at home with SBP’s in 70’sOrthostasis at home with SBP’s in 70’s Decreased minoxidil to 5mg/d and atenolol Decreased minoxidil to 5mg/d and atenolol

to 50mg/dto 50mg/d BP 139/90BP 139/90 K+ (4.7)-palpitations, myalgias resolved.K+ (4.7)-palpitations, myalgias resolved.

Case 4Case 4 77yo female with refractory HTN, diet 77yo female with refractory HTN, diet controlled DM, obesity, OAcontrolled DM, obesity, OA

Case 4Case 4

BP 159/79 (Re-check, 160/79)BP 159/79 (Re-check, 160/79) ROS: Daytime sleepiness, snoring, night-ROS: Daytime sleepiness, snoring, night-

time arousalstime arousals K+ 4.1, Cr 0.87K+ 4.1, Cr 0.87 Sleep study: OSASleep study: OSA Denouement: Awaiting outcome of CPAP Denouement: Awaiting outcome of CPAP

trialtrial

The ACCOMPLISH TrialThe ACCOMPLISH Trial

Study objectiveStudy objective

Comparison of cardiovascular events between Comparison of cardiovascular events between group treated with combination benazepril-HCTZ group treated with combination benazepril-HCTZ versus combination benazepril-amlodipine, with versus combination benazepril-amlodipine, with hypothesis that benazepril-amlodipine would be hypothesis that benazepril-amlodipine would be superior in reducing cardiovascular events.superior in reducing cardiovascular events.

HCTZ

Study designStudy design

Total 11,506 patients recruited for studyTotal 11,506 patients recruited for study Multi-center Multi-center Randomized, double-blind trialRandomized, double-blind trial Similar patient demographic and co-Similar patient demographic and co-

morbidities in each groupmorbidities in each group Intention to treat modelIntention to treat model

Who are the patients?Who are the patients?

This study has a high This study has a high predominance of patients predominance of patients who are elderly, obese, who are elderly, obese, Caucasian, have multiple Caucasian, have multiple co-morbidities (including co-morbidities (including diabetes, dyslipidemia, diabetes, dyslipidemia, and CAD), and difficult to and CAD), and difficult to control HTN, requiring control HTN, requiring multiple agents. multiple agents.

““at high risk for cardiac events”at high risk for cardiac events”

Who are the patients?Who are the patients?

38% Receiving 3 or more drugs at 38% Receiving 3 or more drugs at enrolmentenrolment

Only 37% had BP <140/70Only 37% had BP <140/70 60% had diabetes60% had diabetes Average age 68yrs (fairly geriatric)Average age 68yrs (fairly geriatric)

Study procedures Study procedures (cont’d)(cont’d)Algorithm outlined by study for Algorithm outlined by study for optimization of blood pressure optimization of blood pressure controlcontrol

Patient randomized

20 mg benazepril 5 mg amlodipine

20 mg benazepril 12.5 mg HCTZ

One month

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

40 mg benazepril 5 mg amlodipine

40 mg benazepril 12.5 mg HCTZ

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

Yes Yes No No

Continue current regimen

Continue current regimen

40 mg benazepril 10 mg amlodipine

40 mg benazepril 25 mg HCTZ

Three months

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

BP > 140/90 without diabetes OR

BP > 130/80 with diabetes

Six months

Add other agents Eg beta blocker, alpha blocker,

clonidine, spironolactone

Study EndpointsStudy Endpoints

Primary endpointPrimary endpoint Time to first eventTime to first event One event per patientOne event per patient Composite of a Composite of a

cardiovascular event cardiovascular event and death from and death from cardiovascular causes cardiovascular causes

Secondary endpointsSecondary endpoints Multiple events Multiple events

counted for a patientcounted for a patient Including composite of Including composite of

cardiovascular events, cardiovascular events, hospitalization from hospitalization from heart failure, death heart failure, death from any causefrom any cause

Results: Improved BP ControlResults: Improved BP Control

Both benazepril/ amlodipine and benazepril/ Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood HCTZ combination therapy improved blood pressure controlpressure control

AmlodipineAmlodipine HCTZHCTZ

Mean SBPMean SBP 131.6131.6 132.5132.5

Mean DBPMean DBP 73.373.3 74.474.4

% BP <140/90% BP <140/90 75.475.4 72.472.4

Results: CV Mortality and Events Results: CV Mortality and Events

Benazepril/amlodipine group saw:Benazepril/amlodipine group saw: Decreased primary endpoints at 30 mos.Decreased primary endpoints at 30 mos. Decrease secondary endpoints: death from Decrease secondary endpoints: death from

CV causes, non-fatal MI< strokeCV causes, non-fatal MI< stroke Early cessation of study by safety & Early cessation of study by safety &

monitoring committee when pre-specified monitoring committee when pre-specified thresholds for termination seen in Ace/CCB thresholds for termination seen in Ace/CCB arm d/t efficacyarm d/t efficacy

Kaplan-Meier Curve:Kaplan-Meier Curve:Time to First Primary Composite EndpointTime to First Primary Composite Endpoint

Results: Primary EndpointsResults: Primary Endpoints

Primary Primary endpoint at endpoint at 30 months30 months

Benazepril/Benazepril/Amlodipine Amlodipine (%)(%)

Benazepril/Benazepril/HCTZHCTZ(%)(%)

ARRARR(EER-CER)(EER-CER)(%)(%)

RRRRRR(ARR/CER)(ARR/CER)(%)(%)

AllAll 9.69.6 11.811.8 2.22.2 19.619.6

MaleMale 10.610.6 13.113.1 2.52.5 1919

FemaleFemale 8.18.1 9.79.7 1.61.6 16.416.4

Age >65Age >65 10.110.1 12.412.4 2.32.3 18.518.5

Age >70Age >70 1111 13.813.8 2.82.8 20.220.2

+DM+DM 8.88.8 1111 2.22.2 2020

- DM- DM 10.810.8 12.912.9 2.12.1 16.216.2

Drug Costs Drug Costs

Drug nameDrug name Cost for 30 day supplyCost for 30 day supply

Enalapril 5 mg -20 mgEnalapril 5 mg -20 mg $4$4

HCTZ 12.5-25 mgHCTZ 12.5-25 mg $4$4

Atenolol 25 mg- 100 mgAtenolol 25 mg- 100 mg $4$4

Amlodipine (Norvasc) 5 mgAmlodipine (Norvasc) 5 mg $75$75

Amlodipine (generic) 5 mgAmlodipine (generic) 5 mg $21$21

Adapted from Blue Cross Blue Shield of North Carolina and WalMart $4 pharmacy list

90 supply available from Drugstore.com for $18