refractory hypertension: four cases paul r. chelminski, md, mph, facp associate professor of...
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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