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

2. Objectives 1.Review JNC-7 Guidelines 2.Understand common barriers to achieving blood pressure control 3.Review some causes of secondary hypertension. 4.Review recent advances in our understanding of the HTN management

3. JNC-7* Highlights  CVD risk doubles with each 20/10mmHg increment over 115/75  SBP more important CV risk factor  Two or more agents usually required  Thiazides are first choice and first line  Consider 2 agents if BP >20/10 above goal  Targets –140/90 –130/80 if diabetic or CKD *Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure, 7 th Report http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf.http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf

4. HTN Classification

5. Meds: Compelling Indications

6. HTN Control: Clinical Impact  Decreased CVD Incidence –Stroke:35-40% –MI: 20-25% –CHF: >50%  12mmHg BP reduction over 10 yrs will prevent one death in every 11 patients  NNT is 9 patients with underlying CVD or target organ damage

7. BP Control in Clinical Settings  >70% non-diabetic & diabetic patients with sub-optimal control  91% adherent to regimens  70% taking fewer than 3 antihypertensives  “Therapeutic Inertia”: –45% did not have therapy intensified at first f/u visit –36% had no change at 2 nd f/u visit

8. Challenges to Improving Blood Pressure Control Four Cases of Refractory Hypertension

9. Barriers to HTN control  Cost  Medication side effects  Lack of gratifying response to therapy (patient does not feel better)  Need for lifestyle changes  Tedium: titration- requiring multiple visits & close monitoring by MD & patient

10. Case 1 Visit 1  61 yo female with HTN, hyperparathyroidism, h/o DVT  Presents with “pins & needles” in LE’s  Meds –coumadin, Sensipar –amlodipine, lisinopril, furosemide, HCTZ, metoprolol  Social Hx: non-smoker,uninsured  BP 194/129 (re-check, 172/111); ?non- adherence to one medication; recent SBP’s ~140  Labs: Na 145, K 3.7, Cr 0.8, Ca 11.7, B12 465  Dispo: Restart meds & f/u 4 days

11. Case 1 Visit 2  c/o Fatigue  Patient confirms medications  BP 204/132 (re-check, 210/135)  Receives clonidine in clinic & admitted for hypertensive urgency & management of hypercalcemia

12. Case 1 Hospitalization & Visit 3  Hydrated with decrease in Ca++  Source of HTN identified: non-adherence d/t inability to afford meds  D/C Meds: lisinopril, metoprolol, furosemide (Walmart $4drugs to rescue)  BP at f/u 147/101  Amlodipine added

13. Obstacles to Optimizing HTN Management  Adherence –Cost –Literacy!  Clinical Uncertainty –50% doctors don’t intervene due to uncertainty about accuracy of triage BP (home blood pressures lower)  Competing Medical Demands –Trial evidence conflicting about influence of multiple comorbididities  Time constraints –Largely unstudied

14. Case 2  54 yo female with HTN, diabetes, hypercholesterolemia  BP Meds: amlodipine, lisinopril, HCTZ spironolactone  BP 7/09: 166/83; A1c 9.0%: Substitute chlorthalidone for HCTZ  BP 1/09: 164/68; A1c: 7.3%: ?Non- adherence to one med

15. Case 2  Social Hx: No tobacco; no ETOH; h/o cocaine use but denies current.

16. Drugs That Cause HTN  Drugs of abuse –Cocaine, methamphetamine –Alcohol  OTC decongestants  Prescription –Venlafaxine/SNRIs –Estrogens/OCP’s –Corticosteroids –Namenda –Erythropoietin –Tacrolimus/Cyclosporin

17. Case 3  62 yo male with HTN, palpitations, myalgias  Meds: felodipine (5mg), atenolol (100mg), benazepril (20mg), minoxidil (10mg prn elevated BP), KCL 80mEq/d  Social: no tobacco; retired farmer  ROS: no CP, no SOB/DOE, no syncope  BP 182/99, P 64. +S4 gallop  Labs: K+ 2.8; aldo 90, renin <0.2 (ratio=450)

18. Case 3  Dx: Hyperaldosteronism  Etiology: Adrenal adenoma (rare malignancy), adrenal hyperplasia  W/U: –Aldo/Renin: Ratio >30 suggests primary hyperaldosteronism –MRI of abdomen  Rx –Medical: spironolactone –?Surgery

19. Case 3: Denouement  Spironolactone, 100mg bid started  Orthostasis at home with SBP’s in 70’s  Decreased minoxidil to 5mg/d and atenolol to 50mg/d  BP 139/90  K+ (4.7)-palpitations, myalgias resolved.

20. Case 4  77yo female with refractory HTN, diet controlled DM, obesity, OA

21. Case 4  BP 159/79 (Re-check, 160/79)  ROS: Daytime sleepiness, snoring, night- time arousals  K+ 4.1, Cr 0.87  Sleep study: OSA  Denouement: Awaiting outcome of CPAP trial

22. The ACCOMPLISH Trial

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

24. Study design  Total 11,506 patients recruited for study  Multi-center  Randomized, double-blind trial  Similar patient demographic and co- morbidities in each group  Intention to treat model

25. Who are the patients? This study has a high predominance of patients who are elderly, obese, Caucasian, have multiple co-morbidities (including diabetes, dyslipidemia, and CAD), and difficult to control HTN, requiring multiple agents. “at high risk for cardiac events”

26. Who are the patients?  38% Receiving 3 or more drugs at enrolment  Only 37% had BP <140/70  60% had diabetes  Average age 68yrs (fairly geriatric)

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

28. Study Endpoints Primary endpoint  Time to first event  One event per patient  Composite of a cardiovascular event and death from cardiovascular causes Secondary endpoints  Multiple events counted for a patient  Including composite of cardiovascular events, hospitalization from heart failure, death from any cause

29. Results: Improved BP Control  Both benazepril/ amlodipine and benazepril/ HCTZ combination therapy improved blood pressure control AmlodipineHCTZ Mean SBP 131.6132.5 Mean DBP 73.374.4 % BP <140/90 75.472.4

30. Results: CV Mortality and Events Benazepril/amlodipine group saw:  Decreased primary endpoints at 30 mos.  Decrease secondary endpoints: death from CV causes, non-fatal MI< stroke  Early cessation of study by safety & monitoring committee when pre-specified thresholds for termination seen in Ace/CCB arm d/t efficacy

31. Kaplan-Meier Curve: Time to First Primary Composite Endpoint

32. Results: Primary Endpoints Primary endpoint at 30 months Benazepril/ Amlodipine (%) Benazepril/HCTZ(%)ARR(EER-CER)(%)RRR(ARR/CER)(%) All9.611.82.219.6 Male10.613.12.519 Female8.19.71.616.4 Age >65 10.112.42.318.5 Age >70 1113.82.820.2 +DM8.8112.220 - DM 10.812.92.116.2

33. Drug Costs Drug name Cost for 30 day supply Enalapril 5 mg -20 mg $4 HCTZ 12.5-25 mg $4 Atenolol 25 mg- 100 mg $4 Amlodipine (Norvasc) 5 mg $75 Amlodipine (generic) 5 mg $21 Adapted from Blue Cross Blue Shield of North Carolina and WalMart $4 pharmacy list 90 supply available from Drugstore.com for $18