Resistant Hypertension

1. Resistant Hypertension

2. Outline • Definition • Prevalence • Risk Factors • Secondary / Identifiable Causes HTN • Elaboration on primary aldosteronism • Treatment • Assessing accurately • Evaluate lifestyle factors • Minimize interfering drugs • If appropriate, screen for secondary causes • Medications

3. Definition • Blood pressure greater than goal in spite of concurrent use of 3 optimally dosed medications, with one of the medications being a diuretic. • Controlled blood pressure requiring 4 or more medications to do so. • Normal blood pressure per JNC 7: <120 /80 • Goal for diabetic patients per the ADA and JNC 7: < 130/80 • Classification of Blood Pressure for Adults per JNC 7 • Prehypertension 120-139/80-89 • Stage 1 HTN 140-159/90-99 • Stage 2 HTN > 160/100

4. Prevalence • Actual prevalence unknown • Cross-sectional studies and hypertension outcome studies suggest that it is not uncommon • National Health and Nutrition Examination Survey (NHANES)(8) • 53% controlled < 140/90 • 37% with CKD controlled to < 130/80 • 25% with DM controlled to <130/80 • Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)(13) • After 5 yr f/u, 34% uncontrolled on an average of 2 medications

5. Risk Factors Associated with Resistant Hypertension • Older age • High baseline blood pressure • Obesity • Excessive dietary salt ingestion • Excessive alcohol ingestion • Chronic kidney disease • Diabetes • Left ventricular hypertrophy • Black race • Female sex • Residence in southeastern United States • Inadequate diuretic therapy • Use of certain drugs: NSAIDS, sympathomimetics, oral contraceptives, cyclosporine and tacrolimus, stimulants, ephedra, ma haung, bitter orange, licorice

6. Secondary or Identifiable Causes of Resistant Hypertension • Common • Obstructive sleep apnea • Renal parenchymal disease • Primary aldosteronism • Renal artery stenosis • Uncommon • Pheochromocytoma • Cushing’s disease • Hyperparathyroidism • Aortic coarctation • Intracranial tumor

7. Primary Aldosteronism • Common in patients with resistant hypertension • Studies of resistant hypertension showing prevalence between 17 to 23%(1,5,10,11,12) • Circulating aldosterone levels positively correlate with incident, resistant, and obesity- and obstructive sleep apnea-related hypertension, as well as impaired LV function • The Endocrine Society in their 2008 Clinical Practice Guideline(6) regarding Primary Aldosteronism recommend screening the following patient groups: • JNC 7 Stage 2 HTN, ie BP > 160/100 • Resistant HTN • HTN with either spontaneous or diuretic-induced hypokalemia • HTN with adrenal incidentaloma • HTN with family history of early-onset HTN or CVA at < 40 yr age

8. More on primary aldosteronism • How aldosterone effects blood pressure • Acts on renal cortical collecting ducts via mineralocortocoid receptor which increases expression of the sodium/potassium ATPase, resulting in reabsorption of sodium and excretion of potassium • Non-genomically activates the amiloride-sensitive epithelial sodium channel (ENaC) in cortical collecting duct resulting in reabsorption of sodium and excretion of potassium (insulin does this as well) • Hypokalemia induces hypertension (14) • Several studies demonstrating reduced systolic and diastolic blood pressures with use of spironolactone, eplerenone, and amiloride (2,4) • One study showing reduction of systolic and diastolic blood pressures by 25 and 12 mm Hg , respectively. • Recommended screening test is a morning plasma aldosterone/renin activity ratio, with a high (abnormal) ratio being 20 to 30 or greater when aldosterone reported in nanograms/dl and renin activity in nanograms/ml/hour. (1,6)

9. Therapeutic Approach to Resistant Hypertension • Accurate assessment of blood pressure • Proper technique: sitting 5 minutes with back supported, arm at heart level, air bladder encircling at least 80% of arm, measure in both arms (and in a leg at least once), take at least two measurements separated by one minute and average, and do this at least twice • Exclude white coat HTN • Consider pseudohypertension

10. Evaluate Lifestyle Factors • Obesity • Excessive salt use • AHA recommends use of 2.3 gram of sodium a day or less (= 100 meq of sodium) • DASH low sodium diet • Excessive alcohol use • Limit for men is 24 ounces beer or 10 ounces wine or 3 ounces of 80 proof liquor/day • Limit for women is half of men’s

11. Drug –induced causes of resistant hypertension • Inadequate diuretic therapy • Inadequate doses of anti-hypertensives • Noncompliance with prescribed BP meds • Use of the following classes of drugs: • NSAIDS, including ASA and acetominophen • Cocaine, amphetamines • Sympathomimetics (decongestents, anorectics) • Oral contraceptive hormones • Cyclosporine and tacrolimus • Erythropoietin • Licorice (included in chewing tobacco) • Herbs such as ma haung, ephedra, bitter orange

12. Screening for Secondary/Identifiable Causes of HTN • Chronic kidney disease Estimated GFR • Coarctation of the aorta Measure leg pressure, CT angiography • Cushing syndrome, chronic steroid RX History/dexamethasone suppression • Drug-induced/related History; drug screening • Pheochromocytoma 24-hour urinary metanephrine,normetanephrine • Primary aldosteronism 24-hour urinary aldosterone level or aldosterone/renin activity ratio • Renovascular hypertension Doppler flow study; magnetic resonance angiography • Sleep apnea Sleep study with O2 saturation • Thyroid/parathyroid disease TSH; serum

13. Medications • General principle: combine agents of different mechanisms • Little data assessing the efficacy of specific combinations of 3 or more drugs • Need to consider co-morbid conditions when choosing agents, eg. CHF, DM, albuminuria, ischemic heart disease, LVH • Notes from JNC 7 and AHA Scientific Statement re: Resistant HTN • Chlorthalidone should be preferentially used as opposed to hydrochlorothiazide • In patients with eGFR < 60 ml/min or CHF, may need to use loop diuretic • Spironolactone, eplerenone, and amiloride all have studies showing good effects, but unable to use in patient with serum K+ > 5.0 or serum Creatinine men > 2.5 or in women >2.0 • In regards to LVH, order of preference is diuretics, ACEi, dihydropine CCB, and BB • Labetolol, having both beta and alpha blocking properties, is sometimes more effective than selective beta only blockers

14. Resources • Resistant Hypertension: Diagnosis, Evaluation, and Treatment. A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Published online Apr 7, 2008, located at http://hyper.ahajournals.org • Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. HTN. 2003; 42: 1206-1252 • Enac, Hormones, and HTN. Published online May 11, 2010, located at http://www.jbc.org/cigi/doi/10.1074/jbc.R109.025049 • Aldosterone Receptor Antagonists Circulation. 2010; 121: 934-939

15. Resources • Hyperaldosteronism Among Black and White Subjects With Resistant Hypertension HTN. 2002; 40: 892-896 6. Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology & Metabolism 2008. 93; 3266-3281 • Nishizaka MK Am J Hypertension 2003; 16: 925-930 • NHANES. Trends in Prevalence, Awareness, Treatment and Control of HTN in the US, 1988-2000. JAMA 2003; 290: 199-206 • J. Clinical Hypertension 2002; 4: 393-404 • Am J Kidney Dis. 2001; 37: 699-705 • J Hypertension 2004; 22: 2217-2226 • J Am CollCardiol 2006; 48: 2293-2300 • ALLHAT. JAMA. 2002; 288: 2981-2997 • CurrHypertens Rep . 2008; 10: 496-503