1. Treatment-Resistant Hypertension: Diagnosis and Management Power Over Pressure www.poweroverpressure.com

2. A particularly complex clinical challenge Blood pressure (BP) that remains above goal, in spite of… *All medications should be titrated to the maximum in-label doses or until BP control is achieved, except in cases of intolerance, in which case treatments should be optimized to the maximum tolerated doses † Patients who require  4 antihypertensive agents to achieve BP control are also considered treatment resistant, according to some sources. 1 1.Calhoun DA, et al. Circulation. 2008;117:e510-e526. 2.Mancia G, et al. Eur Heart J. 2007;28:1462-1536. Treatment-resistant hypertension is defined as: 1,2 compliance with maximum doses*… of  3 antihypertensive medications † … from different classes, ideally including a diuretic… BP Goal Reversible causes identified and addressed Power Over Pressure www.poweroverpressure.com

3. A common and increasing problem 1.Persell, S. Hypertension. 2011;57:1076-1080. 2.Hypertension and cardiovascular disease. World Heart Federation. 2011. http://www.world-heart- federation.org/cardiovascular-health/cardiovascular-disease-risk-factors/hypertension/. Accessed March 2, 2012. 3.Lloyd-Jones D, et al. Circulation. 2010;121:e46-e215. 4.Calhoun DA, et al. Circulation. 2008;117:e510-e526. 5.Egan BM, et al. Circulation. 2011;124:1046-1058. 100 million people worldwide (15% to 20% of uncontrolled hypertension) are estimated to have treatment-resistant hypertension 1,2,3 Despite focused efforts, the percentage of patients resistant to treatment has not fallen with newer medications and strategies; rather it has increased by 62% in the last 20 years* 4,5 *In the time periods 1988-1994 vs 2005-2008, the proportion of treated uncontrolled hypertensive patients reportedly taking ≥3 BP medications increased from 16% to 28%. Power Over Pressure www.poweroverpressure.com

4. Not all patients with uncontrolled hypertension are treatment resistant Uncontrolled Hypertension Includes patients who lack BP control for any reason: 1 Inadequate treatment regimens Poor adherence Undetected secondary hypertension True treatment resistance 1.Calhoun DA, et al. Circulation. 2008;117:e510-e526. 2.Mancia G, et al. Eur Heart J. 2007;28:1462-1536. Treatment-Resistant Hypertension BP that remains above goal with maximum tolerated doses of ≥3 antihypertensive medications* of different classes; ideally, 1 of the 3 agents should be a diuretic 1,2 *Patients who require  4 antihypertensive agents to achieve BP control are also considered treatment resistant, according to some sources. 1 Power Over Pressure www.poweroverpressure.com

5. Black race Excessive dietary salt ingestion Who is at risk? *Based on analyses of data from the Framingham Study and The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Calhoun DA, et al. Circulation. 2008;117:e510-e526. Obesity High baseline blood pressure Older age Chronic kidney disease Diabetes Left ventricular hypertrophy Female sex Patient Characteristics Associated With Treatment-Resistant Hypertension* Power Over Pressure www.poweroverpressure.com

6. In office: Was correct BP measurement technique followed? At home: Has white- coat effect been ruled out? Power Over Pressure www.poweroverpressure.com

7. Technique is a common cause of pseudoresistance A cuff that is too small may cause an erroneously elevated reading 1,2 1.Makris A, et al. Int J Hypertens.2011:598694. 2.Pickering T, et al. Hypertension. 2005;45:142-161. Allow patient to sit quietly for 5 minutes, legs uncrossed with the arm supported at heart level before the reading is taken 1,2 Tips for obtaining accurate office BP readings Other factors that can effect BP readings include recent caffeine, nicotine, or alcohol consumption, full bladder, and background noise 2 Power Over Pressure www.poweroverpressure.com

8. “White-coat” effect What Is It? –BP that is elevated in the clinic setting but significantly lower at home 1 –20%-30% of patients with hypertension may experience white-coat effect 1 When to Suspect? –White-coat resistance may be present in patients with consistently elevated BP but no evidence of target organ damage 2 What to do? – Ensure that the reading is representative of the patient’s usual daytime BP – Automated in-office and out-of-office BP monitoring techniques, including ambulatory BP monitoring and home BP monitoring, can be used to detect white-coat resistance 2 – Home BP monitoring may also increase adherence 3 Power Over Pressure www.poweroverpressure.com 1.Calhoun DA, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526. 2.Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. 3.Parati G, et al. J Hypertens. 2008;26:1505-1526.

9. Automated office BP measurement (AOBP) AOBP has several advantages: Minimizes potential for user error Enables efficient collection of multiple BP readings Reduces patient anxiety and aids in detection of white-coat effect –Average of 5 BP readings taken 1 minute apart, while patient is alone in room, has been shown to approach average waking BP Myers M, et al. Hypertension. 2010;55:195-200. Power Over Pressure www.poweroverpressure.com

10. Is the patient receiving 3 drugs of different classes, preferably including a diuretic, at optimal doses? Does the patient adhere to the treatment regimen? Has the adequacy of pharmacologic therapy been reassessed and intensified if necessary? Power Over Pressure www.poweroverpressure.com

11. Optimizing combination therapy An effective treatment regimen should target multiple mechanisms responsible for BP control 1 –While 3-drug combinations have not been extensively studied, the combination of an ACEI or ARB, a CCB, and a thiazide-like diuretic is effective and well-tolerated 2 If BP control is not achieved, dosages should be titrated to the maximum tolerated or in-label doses 1,2 1.Moser M, Setaro J. N Eng J Med. 2006;355:385-392. 2.Calhoun D, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526. Power Over Pressure www.poweroverpressure.com ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CCB = calcium channel blocker.

12. Combinations of drugs with complementary mechanisms of action improve efficacy and reduce side effects *Not proven beneficial in controlled trials. Reproduced with permission from Mancia G, et al. Eur Heart J. 2007;28:1462-1536. Diuretics  -blockers*  -blockers ARBs CCBs ACEIs Solid lines indicate preferred combinations. Power Over Pressure www.poweroverpressure.com

13. Spironolactone Design: Uncontrolled extension of the ASCOT trial Patients who did not achieve BP control on their assigned 3-drug regimen had additional agents added at investigator’s discretion Population: 1411 patients prescribed spironolactone for HTN in addition to their trial-assigned regimen Treatment: spironolactone 25 mg once daily (median dose) Results: With the addition of spironolactone, mean BP fell by 21.9/9.5 mm Hg (P<0.001). Chapman N, et al. Hypertension. 2007;49:839-845. Spironolactone can be effective in many patients with treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Adverse events*: Experienced by 13% of patients. Gynecomastia (6%) and biochemical abnormalities (2%), mainly hyperkalemia, were most frequent *Among trial participants prescribed spironolactone for any reason. Please see product Prescribing Information for complete information about adverse events.

14. Poor adherence is a common cause of pseudoresistance Van Wijk BLG, et al. J Hypertens. 2005;23:2101-2107. Within just 1 year, more than 1 in 3 patients had already discontinued their medication After 10 years, almost 2 in 3 patients did not take their antihypertensive medications continuously 39% Non-users 39% Continuous users 22% Restarters Percentage of Patients at 10 Years Power Over Pressure www.poweroverpressure.com

15. Tips for assessing and improving medication adherence Signs of nonadherence 1 –Missed office visits –Lack of physiological evidence of therapy, such as No change in BP Absence of anticipated common side effects Check for suspected nonadherence by –Discussing medication use with spouse or caregiver 2 –Verifying prescription refills with the pharmacy –Reviewing factors causing nonadherence and counseling patients on importance of therapy 3 1.Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. 2.Calhoun DA, et al. Circulation. 2008;117:e510-e526. 3.Hill M, et al. J Clin Hypertens. 2010;12:757-764. Power Over Pressure www.poweroverpressure.com

16. Does the patient take interfering substances? Does the patient limit dietary salt intake? Is the patient a heavy alcohol drinker? Is the patient obese? Power Over Pressure www.poweroverpressure.com

17. Patient factors may contribute to treatment resistance Use of interfering substances Certain medications or other drugs may cause elevated BP or inhibit the effects of antihypertensive medications –Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors –Sympathomimetic drugs (ephedra, phenylephrine, cocaine, amphetamines, etc) –Herbal supplements –Anabolic steroids –Appetite suppressants –Erythropoietin –Oral contraceptives Question patients about the use of interfering substances –If possible, discontinue use of these agents; otherwise, consider modifying antihypertensive therapy Calhoun DA, et al. Circulation. 2008;117:e510-e526. Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. Power Over Pressure www.poweroverpressure.com

18. What to expect: lifestyle modification effects on BP Chobanian AV, et al. JAMA. 2003;289:2560-2572. Blumenthal JA, et al. Arch Intern Med. 2000;160:1947-1958. Table courtesy of Hypertension Online. www.hypertensiononline.org Modifications*Recommendation Approximate SBP Reduction Reduce weight Maintain normal body weight (BMI of 18.5-24.9 kg/m 2 ) 3-20 mm Hg Adopt DASH diet Rich in fruit, vegetables, and low-fat dairy; reduced saturated and total fat content 8-14 mm Hg Reduce dietary sodium<100 mmol (2.4 g)/day2-8 mm Hg Increase physical activity Aerobic activity >30 min/day, most days of the week 4-9 mm Hg Moderate alcohol consumption Men: ≤2 drinks/day Women: ≤1 drink/day 2-4 mm Hg *Combining  2 of these modifications may or may not have an additive effect on blood pressure reduction. SBP = systolic blood pressure; BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension. Power Over Pressure www.poweroverpressure.com

19. Understanding stages of change for health-related behaviors 1.Glanz K, Bishop DB. Ann Rev Pub Health. 2010;31:399-418. 2.Prochaska, JO. Med Decis Making. 2008;28:845-849. Contemplation Precontemplation Preparation Action Maintenance Behavioral change is a complex process Sustained behavioral changes in diet and exercise are difficult Movement is not always in a linear manner Prepare the patient in the likely occurrence of relapse Power Over Pressure www.poweroverpressure.com

20. Have secondary causes, particularly renal parenchymal disease, been evaluated? If other possible causes of uncontrolled BP have been eliminated, consider referral to a hypertension specialist for treatment-resistant hypertension. Power Over Pressure www.poweroverpressure.com

21. Difficult-to-control hypertension may be due to underlying conditions A number of medical conditions may contribute to hypertension Patients should be screened for these disorders if suggestive findings are identified upon history taking, physical exam, or basic laboratory testing Patients with treatment-resistant hypertension and a secondary cause will rarely achieve BP control until the underlying cause is treated* Consider consultation with a hypertension specialist for evaluation of secondary causes of hypertension *Many patients with renal artery stenosis or aldosteronism may achieve BP control without diagnosis of the underlying condition. Calhoun DA, et al. Circulation. 2008;117:e510-e526. Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. Kaplan NM, Victor R. Kaplan's Clinical Hypertension. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010. Secondary CauseEst Prevalence (%) Renal artery disease 3.0-4.0 Aldosteronism1.5-15.0 (higher in recent series) Renal parenchymal disease1.0-8.0 (depends on Cr level) Hyperthyroidism or hypothyroidism 1.0-3.0 Coarctation of the aorta<1.0 Cushing’s syndrome<0.5 Pheochromocytoma<0.5 Power Over Pressure www.poweroverpressure.com

22. Referral to hypertension specialists Patients with treatment-resistant hypertension who are motivated to work with a hypertension specialist may benefit from referral 1.Bansal N, et al. Am J Hypertens. 2003;16:878-880. 2.Garg JP, et al. Am J Hypertens. 2005;18:619-626. A retrospective study found that patients with treatment- resistant hypertension achieved an 18/9 mm Hg drop in BP, and control rates increased from 18% to 52% at 1-year follow-up 1 In another retrospective study, 53% of patients with treatment- resistant hypertension were controlled to BP target (<140/90 mm Hg) 2 Power Over Pressure www.poweroverpressure.com

23. Summary Confirm accuracy of BP measurement –Identify and reverse “pseudoresistance” –Consider use of AOBP –Exclude “white-coat” effect Optimize pharmacotherapy and adherence –Implement combination therapy regimen –Consider additional agents to intensify treatment (eg, spironolactone) –Assess adherence to treatment regimen Address lifestyle barriers to BP control –Identify and reverse factors contributing to treatment resistance including interfering substances –Recommend lifestyle modifications (eg, salt intake, alcohol, weight) –Understand stages of change for health-related behaviors Consider referral to a specialist –Rule out secondary causes, particularly renal parenchymal disease –Advise referral to hypertension specialist Several factors are involved in the diagnosis and treatment of true treatment resistant hypertension Power Over Pressure www.poweroverpressure.com