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

2. Not all patients with uncontrolled hypertension are treatment resistant Uncontrolled Hypertension Includes patients who lack blood pressure (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

3. 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

4. Which of these patients have treatment-resistant hypertension? Power Over Pressure www.poweroverpressure.com

5. Which of these patients have treatment-resistant hypertension? Calhoun DA, et al. Circulation. 2008;117:e510-e526. Treatment-resistant hypertension is a diagnosis of exclusion, requiring a systematic approach to evaluation and management Power Over Pressure www.poweroverpressure.com

6. The systematic approach to diagnosis begins with the definition… 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

7. Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement Utilize correct BP measurement technique Rule out white-coat effect Optimize Pharmacotherapy and Adherence Regimen of 3 drugs of different classes, including a diuretic Assess and improve adherence to the treatment regimen Intensify pharmacologic therapy Address Lifestyle Barriers to BP Control Interfering substances Dietary salt intake Alcohol consumption Obesity Consider Referral to a Specialist Treatment for secondary causes of hypertension Hypertension specialist for intensive management of true treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

8. Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement Utilize correct BP measurement technique Rule out white-coat effect Optimize Pharmacotherapy and Adherence Regimen of 3 drugs of different classes, including a diuretic Assess and improve adherence to the treatment regimen Intensify pharmacologic therapy Address Lifestyle Barriers to BP Control Interfering substances Dietary salt intake Alcohol consumption Obesity Consider Referral to a Specialist Treatment for secondary causes of hypertension Hypertension specialist for intensive management of true treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

9. Technique is a common cause of pseudoresistance A cuff that is too small may cause an erroneously elevated reading 1,2 –Properly sized cuff rule-of-thumb: the cuff’s air bladder should encircle at least 80% of the patient’s arm circumference 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 with the arm supported at heart level before the reading is taken 1,2 –Patient should remove clothing that constricts upper arm 2 –The average of 2 readings taken a minute apart should be recorded as the patient’s blood pressure 1 –If BP is significantly different between the 2 arms, use the higher reading to guide treatment decisions 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 (including conversation) 2 Power Over Pressure www.poweroverpressure.com

10. Eliminating “white-coat” effect What Is It? –Elevated BP in physician’s office, but significantly lower when measured at home 1 How Prevalent? –A recent Spanish study of 8,295 patients with treatment-resistant hypertension found that 37.5% actually had office-resistant hypertension 2 When to Suspect? –White-coat resistance may be present in patients with consistently elevated BP but no evidence of target organ damage 3 How to Screen? –Consider repeated at-home BP measurements to rule out white- coat resistance 3 –Where available, 24-hour ambulatory BP monitoring (ABPM) may be used for further diagnostic evaluation 3 Power Over Pressure www.poweroverpressure.com 1.Calhoun D, et al. Circulation. 2008;117;e510-e526. 2.de la Sierra A, et al. Hypertension. 2011;57:898-902. 3.Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

11. Automated BP measurement Automated office BP measurement has several advantages 1 : 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 Home BP measurement is a useful tool: Average of as few as 6 readings may achieve similar accuracy for measurement of true ambulatory BP as ABPM 2 May improve adherence to the treatment regimen 3 Affordable and accessible 3,4 Considerations: –Patients should be trained in proper BP measurement technique 3,4 –Patients should utilize validated monitors to ensure accuracy (wrist or finger cuffs should be avoided) 3,4 –Patients should bring new devices to clinic to confirm accuracy 4 1.Myers M, et al. Hypertension. 2010;55:195-200. 2.Chatellier G, et al. Am J Hypertens. 1996;9:644-652. 3. Parati G, et al. J Hypertens. 2008;26:1505-1526. 4. Pickering TG, White WB. J Am Soc Hypertens. 2008;2:119-124. Power Over Pressure www.poweroverpressure.com

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13. Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement Utilize correct BP measurement technique Rule out white-coat effect Optimize Pharmacotherapy and Adherence Regimen of 3 drugs of different classes, including a diuretic Assess and improve adherence to the treatment regimen Intensify pharmacologic therapy Address Lifestyle Barriers to BP Control Interfering substances Dietary salt intake Alcohol consumption Obesity Consider Referral to a Specialist Treatment for secondary causes of hypertension Hypertension specialist for intensive management of true treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

14. Poor adherence is a common cause of pseudoresistance 1.Van Wijk BLG, et al. J Hypertens. 2005;23:2101-2107. 2.Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. 3.Calhoun DA, et al. Circulation. 2008;117:e510-e526. 4.Hill M, et al. J Clin Hypertens. 2010;12:757-764. Within just 1 year, >1 in 3 patients had already discontinued their medication 1 After 10 years, almost 2 in 3 patients did not take their antihypertensive medications continuously 1 39% Non-users 39% Continuous users 22% Restarters Percentage of patients utilizing antihypertensive agents at 10 years 1 Signs of nonadherence 2 Missed office visits Lack of physiological evidence of therapy, such as o No change in BP o Absence of anticipated common side effects Check for suspected nonadherence by Discussing medication use with spouse or caregiver 3 Verifying prescription refills with the pharmacy Reviewing factors causing nonadherence and counseling patients on importance of therapy 4 Power Over Pressure www.poweroverpressure.com

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16. Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement Utilize correct BP measurement technique Rule out white-coat effect Optimize Pharmacotherapy and Adherence Regimen of 3 drugs of different classes, including a diuretic Assess and improve adherence to the treatment regimen Intensify pharmacologic therapy Address Lifestyle Barriers to BP Control Interfering substances Dietary salt intake Alcohol consumption Obesity Consider Referral to a Specialist Treatment for secondary causes of hypertension Hypertension specialist for intensive management of true treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

17. Interfering substances 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. Patient factors may contribute to treatment resistance Calhoun DA, et al. Circulation. 2008;117:e510-e526. Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. Modifiable lifestyle factors High sodium intake (urinary sodium excretion >150 mmol/day) may contribute to treatment-resistant hypertension both by increasing BP directly and by blunting the BP-lowering effect of antihypertensive drugs –Elderly patients, black patients, and patients with chronic kidney disease may be more sensitive to salt intake Excessive alcohol intake of >3-4 drinks per day may also contribute to treatment- resistant hypertension Obesity is associated with more severe hypertension, requirement for increased number of antihypertensive medications, and increased likelihood of never achieving BP control –It is estimated that >40% of patients with treatment-resistant hypertension are obese Obesity Excessive dietary salt ingestion Excessive alcohol ingestion Power Over Pressure www.poweroverpressure.com

19. 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. http://www.hypertensiononline.org/slides2/slide01.cfm?tk=24&dpg=5. Accessed April 27, 2012 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

20. Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement Utilize correct BP measurement technique Rule out white-coat effect Optimize Pharmacotherapy and Adherence Regimen of 3 drugs of different classes, including a diuretic Assess and improve adherence to the treatment regimen Intensify pharmacologic therapy Address Lifestyle Barriers to BP Control Interfering substances Dietary salt intake Alcohol consumption Obesity Consider Referral to a Specialist Treatment for secondary causes of hypertension Hypertension specialist for intensive management of true treatment-resistant hypertension Power Over Pressure www.poweroverpressure.com Moser M, Setaro JF. N Engl J Med. 2006;355:385-392.

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. Summary: diagnosis and management of treatment-resistant hypertension Identify and reverse “pseudoresistance” –Confirm proper measurement technique –Exclude “white-coat” effect –Assess adherence to treatment regimen Identify and reverse factors contributing to true resistance –Interfering substances –Modifiable lifestyle factors Obesity Excessive sodium intake Excessive alcohol intake Identify and, if possible, reverse causes of secondary hypertension –Consider consultation with a hypertension specialist for evaluation of secondary causes of hypertension The diagnosis and management of true treatment-resistant hypertension is accomplished through a process of exclusion Power Over Pressure www.poweroverpressure.com