Treatment-Resistant Hypertension: Diagnosis and Management

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… 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 • *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 • Calhoun DA, et al. Circulation. 2008;117:e510-e526. • Mancia G, et al. Eur Heart J. 2007;28:1462-1536. Power Over Pressure www.poweroverpressure.com

3. A common and increasing problem • 100 million people worldwide (15% to 20% of uncontrolled hypertension) are estimated to have treatment-resistant hypertension1,2,3 • 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%. Persell, S. Hypertension. 2011;57:1076-1080. 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. Lloyd-Jones D, et al. Circulation. 2010;121:e46-e215. Calhoun DA, et al. Circulation. 2008;117:e510-e526. Egan BM, et al. Circulation. 2011;124:1046-1058. 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 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 diuretic1,2 • *Patients who require 4 antihypertensive agents to achieve BP control are also considered treatment resistant, according to some sources.1 Calhoun DA, et al. Circulation. 2008;117:e510-e526. Mancia G, et al. Eur Heart J. 2007;28:1462-1536. Power Over Pressure www.poweroverpressure.com

5. Who is at risk? Patient Characteristics Associated With Treatment-Resistant Hypertension* Older age Obesity Female sex Diabetes Chronic kidney disease Excessive dietary salt ingestion Black race High baseline blood pressure Left ventricular hypertrophy *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. 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 • Tips for obtaining accurate office BP readings • A cuff that is too small may cause an erroneously elevated reading1,2 • Allow patient to sit quietly for 5 minutes, legs uncrossed with the arm supported at heart level before the reading istaken1,2 • Other factors that can effect BP readings include recent caffeine, nicotine, or alcohol consumption, full bladder, and background noise2 Makris A, et al. Int J Hypertens.2011:598694. Pickering T, et al. Hypertension. 2005;45:142-161. 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 home1 • 20%-30% of patients with hypertension may experience white-coat effect1 • When to Suspect? • White-coat resistance may be present in patients with consistently elevated BP but no evidence of target organ damage2 • 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 resistance2 • Home BP monitoring may also increase adherence3 • Calhoun DA, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526. • Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. • Parati G, et al. J Hypertens. 2008;26:1505-1526. Power Over Pressure www.poweroverpressure.com

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 Power Over Pressure www.poweroverpressure.com Myers M, et al. Hypertension. 2010;55:195-200.

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 control1 • 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-tolerated2 • If BP control is not achieved, dosages should be titrated to the maximum tolerated or in-label doses1,2 ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CCB = calcium channel blocker. Moser M, Setaro J. N Eng J Med. 2006;355:385-392. Calhoun D, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526. Power Over Pressure www.poweroverpressure.com

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

13. Spironolactone Spironolactone can be effective in many patients with treatment-resistant hypertension • 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). • 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. Power Over Pressure www.poweroverpressure.com Chapman N, et al. Hypertension. 2007;49:839-845.

14. Poor adherence is a common cause of pseudoresistance • 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 Van Wijk BLG, et al. J Hypertens. 2005;23:2101-2107.

15. Tips for assessing and improving medication adherence • Signs of nonadherence1 • 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 caregiver2 • Verifying prescription refills with the pharmacy • Reviewing factors causing nonadherence and counseling patients on importance of therapy3 • Moser M, Setaro JF. N Engl J Med. 2006;355:385-392. • Calhoun DA, et al. Circulation. 2008;117:e510-e526. • 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 *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. 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 Power Over Pressure www.poweroverpressure.com

19. Understanding stages of change for health-related behaviors • 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 Maintenance Action Preparation Contemplation Precontemplation Glanz K, Bishop DB. Ann Rev Pub Health. 2010;31:399-418. Prochaska, JO. Med Decis Making. 2008;28:845-849. 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. 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 • 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-up1 • In another retrospective study, 53% of patients with treatment-resistant hypertension were controlled to BP target (<140/90 mm Hg)2 Bansal N, et al. Am J Hypertens. 2003;16:878-880. Garg JP, et al. Am J Hypertens. 2005;18:619-626. Power Over Pressure www.poweroverpressure.com

23. Summary Several factors are involved in the diagnosis and treatment of true treatment resistant hypertension • 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 Power Over Pressure www.poweroverpressure.com