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

2. BP treatment goals optimize CV risk reduction mm Hg <140 Uncomplicated hypertension <80 <90 <130 CKD Diabetes Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Mancia G, et al. Eur Heart J. 2007;28:1462-1536 Power Over Pressure www.poweroverpressure.com CV = cardiovascular; SBP = systolic blood pressure; DBP = diastolic blood pressure; CKD = chronic kidney disease.

3. Rationale for antihypertensive treatment: reduce CV risk Cumulative Incidence of Major Cardiovascular Events (%) 16 12 10 8 6 4 2 0 14 246810 12 Time (Years) Optimal (N=1005) <120/80 mm Hg Normal (N=1059) 120-129/80-84 mm Hg High-Normal (N=903) 130-139 / 85-89 mm Hg Blood Pressure: 0 Impact of High-Normal Blood Pressure on Risk of Major Cardiovascular Events in Men Longitudinal data obtained from the Framingham Heart Study. Overall, those with high-normal BP had a 2-fold increase in relative risk for CV event compared with those with optimal BP levels (<120/80 mm Hg). Used with permission from: Vasan RS, et al. N Engl J Med. 2001;345:1291-1297. Power Over Pressure www.poweroverpressure.com BP level has a strong, continuous, and significant positive association with CV disease outcomes.

4. Despite advances in the treatment of hypertension…. Rauwolfia serpentina, Ganglion blockers, Veratrum alkaloids, Hydralazine, Guanethidine, Thiazide diuretics Potassium thiocyanate, Kempner diet, lumbodoral sympathectomy 1940s19501960s1970s1980s1990s2000 α 2 -adrenergic-receptor agonists, Spironolactone, β-adrenergic-receptor antagonists CCBs ARBs RIs 1.Chobanian AV. N Engl J Med. 2009;361:878-887. 2.European Society of Hypertension History. ESH. http://www.eshonline.org/About/ESHinBrief.aspx. Accessed July 27, 2011. 3.Calhoun D, et al. Circulation. 2008;117:e510-e526. 4.Egan BM, et al. Circulation. 2011;124:1046-1058 …the percentage of people with treatment-resistant hypertension continues to increase 3,4 1989 ESH formed CCB = calcium channel blocker. ACEI = angiotensin-converting-enzyme inhibitor. ARB = angiotensin receptor blocker. RI = renin inhibitor. 2004 1,2 JNC 7 guidelines published 2003 ESH-ESC guidelines published 1985 ASH founded 1967 α 2 -adrenergic-receptor antagonists, ACEIs 1st VA cooperative study 1976 JNC 1 guidelines published Power Over Pressure www.poweroverpressure.com

6. Mechanisms of action of major medication classes 1.Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008. 2.Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Calcium-channel blockers Centrally acting antihypertensives β-blockers reset peripheral resistance β -blockers Baroreceptor discharge α 1 -blockers ARBs Renin Angiotensinogen Angiotensin I Angiotensin II Aldosterone Thiazide diuretics ACEIs β -blockers Ca 2+ AT α1α1 Vascular smooth muscle Peripheral resistance Na + Vasodilation Any medication that causes a sustained reduction in BP must reset the renal threshold for pressure naturesis to a lower pressure level, either directly or indirectly Multiple available therapies target RAAS, thereby inhibiting the effects of SNS activity 1,2 ACEIs Decrease production of angiotensin II ARBs Bind and block the angiotensin AT 1 receptor DRIs Directly inhibit renin β-blockers Reduce renin release Diuretics Inhibit water and sodium retention RAAS = renin-angiotensin-aldosterone system; ACEI = angiotensin- converting enzyme inhibitor; ARB = angiotensin-receptor blocker; DRI = direct renin inhibitor. Power Over Pressure www.poweroverpressure.com

7. Mechanisms of action of major medication classes (cont) CCBs Dilate arteries and reduce peripheral resistance α-blockers Block vasoconstrictor effects of NE Centrally acting agents Act on the hypothalamus to reduce sympathetic outflow Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008. CCBs Centrally acting antihypertensives β-blockers reset peripheral resistance β -blockers Baroreceptor discharge α 1 -blockers ARBs Renin Angiotensinogen Angiotensin I Angiotensin II Aldosterone Thiazide diuretics ACEIs β -blockers Ca 2+ AT α1α1 Vascular smooth muscle Peripheral resistance Na + Vasodilation NE = norepinephrine. Power Over Pressure www.poweroverpressure.com

8. 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

9. 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 ACE inhibitor 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

10. 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.

11. 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

12. The SNS connects the brain, heart, blood vessels, and kidneys, each of which plays an important role in the regulation of BP Signals from the SNS produce a baseline sympathetic tone, which when elevated contributes to the development and progression of disease states including hypertension Promising treatments are based on a new appreciation for the role of the sympathetic nervous system (SNS) Campbell WW. The Autonomic and Peripheral Nervous Systems. In: Campbell, WW, editor. DeJong’s The Neurologic Examination: Incorporating the Fundamentals of Neuroanatomy and Neurophysiology. 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins;2005 p. 535-547. Epinephrine—adrenal glands Norepinephrine—kidney Inhibits digestive activity Stimulates glucose release by liver Dilates pupils Inhibits salivation Relaxes bronchi Accelerates heart Relaxes bladder Contracts rectum Cervical Thoracic Lumbar Power Over Pressure www.poweroverpressure.com

13. Renal denervation as a therapeutic approach Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Renal afferent and efferent sympathetic nerves are key players in the feedback loop of sympathetic hyperactivity associated with hypertension Power Over Pressure www.poweroverpressure.com

14. Renal denervation as a therapeutic approach Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Renal denervation, an investigational* therapy, is a minimally invasive, catheter-based procedure that modulates the output of nerves lying within the renal artery wall, leading into and out of the kidneys Renal sympathetic denervation involves selectively disabling renal nerves within the SNS, thus impacting the mechanical and hormonal activities of the kidneys, as well as the electrical activation of the rest of the SNS Power Over Pressure www.poweroverpressure.com *Device based approaches such as renal denervation and baroreceptor stimulation are not universally approved for use, and are under clinical investigation in some regions (such as the US and Japan).

15. Baroreflex activation therapy as a therapeutic approach 1.Bisognano JD, et al. J Am Coll Cardiol. 2011;58:765-773. 2.Heusser K, et al. Hypertension. 2010;55:619-626. 3.Wustmann K, et al. Hypertension. 2009;54:530-536 Baroreceptor stimulation is an investigational* therapeutic approach that treats hypertension by modulating sympathetic nerve activity 1 Using a system similar to a pacemaker that is surgically and permanently implanted, the therapy is administered via electrical stimulation of the carotid baroreceptors Therapy attempts to normalize sympathovagal imbalance by reducing the activity of the SNS 2 while increasing parasympathetic activity 3 Power Over Pressure www.poweroverpressure.com *Device based approaches such as renal denervation and baroreceptor stimulation are not universally approved for use, and are under clinical investigation in some regions (such as the US and Japan).

16. Summary: management of treatment- resistant hypertension Target BP goals should be adjusted in patients with diabetes or CKD to optimize CV risk reduction Elevated BP has long-term CV consequences Although several classes of drugs exist, the percentage of people with treatment-resistant hypertension continues to rise Combination therapy, including the use of spironolactone, may improve efficacy and reduce side effects Referral to a hypertension specialist may prove beneficial Investigational treatments based on a new appreciation for the role of the SNS are being developed Power Over Pressure www.poweroverpressure.com