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Treatment-Resistant Hypertension: Management Approaches

Treatment-Resistant Hypertension: Management Approaches. Power Over Pressure www.poweroverpressure.com. BP treatment goals optimize CV risk reduction. < 140. Uncomplicated hypertension. < 90. < 130. CKD Diabetes. < 80. mm Hg.

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Treatment-Resistant Hypertension: Management Approaches

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

  2. BP treatment goals optimize CV risk reduction <140 Uncomplicated hypertension <90 <130 CKD Diabetes <80 mm Hg CV = cardiovascular; SBP = systolic blood pressure; DBP = diastolic blood pressure; CKD = chronic kidney disease. 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

  3. 16 14 12 10 8 6 4 2 0 Rationale for antihypertensive treatment: reduce CV risk Impact of High-Normal Blood Pressure on Risk of Major Cardiovascular Events in Men Blood Pressure: High-Normal (N=903) 130-139 / 85-89 mm Hg Normal (N=1059) 120-129/80-84 mm Hg Cumulative Incidence of Major Cardiovascular Events (%) Optimal (N=1005) <120/80 mm Hg 0 12 2 4 6 8 10 Time (Years) BP level has a strong, continuous, and significant positive association with CV disease outcomes. 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

  4. Despite advances in the treatment of hypertension…. Rauwolfia serpentina, Ganglion blockers, Veratrum alkaloids,Hydralazine,Guanethidine,Thiazide diuretics ESH-ESC guidelines published 1st VA cooperative study JNC 1 guidelines published ASH founded ARBs 1940s 1950 1960s 1967 1970s 1976 1980s 1985 1989 1990s 2000 2003 20041,2 Potassium thiocyanate,Kempner diet, lumbodoralsympathectomy JNC 7 guidelines published CCBs RIs ESH formed α2-adrenergic-receptor agonists, Spironolactone,β-adrenergic-receptor antagonists α2-adrenergic-receptor antagonists,ACEIs CCB = calcium channel blocker. ACEI = angiotensin-converting-enzyme inhibitor. ARB = angiotensin receptor blocker. RI = renin inhibitor. …the percentage of people with treatment-resistant hypertension continues to increase3,4 Chobanian AV. N Engl J Med. 2009;361:878-887. European Society of Hypertension History. ESH. http://www.eshonline.org/About/ESHinBrief.aspx. Accessed July 27, 2011. Calhoun D, et al. Circulation. 2008;117:e510-e526. Egan BM, et al. Circulation. 2011;124:1046-1058 Power Over Pressure www.poweroverpressure.com

  5. Mechanisms of action of major medication classes Centrally acting antihypertensives 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 activity1,2 • ACEIs Decrease production of angiotensin II • ARBs Bind and block the angiotensin AT1 receptor • DRIs Directly inhibit renin • β-blockers Reduce renin release • Diuretics Inhibit water and sodium retention Vascular smooth muscle Calcium-channel blockers α1-blockers Ca2+ Baroreceptor discharge α1 AT ARBs Vasodilation β-blockersreset peripheral resistance β -blockers Angiotensinogen Renin β -blockers Angiotensin I Thiazide diuretics ACEIs Angiotensin II Na+ RAAS = renin-angiotensin-aldosterone system; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; DRI = direct renin inhibitor. Aldosterone Peripheral resistance • Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008. • Schlaich MP, et al. Hypertension. 2009;54:1195-1201. Power Over Pressure www.poweroverpressure.com

  6. Mechanisms of action of major medication classes (cont) Centrally acting antihypertensives • 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 Vascular smooth muscle CCBs α1-blockers Ca2+ Baroreceptor discharge α1 AT ARBs Vasodilation β-blockersreset peripheral resistance β -blockers Angiotensinogen Renin β -blockers Angiotensin I Thiazide diuretics ACEIs Angiotensin II Na+ Aldosterone Peripheral resistance NE = norepinephrine. Power Over Pressure www.poweroverpressure.com Izzo JL, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. 2008.

  7. 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

  8. 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 ACE inhibitor 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 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

  9. 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.

  10. 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

  11. Promising treatments are based on a new appreciation for the role of the sympathetic nervous system (SNS) • 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 Dilates pupils Inhibits salivation Cervical Relaxes bronchi Accelerates heart Thoracic Inhibits digestive activity Stimulates glucose release by liver Lumbar Epinephrine—adrenal glandsNorepinephrine—kidney Relaxes bladder Contracts rectum 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. Power Over Pressure www.poweroverpressure.com

  12. Renal denervation as a therapeutic approach • 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 Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

  13. Renal denervation as a therapeutic approach • 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 *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). Power Over Pressure www.poweroverpressure.com Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

  14. Baroreflex activation therapy as a therapeutic approach • Baroreceptor stimulation is an investigational* therapeutic approach that treatshypertension by modulating sympathetic nerve activity1 • 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 SNS2 while increasing parasympathetic activity3 *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). • Bisognano JD, et al. J Am Coll Cardiol. 2011;58:765-773. • Heusser K, et al. Hypertension. 2010;55:619-626. • Wustmann K, et al. Hypertension. 2009;54:530-536 Power Over Pressure www.poweroverpressure.com

  15. 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

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