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Recent advances in the management of resistant hypertension

Recent advances in the management of resistant hypertension. Scope. Resistant hypertension Introduction Prevalence Management Additional drug/combinations Newer therapies Conclusions. Resistant HT. The Joint National Committee 7 defines resistant hypertension as

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Recent advances in the management of resistant hypertension

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  1. Recent advances in the management of resistant hypertension

  2. Scope • Resistant hypertension • Introduction • Prevalence • Management • Additional drug/combinations • Newer therapies • Conclusions

  3. Resistant HT • The Joint National Committee 7 defines resistant hypertension as • Failure to achieve goal BP (140/90 mm Hg for the overall population and 130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) when a patient adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic Hypertension 2003;42:1206 –52.

  4. Resistant HT: Introduction (Contd) • This definition does not apply to patients who have been recently diagnosed with HT • Moreover, resistant HT is not synonymous with uncontrolled HT • Uncontrolled HT includes all hypertensive patients who lack BP control under treatment, namely, • those receiving an inadequate treatment regimen, those with poor adherence, and those with undetected secondary HT, as well as those with true treatment resistance J Am Coll Cardiol 2008;52:1749–57

  5. Resistant HT: Introduction (Contd) • Patients with resistant HT may achieve BP control with full doses of • 4 or more antihypertensive medications J Am Coll Cardiol 2008;52:1749–57

  6. Resistant HT: Prevalence • The prevalence of resistant HT in the general population is unknown • Small studies, however, demonstrate a prevalence of resistant HT that ranges from approx. • 5% in general medical practice to • 50% in nephrology clinics J Hypertens 2005;23:1441– 4.

  7. Office resistance 6% Unknown 6% Nonadherence 16% Psychological causes 9% Secondary HTN 5% Interfering substances 1% Drug-related causes 58% Resistant HT: Primary Cause Cause of resistance found in 133/141 – 94% (83/91 – 91%) cases Am J Hypertens 2003;16:925-930

  8. Pseudo-resistance • Lack of BP control with appropriate treatment in a patient who does not have resistant hypertension • Factors include • Suboptimal BP measurement technique; • The white-coat effect; and • Poor adherence to prescribed therapy J Am Coll Cardiol 2008;52:1749–57

  9. Pseudo-resistance (Contd) Causes of Pseudo-Resistant Hypertension J Am Coll Cardiol 2008;52:1749–57

  10. Resistant HT Factors Contributing to Resistant HT J Am Coll Cardiol 2008;52:1749–57

  11. Resistant HT (Contd) • Step-by-Step Physician Guide for Evaluation and Management of Patients Appearing to Have Resistant HT J Am Coll Cardiol 2008;52:1749–57

  12. J Am Coll Cardiol 2008;52:1749–57

  13. Journal of Human Hypertension 2004;18:139–185

  14. Compelling and possible indications, contraindications and cautions for the major classes of antiHT drugs Journal of Human Hypertension 2004;18:139–185

  15. What additional agents to add? • What combinations work?

  16. Diuretics • Studies indicate that patients with resistant HT • Frequently have inappropriate volume expansion contributing to their treatment resistance such that a diuretic is essential to maximize BP control • In most patients, use of a long-acting thiazide diuretic will be most effective Circulation. 2008;117:e510-e526

  17. Diuretics (Contd) • In a blinded comparison of hydrochlorothiazide 50 mg and chlorthalidone 25 mg daily, the latter provided greater 24-hour ambulatory blood pressure reduction, with the largest difference occurring overnight • Given the outcome benefit demonstrated with chlorthalidone and its superior efficacy compared with hydrochlorothiazide, • Chlorthalidone should be preferentially used in patients with resistant HT Circulation. 2008;117:e510-e526

  18. Diuretics (Contd) • In patients with oedema or more advance renal impairment, for example, serum creatinine >200 mmol/l, • Thiazide/thiazide-like diuretics may be ineffective and a • Loop diuretic (eg furosemide) may be required, often in higher doses than used conventionally Journal of Human Hypertension 2004;18:139–185

  19. Mineralocorticoid Receptor Antagonists • Consistent with reports of a high prevalence of primary aldosteronism in patients with resistant HT have been studies demonstrating that • Mineralocorticoid receptor antagonists provide significant antihypertensive benefit when added to existing multidrug regimens Circulation. 2008;117:e510-e526

  20. Mineralocorticoid Receptor Antagonists(Contd) • Spironolactone • Used for resistant HT with normal aldosterone levels, 12.5-50mg/daily • Additional benefits: antiproteinuric, improves heart failure survival (RALES) • 10% gynecomastia • Not when creatinine > 2.5, K > 5.0

  21. Drug Combinations • Chlorthalidone 25mg + spironolactone 12.5-50 mg • Excellent diuretic maximization, also vs hypokalemia • Chlorthalidone, can • ↓ s. K+ enough to cause cardiac arrest • Aldosterone blockers spironolactone eplerenone can • Protect vulnerable patients and • Significantly reduce BP resistant to ≥ 3 drugs, • A logical way to provide maximal anti-HT efficacy and to prevent hypokalemia might be a • Combination of chlorthalidone and spironolactone 12.5/25.0 mg/d Hypertension 2009;54;951-953

  22. Drug Combinations (Contd) • ACEI plus ARB • Mostly 4-8 week studies • Risk of ARF in animal studies • Additional reduction mild: 4/3 mm Hg • Best application in proteinuric patients

  23. Direct Vasodilators • Hydralazine sequence is 25 BID to 50 BID to 100mg BID • Minoxidil sequence is 2.5mg, to 5mg, to 5mg BID, to 10 mg BID, to 20 mg BID • Need a BB and a diuretic on board • Watch for headache and fluid retention

  24. Direct Vasodilators (Contd) • Minoxidil • Excellent drug for resistant HT • Direct vasodilator causing reflex tachycardia and fluid retention • Need BB on board to prevent myocardial ischemia • Dosage range 2.5mg to 20 mg BID • Temporarily discontinue drug with marked edema, than restart with more diuretic • 90% ST-T change within 2 weeks, later resolve

  25. α1-Adrenergic Receptor Blockers • Not to be used for monotherapy: ALLHAT (class effect) • May be used as an add-on for resistant hypertension • May cause urinary incontinence, especially in females, due to bladder outlet relaxation

  26. Additional Agents/ Devices • Combined alpha- and beta-blockers (labetalol, carvedilol) • Reserpine 0.05-0.1 mg • Isosorbide vs augmentation pressure • Device-guided slow breathing exercises (Resperate) • Device-mediated electrical carotid sinus baroreceptor stimulation • Thoracic bioimpedance measurements

  27. Resistant HT: Newer approaches • Under evaluation • Endothelial receptor antagonist • Catheter-based renal sympathetic denervation

  28. Endothelial receptor antagonist • Class of agents that may prove useful for resistant HT is endothelin-receptor antagonists (ERAs) • In patients with mild-to-moderate essential HT, both nonselective and selective (type A receptor) ERAs • Produce BP reductions comparable to those of common antihypertensive agents, but • Concerns about adverse events precluded their use as a treatment option for uncomplicated hypertension

  29. Darusentan • However, a selective ERA recently tested in 115 patients with resistant HT, • Demonstrated a dose-dependent decrease in BP • The largest reductions (11.5/6.3 mm Hg) were observed after 10 weeks of follow-up with the largest dose, and • The drug was generally well tolerated • Ongoing phase III clinical trials with such agents are awaited to provide further information in this interesting field Clin Hypertens (Greenwich) 2007;9:760 –9

  30. Darusentan (Contd) • Lancet 2009 • Randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia Lancet 2009; 374:1423-1431

  31. Darusentan (Contd) • Results • The mean reductions in clinic systolic and diastolic blood pressures were • 9/5 mm Hg (SD 14/8) with placebo, • 17/10 mm Hg (15/9) with darusentan 50 mg, • 18/10 mm Hg (16/9) with darusentan 100 mg, • 18/11 mm Hg (18/10) with darusentan 300 mg (p<0·0001 for all effects) Lancet 2009; 374:1423-1431

  32. Darusentan (Contd) • Results (Contd) • The main adverse effects were related to fluid accumulation • Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo • One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events Lancet 2009; 374:1423-1431

  33. Darusentan (Contd) • Interpretation • Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed Lancet 2009; 374:1423-1431

  34. Catheter-based renal sympathetic denervation • Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. • Lancet. 2009;373(9671):1275-1281.

  35. Catheter-based renal sympathetic denervation (Contd) • Proof-of-principle study showing that a • Novel catheter-based device produced renal denervation and a substantial decrease in blood pressure in a select group of 45 patients with resistant HT Lancet. 2009;373(9671):1275-1281

  36. Catheter-based renal sympathetic denervation (Contd) • Systolic and diastolic BP after the procedure (while maintaining patients on their usual antihypertensive medication therapy) were decreased by • 14/10, 21/10, 22/11, 24/11, and 27/17 mm Hg at 1, 3, 6, 9, and 12 months, respectively Lancet. 2009;373(9671):1275-1281

  37. Catheter-based renal sympathetic denervation (Contd) • The development of this novel catheter-based technology offers • An opportunity for clinical investigators to examine the impact of selective renal denervation on resistant HT • For clinicians learning of this new technology, • Data are too preliminary to rush to judgment American Journal of Kidney Diseases,54;2009: pp 795-797

  38. Catheter-based renal sympathetic denervation (Contd) • Hence, further rigorous investigation is required to • Identify hypertensive patients who might benefit from catheter-induced renal sympathetic denervation American Journal of Kidney Diseases,54;2009: pp 795-797

  39. Conclusions • Resistant HT is common in nephrology clinics • 4 or more drugs may be used for management

  40. Conclusions: Summary of Med Changes • Use chlorthalidone 25mg • Add spironolactone 12.5 – 50 mg • Consider adding hydralazine or minoxidil • Consider alpha1-blocking agents,and combination alpha-beta blockers • Loop diuretic (eg furosemide) may be required, often in higher doses than used conventionally

  41. Conclusions • Newer therapies like catheter-based renal sympathetic denervation, darusentan are under evaluation

  42. Thank You!

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