Resistant hypertension

Resistant hypertension

1. RESISTANT HYPERTENSION Recognition and Management Prem Mohan Jha DNB Nephro SR Max Super Speciality Hospital, Vaishali 11/17/2020 1

2. Introduction Hypertension is the world’s leading risk factor for CVD, stroke, disability, and death. A large proportion of hypertensive adults, still fail to achieve their recommended BP treatment targets. These individuals remain at increased risk for target organ damage, morbidity, and mortality despite ongoing antihypertensive drug therapy. 11/17/2020 2

3. Definition of rHTN 11/17/2020 3

4. www.thelancet.com Vol 386 October 17, 2015 Blood pressure that remains above goal in spite of the concurrent use of 3 anti hypertensive agents of different classes. Ideally, one of the 3 agents should be a diuretic. Prescribed at optimal dose amounts. 11/17/2020 4

5. Prevalence 11/17/2020 5

6. www.thelancet.com Vol 386 October 17, 2015 Without CKD : 0.5 – 14.3% With CKD : 1.6 – 24.7% 11/17/2020 6

7. Why Hypertension Is Important High BP causes : 50 % of all stroke deaths 50% of all congestive heart failure 35% of all cardiovascular deaths 25 % of all premature deaths. Prevalence and prognostic significance of apparent treatment resistant hypertension in chronic kidney disease : Report from the Chronic Renal Insufficiency Cohort Study . Hypertension 67: 387–396, 2016 11/17/2020 7

8. High Risk Patients Older age Obesity Black Female Southeast united states DM CKD High salt intake High baseline BP LVH https://www.ahajournals.org/journal/hyp 11/17/2020 8

9. Causes Apparent Cause Poor adherence Improper techniques of BP measurement White coat effect Treatment inertia True Resistant Hypertension Life style Factors Obesity Alcohol Inactivity Dietary pattern Drug related Sleep Apnoea Secondary causes https://www.ahajournals.org/journal/hyp 11/17/2020 9

10. Nonadherence There is no gold standard for measuring adherence. Indirect methods such as pill count, self-report, and prescription refill Data. Simple, inexpensive, and widely used. However, they can easily be manipulated to overestimate adherence. Direct methods such as urine or blood measurement of drug or metabolites is considered more robust but is relatively expensive, is of limited availability, and does not perfectly reflect level of adherence. All methods have limitations, and ideally, accurate assessment of adherence should involve a combination of approaches. https://www.ahajournals.org/journal/hyp 11/17/2020 10

11. Poor BP Measurement Technique Emptying a full urinary bladder Sitting with legs uncrossed Back, arm, and feet supported in a quiet room Seated atleast 5 minutes before the first reading. Choosing a BP cuff with a proper size bladder Obtaining a minimum of 2 readings 1 minute apart https://www.ahajournals.org/journal/hyp 11/17/2020 11

12. White-Coat Effect The white-coat effect is the observation of repeated BP elevations in the office with controlled or significantly lower BP outside the office. A clinically significant white-coat effect may be present in 28% to 39% of individuals with rHTN by office BP measurement. The white-coat effect can be easily identified by 24-hour ABPM. https://www.ahajournals.org/journal/hyp 11/17/2020 12

13. Lifestyle Factors 11/17/2020 13

14. Obesity Recent findings from the NHANES of 13 375 hypertensive adults demonstrate that body mass index ( BMI) ≥30 kg/m2 approximately doubles the risk for rHTN . Spanish Ambulatory Blood Pressure Monitoring Registry. Kaiser Permanente Southern California health system. Confirmed the same findings. https://www.ahajournals.org/journal/hyp 11/17/2020 14

15. Ob e sity Obese Pt OSA Inflammation/ oxidative stress SNS activation Na/ volume retention Insulin + leptin resistance Renal dysfunction Other drugs causing hypertension https://www.ahajournals.org/journal/hyp 11/17/2020 15 Endothelial dysfunction

16. Obstructive Sleep Apnea Untreated OSA is strongly associated with hypertension and in normotensive persons predicts development of hypertension Sleep apnea is particularly common in patients with resistant hypertension. In an observational study evaluation of 41 consecutive patients with treatment-resistant hypertension, 83% were diagnosed with unsuspected sleep apnea based on an apnea hypopnea index 10 events/h. Obstructive sleep apnea is observed in 30% to 40% of patients with hypertension and in 60% to 70% of patients with resistant hypertension . Circulation June 24, 2008 11/17/2020 16

17. Dietary Sodium Excess volume retention, Vascular dysfunction, Arterial stiffness, Sympathetic activation, Impaired reninangiotensin axis suppression, Mineralocorticoid receptor activation, Immune cell modulation. https://www.ahajournals.org/journal/hyp 11/17/2020 17

18. Alcohol The dose-response association may differ between men (linear) and women (J shaped)164 and can be modified by metabolic genes. Nonetheless, heavy alcohol intake (>30–50 g/d) is a well-established risk factor for hypertension. https://www.ahajournals.org/journal/hyp 11/17/2020 18

19. Dietary Pattern and Other Risk Factors The Dietary Approaches to Stop Hypertension (DASH) eating pattern is well established to reduce BP, by 6.7/3.5 mm Hg in a recent meta-analysis. Psychosocial stressors ( eg , occupational stress, low social support), negative personality traits (anxiety, anger, depression), and reduced sleep duration/ quality have also been associated with high BP. 11/17/2020 19

20. Drug-Related RH NSAIDs Oral contraceptives Sympathomimetic Cyclosporine, tacrolimus Erythropoietin VEGF inhibitors Cocaine Amphetamines Antidepressants Glucocorticoids , mineralocorticoids https://www.ahajournals.org/journal/hyp 11/17/2020 20

21. Secondary Hypertension: Causes Primary Aldosteronism Renal Parenchymal Disease Renal Artery Stenosis Pheochromocytoma / Paraganglioma Cushing Syndrome Coarctation of the Aorta Other Causes of Secondary Hypertension 11/17/2020 21

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23. Evaluation Of Resistant Hypertension 11/17/2020 23

24. 11/17/2020 24 AHA 2017

25. Management Of Resistant Hypertension 11/17/2020 25

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27. 11/17/2020 27 AHA 2017

28. Lifestyle Modification Weight Loss Dietary Salt Restriction DASH Diet Exercise Alternative Approaches 11/17/2020 28

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30. 11/17/2020 30 A diet rich in fruits, vegetables, and low-fat dairy foods and with reduced saturated an total fat can substantially lower blood pressure. This diet offers an additional nutritional approach to preventing and treating hypertension.

31. Indications, Contraindications, And Adverse Effects For Diuretics 11/17/2020 31 American Journal of Hypertension 29(10) October 2016

32. 11/17/2020 32 American Journal of Hypertension 29(10) October 2016

33. Hypertension . 2011;57:1069-1075 The APBM nighttime systolic, 24-hour ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (difference of 8.6, 9.8, and 6.5 mm Hg; P0.011, 0.004, and 0.011), whereas the fall of the respective diastolic BP values was not significant (3.0, 1.0, and 2.5 mm Hg; P0.079, 0.405, and 0.079). The adverse events in both groups were comparable. In conclusion, spironolactone is an effective drug for lowering systolic BP in patients with resistant arterial hypertension. 11/17/2020 33

34. 11/17/2020 34 Lancet 2015; 386: 2059–68

35. 11/17/2020 35 Spironolactone was the most effective add-on drug for the treatment of resistant hypertension.

36. 11/17/2020 36 J Clin Hypertens (Greenwich). 2016;18:1162–1167. Minoxidil treatment was associated with a significant reduction in blood pressure from 162/83 mm Hg to 135/ 72 mm Hg (P<.0001).

37. Minoxidil Dosing Considerations The beginning dose of minoxidil can be as low as 2.5 mg/d with a maintenance dose generally falling in the range of 10–40 mg/d. Minoxidil can be given from once to three times daily with the most common frequency of administration being twice daily. Although the manufacturer’s maximum recommended dose is 100. 11/17/2020 37

38. Primary Aldosteronism The disorder includes hypertension caused by volume expansion and sympathetic nervous system activation, hypokalemia , metabolic alkalosis , and advanced cardiovascular and renal disease. Stroke (4.2-fold), myocardial infarction (6.5-fold), and atrial fibrillation (12.1-fold). Others : left ventricular hypertrophy, diastolic dysfunction and heart failure, large artery stiffness, oxidative stress, widespread tissue inflammation and fibrosis, and increased resistance vessel remodeling compared with primary hypertension. 11/17/2020 38

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40. Prevalence of primary aldosteronism ≈8% overall in primary hypertension. ≈20% in patients with confirmed rHTN . All resistant hypertension patients should be screened. 11/17/2020 40

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42. Two types of renin assays are in routine clinical use. One measures renin activity, second measures the amount of immunoreactive renin . For the plasma renin activity, the normal range is 1.9 to 3.7 ng Ang I/ml/h , and the lower level of detectability is 0.1 ng Ang I/ml/h. For the direct renin assay, the normal range is typically 13 to 44 IU/ml and lower level of detectability is 6 to 8 IU/ml . Therefore the typical ARR, for a patient with primary hypertension not receiving drugs that alter the renin-angiotensin system, is about 10 : 1 when using the plasma renin activity and 1 : 1 with the direct renin assay. 11/17/2020 42 Aldosterone-Renin Ratio (ARR)

43. Spironolactone , Eplerenone , Amiloride β-adrenergic receptor blockers, Central α2-receptor agonists, Renin inhibitors ACE inhibitors, ARBs, Non–potassium-sparing diuretics, Dihydropyridine CCBs Should be withdrawn 1 month before test Should be withdrawn 2 weeks before test 11/17/2020 43

44. 11/17/2020 44 The Journal of Clinical Endocrinology & Metabolism , Volume 93, Issue 9, 1 September 2008, Pages 3266–3281

45. Adrenal Vein Sampling For determining whether autonomous aldosterone release is due to unilateral or bilateral disease. SELECTIVITY INDEX- The ratio of adrenal vein to inferior vena cava cortisol concentration, should be determined and should be at least 5 : 1 for each adrenal vein sample to confirm successful adrenal vein cannulation . LATERALIZATION INDEX- The ratio of adrenal vein aldosterone to adrenal vein cortisol . Calculated by dividing the greater adrenal vein ratio by the lesser adrenal vein ratio. A lateralization index greater than 2.0 supports a diagnosis of an APA. 11/17/2020 45

46. Treatment Surgical Adrenalectomy Medical Mineralocorticoid Receptor Antagonists. Non– Mineralocorticoid Receptor Blocker Therapy 11/17/2020 46

47. Oral SPIRONOLACTONE 25 to 50 mg/day. Dose titration on a 2- to 4-week basis. Most patients can be treated with maximum dose of 100 mg/day, but occasional patients may require 200 to 400 mg/day, often administered twice a day. EPLERENONE can be used at similar doses and with a similar dose escalation pattern, with the that the general maximum recommended dose is only 100 mg/day. FINERENONE is a novel, selective, nonsteroidal MR blocker that may have less effect on serum potassium. 11/17/2020 47

48. Non– Mineralocorticoid Receptor Blocker Therapy ENaC Inhibitors Amiloride Triamterene Aldosterone Synthase Inhibitors Developmental 11/17/2020 48

49. Renal Artery Stenosis Hypertension accelerated or worsened by renal artery stenosis remains among the most common causes of RH, particularly in older age groups. More recent series indicate that 24% of older subjects (mean age, 71 years) with RH have significant renal arterial disease. Most patients with renovascular disease tolerate ACE inhibitor or ARB therapy without adverse renal effects, but a modest fraction (10%–20%) will develop an unacceptable rise in serum creatinine , particularly with volume depletion. 11/17/2020 49

50. A subset of medically treated patients develop progressive disease syndromes with worsening hypertension, renal insufficiency, or circulatory congestion (“flash pulmonary edema”) , which carry high mortality risks. 11/17/2020 50

51. Restenosis may develop in 15% to 24% of treated patients but may not always be associated with worsening hypertension or kidney function. Duplex imaging to identify increased peak systolic velocity in the renal arteries is most commonly used, often with confirmation by computed tomography angiography or magnetic resonance angiography before invasive studies. 11/17/2020 51

52. USE OF DOPPLER ULTRASONOGRAPHY TO PREDICT THE OUTCOME OF THERAPY FOR RENAL-ARTERY STENOSIS N Engl J Med, Vol. 344, No. 6 February 8, 2001 A renal resistance-index value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure, or kidney survival. 11/17/2020 52

53. Substantial risks but no evidence of a worthwhile clinical benefit from Revascularization in patients with atherosclerotic renovascular disease. N Engl J Med 2009;361:1953-62. 11/17/2020 53 ASTRAL TRIAL

54. Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. 11/17/2020 54 CORAL TRIAL

55. Pheochromocytoma / Paraganglioma The chromaffin cell tumors, pheochromocytoma (adrenal catecholamine producing, 90%) and paraganglioma (extra-adrenal, sympathetic/parasympathetic derived, 10%), are rare even in the hypertensive population, with a prevalence estimated at 0.01% to 0.2%. The prevalence is likely higher in patients referred for RH ( eg , up to 4%). 11/17/2020 55

56. Symptoms : Paroxysmal hypertension Sustained in up to 50% of those with high norepinephrine production Orthostatic in epinephrine -predominant tumors Headache, palpitations, pallor, and piloerection (“cold sweat”). 11/17/2020 56

57. The screening test of choice: Measurement of circulating catecholamine metabolites. Catechol O-methyl transferase releases normetanephrine and metanephrine from the tumors, measured as plasma free (sensitivity, 96%–100%; specificity, 89%–98%) or urinary fractionated (sensitivity, 86%–97%; specificity, 86%–95%) metanephrines . The levels are usually <4 times the upper limit of normal. If still elevated, they can be further evaluated as false positives by clonidine -suppression testing, with 100% specificity and 96% sensitivity of failure to reduce plasma metanephrines by 40%. 11/17/2020 57

58. 11/17/2020 58 The Oncologist 2008;13:000 – 000

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60. Coarctation of the Aorta Patients with operated coarctation of the aorta are likely to have hypertension in adulthood and are at risk for premature CVD, including myocardial infarction, aortic aneurysm, stroke, and heart failure. Because persistent hypertension may be secondary to increased sympathetic tone, β-blockers may be most useful for BP control. Antihypertensive therapy typically also includes an ACE inhibitor or an ARB. If hypertension is resistant to treatment, surgical or catheterbased intervention. 11/17/2020 60

61. Novel Therapies Renal dinnervation Baroreceptor Activation Therapy 11/17/2020 61

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63. Negative Trial n engl j med 370;15 nejm.org april 10, 2014 11/17/2020 63

64. Substantial BP reduction without any major safety signals 11/17/2020 64

65. The weight of the overall evidence suggests that over the long-term, BAT can safely reduce SBP in patients with resistant hypertension. 11/17/2020 65

66. Thank You 11/17/2020 66