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TREATMENT OF COMPLICATED HYERTENSION Joseph L. Izzo Jr, MD Professor of Medicine, Pharmacology, and Toxicology SUNY-Buf

TREATMENT OF COMPLICATED HYERTENSION Joseph L. Izzo Jr, MD Professor of Medicine, Pharmacology, and Toxicology SUNY-Buffalo. Diastolic vs systolic hypertension Prevention vs treatment Compelling indications Other high risk conditions. ISH (SBP >140 mm Hg and DBP <90 mm Hg)

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TREATMENT OF COMPLICATED HYERTENSION Joseph L. Izzo Jr, MD Professor of Medicine, Pharmacology, and Toxicology SUNY-Buf

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  1. TREATMENT OF COMPLICATED HYERTENSIONJoseph L. Izzo Jr, MDProfessor of Medicine, Pharmacology, and ToxicologySUNY-Buffalo

  2. Diastolic vs systolic hypertension • Prevention vs treatment • Compelling indications • Other high risk conditions

  3. ISH (SBP >140 mm Hg and DBP <90 mm Hg) SDH (SBP >140 mm Hg and DBP >90 mm Hg) IDH (SBP <140 mm Hg and DBP >90 mm Hg) 100 80 60 40 20 0 Hypertension Subtypes by Age (NHANES III Untreated Hypertensives) 17% 16% 16% 20% 20% 11% Frequency of hypertension subtypes in all untreated hypertensives (%) <40 40-49 50-59 60-69 70-79 80+ Age (y) Percentages represent the overall distribution of untreated hypertension by age. Franklin et al. Hypertension 2001;37: 869-874.

  4. Anatomy of aCentral Arterial Pulse Wave Augmentation Index = AP/PP Reflected wave Systolic BP Augmentation Pressure (AP) Incident wave Pulse pressure (PP) Mean Arterial Pressure Dicrotic notch Diastolic BP

  5. MAP Integrated static “DC” signal Determined by the CO-SVR product Mainly indicative of distal vasoconstriction Closely related to diastolic pressure PP Pulsatile dynamic “AC” signal Determined by “ventricular-vascular interactions” Early systole: Aortic impedance Late systole: Wave reflections Closely related to systolic pressure Mean Arterial vs. Pulse Pressure: Different Information Provided

  6. InhibitsPromotes Pathogenesis of Systolic and Diastolic Hypertension SYSTOLIC HYPERTENSION  Stroke Volume Central Artery Stiffness Arteriolar Constriction DIASTOLIC HYPERTENSION

  7. BP RESPONSES TO VASODILATORS (Decrease in MAP of 10 mmHg) SYSTOLIC HYPERTENSION -20 - 5 Change in Systolic Pressure (mmHg) DIASTOLIC HYPERTENSION - 6 -12 Change in Diastolic Pressure (mmHg) (modified from Koch-Weser 1973)

  8. ACE and ACE-NEP Inhibitor Effects on Aortic Impedance(Mitchell G, Izzo JL Jr, et al. Circulation 2002, in press)

  9. Diastolic vs systolic hypertension • Prevention vs treatment • Compelling indications • Other high risk conditions

  10. Systolic BP Reduction and CVD Mortality 1.50 MIDAS/NICS/VHAS UKPDS C vs A 1.25 P = 0.003 NORDIL INSIGHT HOT L vs H STOP2/ACEIs HOT M vs H Cardiovascular Mortality Odds Ratio MRC1 1. 00 MRC2 STOP2/CCBs SHEP STONE HEP CAPPP 0.75 EWPHE HOPE Syst-Eur UKPDS L vs H Syst-China RCT70-80 0.50 PART2/SCAT STOP1 ATMH 0.25 -5 0 5 10 15 20 25  Systolic BP (control - experimental, mmHg) Staessen JA, et al. Lancet 2001;358:1305–1315.

  11. Clinical Trialists View Amount of BP lowering is more important than choice of drug class in overall disease prevention

  12. JNC 7 Medication Algorithm Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed Not at Goal BP Optimize dosages or add additional drugsuntil goal BP is achieved.Consider consultation with hypertension specialist.

  13. Why the “discrepancies”? HETEROGENEITY !!!!! Even if we are all created equal (ethically and legally), we are not created equal biologically.

  14. Diastolic vs systolic hypertension • Prevention vs treatment • Compelling indications • Other high risk conditions

  15. JNC 7 Compelling Indication: Definition A high-risk condition associated with hypertension for which there is clinical trial evidence of a specific outcome benefit of a given class of antihypertensive drugs

  16. JNC 7 Compelling Indications for Individual Drug Classes (o = Updated) Compelling Indication Basis Initial Therapy Options TZ BB ACE ARB CCB AA ACC/AHA HF Guideline,MERIT-HF, COPERNICUS, AIRE, SOLVD, RALES, CIBIS, TRACE, Val-HEFT, CHARM ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS, VALIANT ALLHAT, HOPE, ANBP2, LIFE, VALUE, CONVINCE, EUROPA oo o o o o • • • • • • • • • • O • • • • OO A B C D HEART FAILURE (STAGE) POST-MI HIGH CAD RISK

  17. Components of Cardiac Afterload Late-systolic pressure augmentation (wave reflection) Contractility/Aortic impedance (“ventricular-vascular coupling”) Residual systemic (diastolic) pressure (SVR) (DBP > Aortic impedance > Augmentation)

  18. Age and Components of Cardiac Afterload Augmentation Component Younger Older

  19. SEVERE HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY

  20. Heart Failure Death Possible pathway of progression Progression of Cardiovascular Disease Smoking Dyslipidemia Diabetes MI Systolic Dysfunction  SBP Diastolic Dysfunction Obesity Diabetes LVH Normal LV structure & function LV remodeling Subclinical LV dysfunction Overt Failure Months Years Adapted from Levy D. J Am Coll Cardiol 1993

  21. Therapy for CHF NYHA Class Agent I II III IV Statins Diuretics ACEI/ARB Beta Blockers Digoxin Spironolactone ??? ??? No proven mortality benefit, used in symptomatic patients May offer mortality benefit No data for or against ??? Should not be used in this Class Use for mortality benefit Mod. From Eichhorn EJ. Clin Cardiol. 1999;22bb:V21-V29. 8

  22. JNC 7 Compelling Indications for Individual Drug Classes (o = Updated) Compelling Indication Initial Therapy Options TZ BB ACE ARB CCB AA Basis DIABETESCHRONIC KIDNEY DISEASE RECURRENT STROKE NKF-ADA Guideline,UKPDS, ALLHAT • • • • • • • • ?O O NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS, MIRACLE

  23. MDRD Study: Impact of BP Control • Hebert, et al. Hypertension 30;1997.428-35

  24. Aggressive BP Goals: Consensus Across Treatment Guidelines Organization Patient Type BP Goals (mm Hg) ADA Diabetes <130/80 ISHIB African American <140/90 Plus DM or proteinuria >1 g/24 h <130/80 JNC 7 Uncomplicated HTN <140/90 With DM, CKD <130/80 NKF Albuminuria (>300 mg/d or >200 mg/g creatinine), <130/80 with or without diabetes Proteinuria (protein to creatinine ratio “Consider even >500-1000 mg/g) lower than <130/80” WHO-ISH Low risk for CVD SBP<140 Presence of DM, target organ damage, or associated clinical conditions <130/80 ADA: American Diabetes Association; ISHIB: International Society on Hypertension in Blacks; JNC 7: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NKF: National Kidney Foundation; WHO-ISH: World Health Organization/International Society on Hypertension

  25. 100 90 80 70 60 50 40 30 20 10 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 ACEI in Diabetic Renal Disease Overall Deaths: Captopril: 8/207=4% Placebo: 14/202=7% Placebo SCr1.5 Death Dialysis or Transplant (%) *P=.002 vs placebo (Scr1.5 ) Captopril* SCr1.5 Placebo SCr<1.5 Captopril SCr<1.5 Years of Follow Up Lewis EJ et al. N Engl J Med 1993;329:1456-1462.

  26. 30 20 10 30 0 0 12 24 36 48 P 20 L 10 50 0 40 0 12 24 36 48 30 20 10 0 0 12 24 36 48 P (+ CT) P (+ CT) L (+ CT) L (+ CT) ESRD RENAAL 10 Components Risk Reduction: 28% p=0.002 P % with event L Doubling of Serum Creatinine Risk Reduction: 25% p=0.006 Months 762 715 610 347 42 751 714 625 375 69 % with event ESRD or Death Risk Reduction: 20% p=0.010 P % with event L Months P (+ CT) 295 762 689 554 36 L (+ CT) 52 751 692 583 329 Months 762 715 610 347 42 751 714 625 375 69

  27. Any anti- hypertensive BP Drugs in Chronic Kidney Disease Pathogenetic steps Increased renal perfusion pressure Glomerular capillary hypertension Proteinuria Focal glomerulosclerosis Glomerular and tubular dropout End-Stage Disease ACEI or ARB

  28. Clinical Trials and Renal Outcomes Based on Proteinuria Reduction Progression of diabetic nephropathy/ESRD Protection No Protection • Captopril • Ramipril (AASK/REIN) • Losartan (RENAAL) • Irbesartan (IDNT) • Amlodipine (IDNT) • Amlodipine (AASK) • Isradipine (STENO) • Nifedipine 30-35% proteinuria No proteinuria ESRD = End Stage Renal Disease Lewis EJ et al. N Engl J Med. 1993;329:1456-1462; Wright JT et al. JAMA. 2002; 288(19):2421-2431; Ruggenenti P et al. Lancet. 1999;354(9176):359-364; Brenner BM et al. N Engl J Med. 2001;345(12):861-869; Lewis EJ et al. N Engl J Med. 2001;345(12):851-860; Norgaard K et al. Blood Press.1993;2(4):301-308; Abbott K et al. J Clin Pharmacol. 1996;36;274-279.

  29. JNC 7: BP Thresholds* and Goals for Initial Use of 2-Drug Combinations Initial BP Goal BP (mmHg) (mmHg) Condition >160/100* <140/90 No diabetes or chronic kidney disease (CKD) >150/90* <130/80 Diabetes (FBS > 125 mg/dL x 2) CKD: (eGFR < 60 or albuminuria > 300 mg/d) * >20/10 mmHg above goal

  30. Probable dose-response relationships for BP and albuminuria BP Albuminuria Effect  l l l l Log Dose 

  31. Combination Therapy Is Usually Requiredto Reach JNC Goals “Most patients with HTN will require 2 or more agents to achieve goal of <140/90 (<130/90 in DM or CKD)” -JNC 7 Trial SBP mm Hg Mean Number of Agents AASK 128 INVEST 133 HOT 138 ALLHAT 138 IDNT 138 RENAAL 141 UKPDS 144 2.4 2.0 Mean 2.0, Median 2.8 agents Met JNC Goals 3.0 1.9 4.0 SBP <140 4.1 Did not Meet JNC Goals 3.0 75% of patients required3 or more agents Chobanian AV et al. Hypertension. 2003; 42(6):1206-1252; Chart adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661; ALLHAT Officers. JAMA. 2002;288:2981-2997;Hansson L et al. Lancet. 1998;351:1755-1762; Pepine CJ et al. JAMA. 2003;290(21):2805-2816; Wright JT et al. Arch Intern Med. 2002;162:1636-1643; UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713; Brenner BM et al. N Engl J Med. 2001;345(12):861-869; Sica DA, Bakris GL. J Clin Hypertension. 2002;4(1):52-57.

  32. Diastolic vs systolic hypertension • Prevention vs treatment • Compelling indications • Other high risk conditions

  33. Resistant hypertension BP above target despite use of 3 or more antihypertensive drugs, one of which is a diuretic

  34. Selected conditions associated with resistant hypertension • Non-adherence • Sleep apnea • Renal failure • Interfering drugs

  35. TREATMENT OF COMPLICATED HYERTENSIONJoseph L. Izzo Jr, MDProfessor of Medicine, Pharmacology, and ToxicologySUNY-Buffalo

  36. 0 6 12 18 24 30 36 42 48 54 60 66 Month RAAS Blockade: Treatment Benefit Seen at All Albuminuria Baseline Levels Primary Composite Endpoint of LIFE Trial Stratified by Time-varying Albuminuria 24 Albuminuria (urine albumin/creatinine ratio in mg/g) 20  44 45 - 88 89 - 265 16 > 265 Losartan Endpoint (Event Rate in %) Atenolol 12 8 4 0 Ibsen H et.al J Hypertension. 2004;22:1805-1811.

  37. Older Concepts of Systolic Hypertension • Basically a function of aging; accelerated by hypertension • Irreversible process involving increased aortic stiffness due to • Aortic dilatation (increased wall tension) • Aortic wall thickening • Replacement of elastin with collagen • Therapy directed at lowering vascular resistance

  38. Newer Concepts of Systolic Hypertension • Can occur at any age (esp. in women) • Increased aortic stiffness can be structural or functional • Can be caused by smaller aorta with normal elastic properties (radius is a major factor in aortic impedance) • Age-related dilation (remodeling) may be a secondary adaptation to reduce PP • Therapy may be directed at reducing vasoconstriction or increasing aortic elasticity

  39. “Compartments” of the Cardiovascular System • Heart • Central arteries (aorta) • Peripheral conduit arteries (brachial, etc) • Arterioles (resistance vessels) • Capillaries • Veins Key Concept: Changes in these vascular “compartments” with aging and hypertension are non-uniform but are interdependent

  40. Central Arterial Stiffness and PPPathophysiologyElastic vessels Inelastic vessels SYSTOLE DIASTOLE SYSTOLE DIASTOLE STROKE VOLUME STROKE VOLUME ( ) AORTA AORTA RESISTANCE ARTERIOLES RESISTANCE ARTERIOLES Increased SBP PRESSURE (FLOW) PRESSURE (FLOW) Wide PP Decreased DBP Adapted from Izzo JL. J Am Geriatr Soc. 1981;29:520-524.

  41. Impedance and arterial radius • Impedance is the pulsatile equivalent of resistance Characteristic aortic impedance: Zc  √Eh/r5 E = elastic modulus; h = wall thickness; r = radius Zc varies inversely with r2.5

  42. Age, Gender, PP and Aortic Root Diameter (Framingham) Vasan, et al. Circulation 1995

  43. BP and Aortic Root Diameter (Framingham) Vasan, et al. Circulation 1995

  44. Aortic Dilatation and BP (LIFE Study) Bella, et al. Am J Cardiol 2002

  45. Pulse Wave Transmission and Reflection • There are forward-traveling and backward-traveling (reflected) waves in the arterial tree • An arterial pulse contour at any point along the arterial tree is the sum of the forward-traveling and backward-traveling pressure waves at that point.

  46. Determinants of Central Systolic Pressure Augmentation • Timing of reflected wave return • Pulse wave velocity (principally arterial stiffness-related) • Location of reflecting site (varies physiologically) • Amplitude of reflected wave • Reflection coefficient (principally vasoconstriction-related)

  47. Age and Reflected Waves ELASTIC VESSELS STIFF VESSELS PWV 8 M/SEC PWV 12 M/SEC Systolic Augmentation Pressure FORWARD-TRAVELING WAVE BACKWARD-TRAVELING WAVE ACTUAL (COMPOSITE) WAVE PWV = pulse wave velocity. Modified from Asmar, R. Arterial Stiffness

  48. Functional Dependency of Reflected Waves on Systemic Hemodynamics RADIAL AP = 20 AP = 2 AP = - 8 CENTRAL NORMAL NOREPINEPHRINE EPINEPHRINE (HYPERTENSION)

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