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Optimal Therapeutic Decisions in HTN and Combined Diseases

Optimal Therapeutic Decisions in HTN and Combined Diseases. Timothy A. Denton, M.D., F.A.C.C. High Desert Heart Institute Victorville, CA. Barney Gumble. 57 year old male Central obesity LDL-C 190 mg/dl TG’s 280 mg/dl HDL 30 mg/dl BP 158/96. Review Articles.

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Optimal Therapeutic Decisions in HTN and Combined Diseases

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  1. Optimal Therapeutic Decisionsin HTNand Combined Diseases Timothy A. Denton, M.D., F.A.C.C. High Desert Heart Institute Victorville, CA

  2. Barney Gumble • 57 year old male • Central obesity • LDL-C 190 mg/dl • TG’s 280 mg/dl • HDL 30 mg/dl • BP 158/96

  3. Review Articles Franco V, et al. Hypertensive Therapy: Part I Circluation 2004;109:2953-2958 Franco V, et al. Hypertensive Therapy: Part II Circulation 2004;109:3081-3088

  4. Epidemiology of HTN Harrison’s Principles of Internal Medicine, 12th Edition

  5. Physiology of HTN • Primary Hypertension • ? Central / peripheral adrenergic • ? renal • ? hormonal • ? vascular

  6. Classification of BP for Adults SBP=systolic BP; DBP=diastolic BP. *JNC 7 Report. JAMA 2003;289:2560-2572.

  7. HTN End-organ Damage Eyes spasm AV nicking exudates edema Brain CVA Lungs rales Neck bruits JVD Abd Bruits ARF/CRF Proteinuria Heart S4 S3 Murmur CAD MI Ext pulses edema

  8. DM = 10.2 million, UnDx DM = 5.4 million Diabetes Care 1998;21:518

  9. Hypertension is Prevalent Among Diabetic Adults Diabetes alone 29% 71% Diabetes + HTN* * Hypertension defined according to JNC-6: BP 130/85 mm Hg NHANES III = Third US National Health and Nutrition Examination Survey (1988–1994). Geiss LS et al. Am J Prev Med. 2002;22:42-8.

  10. Most Hypertensive Patients Have Complex Hypertension Framingham Offspring Study Men aged 18–74 No additional CV risk factors 19% 81%  1 additional CV risk factor 7 Kannel WB. Am J Hypertens. 2000;13:3S-10S.

  11. Adipocyte Secretion Insulin sensitizer Kahn JCI 2000;106:473 (modified)

  12. Leptin Effects Kahn JCI 2000;106:473 (modified)

  13. HTN - DM Interaction • Obesity increases blood pressure • 50% of HTN pts are insulin resistant • Hi insulin levels raise BP • FFA’s inhibit vasodilatation • Poor vasodilation = no glucose to muscles HOPE - ACE decreases insulin resistance • Hi insulin increases Na and H20 renal tubular cells Ginsberg, JCI 2000;106:453

  14. SBP is a Stronger Predictor of CHD Mortality than DBP CHD Death Rate/10,000 Person-Years Diastolic BP (mm Hg) Systolic BP (mm Hg) MRFIT 10 Adapted from Neaton and Wentworth.

  15. 40 42 36 30 21 24 14 18 10 12 6 4 6 0 Complex Hypertension Increases Mortality Risk 10-Year Probability of Event (%) SBP 150-160 + + + + + + Cholesterol 240-262 - + + + + + HDL-C 33-35 - - + + + + Diabetes - - - + + + Cigarettes - - - - + + ECG-LVH - - - - - + 11 Kannel WB. Am J Hypertens. 2000;13:3S-10S.

  16. Stamler, Diabetes Care 1993

  17. Outcome Effects of DM and HTN - UKPDS Adler BMJ 2000;321:412

  18. Barney Gumble • 57 year old male • Central obesity • LDL-C 190 mg/dl • TG’s 280 mg/dl • HDL 30 mg/dl • BP 158/96

  19. CHF What is diastolic dysfunction?

  20. CHF Dilated Normal Hypertrophic

  21. What are the effects of LDL, DM and HTN? • Endothelial dysfunction • Endothelial damage • Low HDL • High LDL • Lipid deposition • Protein glycosylation • Plaque instability • Acute coronary events • Death

  22. 40-49 50-59 60-69 Years of age 70-79 80-89 Lowering of SBP by 20 mm Hg Reduces Cardiovascular Risk by Half Other vascular causes Stroke IHD 0 -10 N=958,074 -20 -30 % mortality reduction for each 20 mm Hg drop in SBP -40 -50 -60 -70 *Data from a meta-analysis of 1 million adults in 61 prospective studies who had no prior vascular disease.Lewington S et al. Lancet. 2002;360:1903-1913. 17

  23. Goals of Medical Therapy • Lower blood pressure • Prolong survival • Improve QOL • Decrease complications

  24. Therapy of HTN • Diet DASH diet (~11 mmHg) Low Na (~4.7 mmHg) • Exercise (~9 mmHg) • Modify ETOH intake (~3 mmHg) • Weight loss (~5 mmHg / 10 lbs) • Drugs

  25. Effect of Weight Change on DM Onset Relative Risk for DM Development Colditz et al, AIM 1995;122:481

  26. Angiotensinogen Inactive products Renin Inhibitor Renin increase nitric oxide, prostacyclin (improved endothelial function ? anti-atherosclerotic?) non-ACE alternative pathways (chymase, cathepsin G, chymostatin ATII generation) Angiotensin I ACE Inhibitor ACE ACE hypotension Angiotensin II Bradykinin ? angioedema AT1 receptor Inhibitor cough Vaso- constriction Vaso- dilatation Vasopressin Endothelin-1 Adapted, Bonn, D. Lancet 1998;352:378

  27. HOPE Trial Heart Outcomes Prevention Evaluation Study NEJM 2000;342:145-153

  28. Results HOPE Trial, NEJM 2000;342:145-153

  29. Results HOPE Trial, NEJM 2000;342:145-153

  30. Results HOPE Trial, NEJM 2000;342:145-153

  31. Results HOPE Trial, NEJM 2000;342:145-153

  32. Results HOPE Trial, NEJM 2000;342:145-153

  33. Results HOPE Trial, NEJM 2000;342:145-153

  34. Summary • Ramipril decreased CV mortality MI and CVA all-cause mortality Revascularization rates DM complications CHF Worsening angina New onset DM • Effects were see in all groups except those without cardiovascular disease HOPE Trial, NEJM 2000;342:145-153

  35. Implications • We have a new standard of care • All patients with vascular disease should be considered for ACE inhibition (e.g., ramipril)

  36. Antihypertensive Treatments and Incidence of New Onset Diabetes Study % Higher Incidence in Patients Using Diuretics, β-blockers CAPPP diuretics, β-blockers 13% vs captopril CHARM placebo ± SOC 16% vs candesartan ± SOC INVEST atenolol ± HCTZ or 17% vs verapamil SR ± HCTZ or trandolapril trandolapril INSIGHT co-amilozide ± β-blocker 30% vs nifedipine GITS LIFE atenolol 33% vs losartan ALLHAT chlorthalidone 18% vs amlodipine 43% vs lisinopril HOPE placebo ± SOC 50% vs ramipril ± SOC Lancet. 1999;353:611-616. Lancet. 2003;362:759-766. JAMA. 2003;290:2805-2816. Lancet. 2000;356:366-372. Lancet. 2002;359:995-1003. JAMA. 2002;288:2981-2997. N Engl J Med. 2000;342:145-153.

  37. 70 Placebo 60 Trandolapril 50 40 Mortality rate (%) Log rank P=0.04 Relative Risk 0.89, 95% Cl 0.80-0.99 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Years since randomization No. pts at risk 876 677 615 576 524 475 434 385 351 310 265 Trandolapril 873 647 564 497 463 417 398 338 299 273 245 Placebo Trandolapril: Reduces Mortality in Patients with LV Dysfunction Post-MI In the TRACE Study, the mortality curves diverged early on, favoring trandolapril, and remained distinct for 10 years of follow-up. 50 Buch P. et al. JACC 2004;1012-128:159A.

  38. Trandolapril: Survival Benefits Among Post-MI Diabetics TRACE StudyPost-MI Diabetic Patient Long-term Survival Benefits (n=237) Cardiovascular Death Sudden Death Progression to Heart Failure 0% -10% -20% % Odds Reduction -30% -40% -44% -50% -54% -60% P=0.01 -62% -70% P=0.01 P<0.001 51 Gustafsson I et al. J Am Coll Cardiol. 1999;34:83-9.

  39. Key Points for Optimal Hypertension Management <140/90mm Hg <130/80 mm Hg in diabetes or renal disease JNC 7BPGoals • JNC 7 recommends: • If SBP >20 mm Hg, DBP >10 mm Hg over goal, • consider initiating with 2-drug combination JNC 7 Report. Hypertension. 2003;42(6):1206-1252.

  40. HTNis one of the few diseases in which we make the MAJOR therapeutic drug decisions based on comorbidity

  41. Classes of Anti-Hypertensives (1999 PDR) Adrenergic blockers Alpha/Beta adrenergic blockers ACE inhibitors ACE + Ca blockers ACE + diuretics ARB’s ARB’s with diuretics Beta blockers Beta blockers with diuretics Calcium blockers Diuretics Rauwolfia derivatives Vasodilators

  42. Preparations of Anti-Hypertensives by Class (1999 PDR) Adrenergic blockers Alpha/Beta adrenergic blockers ACE inhibitors ACE + Ca blockers ACE + diuretics ARB’s ARB’s with diuretics Beta blockers Beta blockers with diuretics Calcium blockers Diuretics Rauwolfia derivatives Vasodilators 6 5 11 4 5 7 2 18 6 25 24 2 18 Total = 133

  43. Compelling Indications* for Antihypertensive Drugs *Compelling indications are based on benefits from outcomes studies or existing clinical guidelines. †The high-risk condition is managed simultaneously with the BP. A combination of agents may be required.Adapted from JNC 7. Guidelines. JAMA. 2003;289(19):2560.

  44. Goal BP (<140/90 mm Hg)Not Attained (<130/80 mm Hg for those with diabetes or chronic kidney disease) Lifestyle modifications Initialdrug choices When BP >20/10 mm Hg above goal, consider initiating with 2 drugs, separate or in fixed combinations Without Compelling Indications With Compelling Indications Stage 1 HTNSBP 140–159, DBP 90–99 mm Hg Thiazide-type diuretics for most. Consider ACEI, ARB, BB, CCB, or combination Stage 2 HTNSBP ≥160, DBP ≥100 mm Hg2-drug combo for most (thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Compelling Indications Other antihypertensives as needed (diuretics, ACEI, ARB, BB, CCB) as needed Goal BP Not Reached Optimize dose/add drugs to reach goal BP Consultation with HTN specialist JNC 7 Algorithm for Treatment of HTN JNC 7 Report. Hypertension. 2003;42(6):1206-1252.

  45. Prevalence of Microalbuminuria in the US Population Microalbuminuria defined as urinary albumin concentration 30 mg/g to 299 mg/g *No hypertension, CVD, diabetes, elevated serum creatinineJones CA et al. Am J Kidney Dis. 2002;39(3):445-459. 28

  46. Definitions of Proteinuria JNC 7 Report. Hypertension. 2003;42(6):1206-1252. Eknoyan G et al. Am J Kidney Dis. 2003;42:617-622.

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