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Newer Antihypertensive Drugs

Newer Antihypertensive Drugs. BushraAbdul Hadi Philadelphia University. Hypertension: A Significant CV and Renal Disease Risk Factor. CAD. CHF LVH. Stroke. Hypertension. Renal disease.  Morbidity  Disability. Peripheral vascular disease.

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Newer Antihypertensive Drugs

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  1. Newer Antihypertensive Drugs BushraAbdul Hadi Philadelphia University

  2. Hypertension: A Significant CV and Renal Disease Risk Factor CAD CHF LVH Stroke Hypertension Renal disease  Morbidity  Disability Peripheral vascular disease National High Blood Pressure Education Program Working Group. Arch Intern Med. 1993;153:186-208.

  3. “Older generation drugs used to bring down the B.P. fairly well at reasonable cost.” Then, Why do we need new drugs ? • Observational and limited controlled trials then showed marginal benefits of BP lowering for CVAs and IHD • Unfriendly dosing schedule • Unpleasant side effects

  4. Vasculopathy continuum CAD CHF CVA PAD Risk Factors Endothelial Dysfunction CKD HTN Metabolic syndrome

  5. Na+ Handling Sympathetic N system RAAS Hypertension Genetics Environment Psycho-social

  6. HTN : Old and New • Diuretics • Reserpine • Guanethidine • Alpha Methyl Dopa ACE Inhibitors Angiotensin Receptor Blockers Beta Blockers Central Alpha Agon. Calcium Channel Blockers Diuretics Direct Vasodilators Aldosterone Anta. NEP Blockers

  7. Potential Pathogenic Propertiesof Angiotensin II • Heart • Myocardial hypertrophy • Interstitial fibrosis • Coronary Arteries • Endothelial dysfunction with decreased release of nitric oxide • Coronary constriction via release of norepinephrine • Formation of oxygen-derived free radicals via NADH (nicotinamide adenine dinucleotide) oxidase • Promotion of inflammatory response and plaque instability • Promotion of low-density lipoprotein cholesterol uptake Adapted from Opie and Gersh. Drugs for the Heart, 2001.

  8. Potential Pathogenic Propertiesof Angiotensin II (continued) • Kidneys • Increased intraglomerular pressure • Increased protein leak • Glomerular growth and fibrosis • Increased sodium reabsorption • Decreased renal blood flow • Adrenal Glands • Increased formation of aldosterone • Coagulation System • Increased fibrinogen • Increased PAI-1 (plasminogen activator inhibitor-1) relative to tissue plasminogen factor Adapted fromOpie and Gersh.Drugs for the Heart, 2001.

  9. The Renin-Angiotensin-Aldosterone (RAA) System Kidneys secreterenin Adrenal cortex secretes aldosterone Liver secretes angiotensinogen Angiotensinconvertingenzyme(ACE) Blood Renin Angiotensinogen Angiotensin I Angiotensin II Aldosterone NA+ retention H2O retention K+ excretion Mg+ excretion Growthfactor stimulation Vascular smooth muscle constriction Sympathetic activation

  10. RAA System Pathways to Target Receptor Sites Na+ K+ Angiotensinogen Aldosterone Adrenal Vascular Myocardial Renal CNS Renin Other ACTH Chymase CE Angiotensin I Angiotensin II Inactive Bradykinin

  11. LIFE: Primary and Select Secondary Outcomes • Losartan Atenolol(n=4,605) (n=4,588) RR (%)p-value • Primary composite† 508 588 -13 .021 • CV mortality 204 234 -11 .21 • Stroke 232 309 -25 .001 • MI 198 188 +7 .49 • Total mortality 383 431 -10 .13 • New onset DM‡ 241 319 -25 <.001 Adjusted* * For degree of LVH and Framingham risk score at randomization † Number of patients with a first primary event ‡ In patients without diabetes at randomization (losartan, n=4,019; atenolol, n=3,979) Adapted from B Dahlöf et al. Lancet. 2002;359:995-1003.

  12. MI, Stroke,CV Death(primaryend point) All-causeDeath CV Death MI Stroke 0 -5 -10 -15 Risk Reduction (%) -16 (P=.005) -20 -20 (P<.001) -22 (P<.001) -25 -26 (P<.001) -30 -32 (P<.001) -35 HOPE: Risk Reduction of CV EventsAssociated with ACEI (RAS Inhibition) Treatment Adapted from The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153.

  13. Mechanism of Action ofAngiotensin II Receptor Antagonists Angiotensinogen Alternate pathways Bradykinin Angiotensin I ACE inhibitors Angiotensin II Inactive peptides AIIRAs ? AT1 receptor Other AT receptors AT2 receptor Vasodilation Attenuate growth and disease progression ?

  14. Val-HeFT Results • Overall mortality was similar in the two groups • 13% RRR (p=.009) in combined end point • Predominantly because of a 27% decrease in hospitalization for HF in the valsartan group • Subgroup analyses: • Valsartan had a favorable effect in patients receiving neither an ACE inhibitor nor a beta-blocker • Valsartan had a favorable effect in patients receiving an ACE inhibitor or a beta blocker • Valsartan demonstrated a statistically non-significant trend towards an adverse outcome in patients receiving an ACE inhibitor and a beta blocker

  15. ADA Guidelines on Management of Diabetic Nephropathy • Hypertensive Type 2 Diabetic Patients* • ARBs are the initial agents of choice • Type 1 Diabetics with or without hypertension* • ACEIs are the initial agents of choice • If one class is not tolerated the other should be substituted * With microalbuminuria and clinical proteinuria. Adapted from American Diabetes Association. Diabetes Care. 2002;25:S85-S89.

  16. 40 30 20 10 0 0 1 2 3 4 Effect of ACE Inhibition on Nephropathy in Type 1 Diabetes Placebo Progression to Death, Dialysis, or Transplant (%) * Captopril Follow-up (y) * P=.006 vs placebo. Adapted from Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.

  17. ACE Inhibitors and ARBs • Captopril • Enanlapril • Lisinopril • Ramipril • Perindopril • Quinapril Losartan Irbesartan Candesartan Valsartan Telmisartan Olmesartan Aliskiren

  18. Proven role of Beta Blockers in Various Indications • - Hypertension • Diabetes Mellitus • CHF • CAD

  19. Effect of Beta-Blockers on mortality following myocardial infarction 25 23 No diabetes mellitus, all Diabetes mellitus, all 20 17 No diabetes mellitus, no beta-blocker 15 13 1 year-mortality (%) No diabetes mellitus, beta-blocker Kjekshus J et al. Eur Heart J 1990; 11: 43-50 10 10 10 7 Diabetes mellitus, no beta-blocker 5 Diabetes mellitus, beta-blocker 0

  20. Usefulness of beta-blocker therapy in patients With Diabetes Mellitus and CAD (BIP) 1.00 0.95 0.90 Survival rate Jonas et al. Am J Cardiol 1996; 77: 1273 et seqq. With ß -blockers 0.85 Without ß -blockers 0.80 P = 0.0001 0.75 1 2 3 4 5 Year

  21. Trial End Point Risk Reduction, % (95% CI) Clinical Trial Combined end point: risk of hospitalization or death US Carvedilol 38% lower risk (18%-53%) P< 0.001 All-cause mortality CIBIS-II (bisoprolol) 34% lower risk P< 0.0001 All-cause mortality MERIT-HF (metoprolol) 34% lower risk (0.53–0.81) P=0.0062 after adjusted interim analysis All-cause mortality 8.5% lower risk P=NS BEST (bucindolol) All-cause mortality 35% lower risk* COPERNICUS (carvedilol) Effect of Beta-Blockers on Mortality in Heart Failure Patients *Preliminary data from XXII Congress of the European Society of Cardiology

  22. Plasma renin ng/ml Angiotensin II pg/ml Aldosterone pg/ml Plasma renin ng/ml Angiotensin II pg/ml Aldosterone pg/ml Baseline 24 weeks Baseline 24 weeks *P<0.05 NS: Non Significant Effects of Metoprolol CR and Placebo on Neurohormonal Activation 250 225 200 175 150 125 100 75 50 25 0 Metoprolol Placebo 250 225 200 175 150 125 100 75 50 25 0 182 NS 165 * 147 129 128 113 105 99 38.9 * 34.3 35.9 30.9 The Resolvd Investigators. 1999.

  23. Effect of -Blocker in Heart Failure • Mega-trials on: metoprolol, bisoprolol, carvedilol & bucindolol. • Consistent good results in mild / moderate HF. • Significant ↓ in rate of hospitalisation. • Fair improvements in symptoms & QOL. • Improvements in hemodynamics of HF & remodeling. • Results in severe HF are not uniform. • Bucindolol in BEST showed no benefits. • Sub-analysis of CIBIS-II (Bisoprolol) & MERIT-HF: ↓ benefits in more severe HF. • COPERNICUS: significant benefits in severe HF.

  24. Lipophilic beta blockers are an ideal choice in patients at high risk of SCD, prior MI, HT,CHF

  25. Beta Blockers • Propranolol • Atenolol • Metoprolol( Sustained Release) • Bisoprolol • Carvedilol

  26. ALLHAT Diuretics Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. Hydrochlorthiazide Metolazone Furosemide Torsemide Amiloride

  27. Calcium Channel Blockers • Very effective in lowering BP • Safe • OD or BID Dose • No significant outcome benefits • Peripheral edema Nifedipine(Long Acting) Amlodepine Verapamil Nicardepine Lercanidipine Felodepine

  28. Miscellaneous • Direct Vasodilators • Dihydrallazine • Minoxidil • Prazosin • Central Alpha Agonists • Clonidine • Moxolidine • Aldosterone antagonists • Spironolactone • Eplerenone • Indapamide

  29. Benefits of Lowering BP Average Percent Reduction Stroke incidence 35–40% Myocardial infarction 20–25% Heart failure 50%

  30. U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

  31. Blood Pressure Classification

  32. Compelling Indications for Individual Drug Classes

  33. Compelling Indications for Individual Drug Classes

  34. Cardiovascular Diseases • Cerebrovascular disease • Indication for treatment, except immediately after ischemic cerebral infarction. • Coronary artery disease • Benefits of therapy well established. • Left ventricular hypertrophy • Antihypertensive agents (except direct vasodilators) indicated. • Reduced weight and decreased sodium intake beneficial.

  35. Cardiovascular Diseases (continued) • Cardiac failure • ACE inhibitors, especially with digoxin or diuretics, shown to prevent subsequent heart failure. • Peripheral arterial disease • Limited or no data available.

  36. New Features and Key Messages • For persons over age 50, SBP is a more important than DBP as CVD risk factor • Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range. • Persons who are normotensive at age 55 have a 90% lifetime risk for developing HTN. • Those with SBP 120–139 mmHg or DBP 80–89 mmHg should be considered prehypertensive who require health-promoting lifestyle modifications to prevent CVD.

  37. JNC-VII New Features and Key Messages (Continued) • Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes. • Certain high-risk conditions are compelling indications for other drug classes. • Most patients will require two or more antihypertensive drugs to achieve goal BP. • If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

  38. Preventable CHD Events from Control of Hypertension in US Adults(Wong et al., Am Heart J 2003; 145: 888-95) (cont.) • The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension • The greatest proportion of preventable CHD events from control of hypertension occurs in women • Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women

  39. -blockers ARBs VPIs Others Directvasodilators ACEinhibitors Thiazidesdiuretics Peripheralsympatholytics Ganglion blockers Veratrumalkaloids Central 2 agonists Calciumantagonists-non DHPs -blockers Calciumantagonists-DHPs Evolution of Antihypertensive Therapies Effectiveness Tolerability 1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001

  40. We are still evolving towards finding an Ideal Antihypertensive

  41. Preventable CHD Events from Control of Hypertension in US Adults(Wong et al., Am Heart J 2003; 145: 888-95) PAR% = population attributable risk (proportion of CHD events preventable), NNT = number needed to treat to prevent 1 CHD event ; <0.01 comparing men and women for PAR%

  42. Compelling Indications for Certain Drug Classes

  43. HTN with CAD • Beta blockers: cardioprotective (reinfarction, arrhythmias and sudden death) • ACE inhibitors: MI with systolic dysfunction- heart failure and mortality improved

  44. Aliskiren is a novel, completely nonpeptide, orally active renin inhibitor that blocks the first and rate-limiting step of the renin-angiotensin system • Alagebrium, an advanced glycation end product (AGE) crosslink breaker, has been shown to reduce SBP in patients with uncontrolled systolic hypertension, • progestin drospirenone and 17beta-estradiol (DRSP/E2), developed for postmenopausal hormone replacement therapy, has been shown to lower both clinic and ambulatory SBP in postmenopausal women

  45. Pathophysiology of Heart Failure Cardiac injury Increased load Activation of RAA System, SNS, and cytokines Reduced systemic perfusion Altered gene expression Growth and remodeling Ischemia and energy depletion Direct toxicity Apoptosis Necrosis Cell death Adapted from: Eichhorn EJ, Bristow MR. Circulation. 1996;94:2285-2296.

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