Lotrel and Diovan Talk

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Published on March 5, 2008

Author: Nikita

Source: authorstream.com

The story of man…..:  The story of man….. The short version God :  God populated the earth with broccoli, cauliflower and spinach…… green & yellow vegetables of all kinds, “A HEALTHY DIET” Slide3:  so man and woman would live long, healthy lives Satan created:  Satan created McDonalds and brought forth the 99 cent double cheeseburger, and the value meal Man said:  Man said “Super size that” and gained pounds GOD:  GOD created healthful yogurt Satan:  Satan created chocolate God said:  God said “try my crispy fresh salad” Satan said :  Satan said “enjoy my Ben and Jerry’s” God said:  God said “I have sent you heart healthy vegetables and olive oil with which to cook them” Satan said:  Satan said “order a pizza… you won’t have to cook…. We deliver !” Man gained pounds and his cholesterol went through the roof:  Man gained pounds and his cholesterol went through the roof God brought forth running shoes:  God brought forth running shoes Man repented, and resolved to lose all those extra pounds:  Man repented, and resolved to lose all those extra pounds Satan brought forth cable TV, with remote control, so man would not have to get up to change channels .:  Satan brought forth cable TV, with remote control, so man would not have to get up to change channels . Man’s waist continued to expand until his pant’s size far exceeded his age :  Man’s waist continued to expand until his pant’s size far exceeded his age Satan:  Satan Began to sponsor Monday Night Football in order to extend man’s weekend celebration God said:  God said “You’re running up the score, Satan” God brought forth:  God brought forth the potato, a vegetable low in fat and brimming with nutrition Satan:  Satan peeled off the skin, sliced the starchy center into chips and deep fat fried them MAN:  MAN clutched his remote control, ate the potato chips and was drowning in his LDL Satan said:  Satan said “This endothelium is inflamed…. Let’s hope it becomes unstable!” Slide23:  Man went into cardiac arrest!!! God sighed, and created :  God sighed, and created interventional cardiologists, angioplasty, drug eluting stents and finally quadruple cardiac bypass surgery! Satan started enrollment in:  Satan started enrollment in HMO’s GOD:  GOD Finally growing weary of Satan antics created: REFERENCES:  REFERENCES WWW.HYPERTENSIONONLINE.ORG WWW.LIPIDSONLINE.ORG CONTENTS:  CONTENTS LOGIC ASCOT SOLACE SELECT SHIELD LEAAD ALERT DIOVAN RAAS:  RAAS Endocrine (Systemic) Phenomenon Servomechanism to Maintain Blood Pressure Autocrine/Paracrine (Tissue Level) Effects Target Organ Damage Irrespective of the Systemic Renin Profile Complications of Hypertension: Target-Organ Damage:  Complications of Hypertension: Target-Organ Damage Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors:   O2 Endothelial Cells and  H2O2 Vascular Smooth Muscle Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors Endothelial Dysfunction Apoptosis Vasoconstriction Leukocyte adhesion Lipid deposition Thrombosis VSMC growth Hypertension Smoking Diabetes LDL Homocysteine www.hypertensiononline.org Albuminuria:  Albuminuria Reflects Endothelial Dysfunction Glomerular Pressures “Nephrological Hgb A1c/ Ldl Cholesterol” Definitions of Microalbuminuria and Macroalbuminuria:  Definitions of Microalbuminuria and Macroalbuminuria AER=Albumin excretion rate CR# =creatinine www.hypertensiononline.org TITRATION of ACEI/ARB AGAINST PROTEINURIA:  TITRATION of ACEI/ARB AGAINST PROTEINURIA It takes ~ 3 months to reduce proteinuria and ~ 6 months for the maximal impact Use the Uprotein/Ucreatinine ratio The creatinine negates any hydration/dehydration issues. You want at least a 50% reduction. Why 50%? There is ~ 30% variation in protein excretion, independently of any intervention. Many of the studies re: benefit with AII intervention was associated with ~ 50% reduction. Additional Parameters for Titration of the ACEI/ARB:  Additional Parameters for Titration of the ACEI/ARB With CKD and HTN One may tolerate ~ 20-25% rise in serum creatinine Equilibrates in ~ 3 months and creatinine may be lower than pretreatment levels Metabolic Issues Revert to the previous dose if the potassium is > 5.5 in the absence of a metabolic acidosis (CO2 >18) Rationale for Combination Therapy:  Rationale for Combination Therapy Lotrel®:  Lotrel® Rationale for ACE-I/CCB Combination:  Rationale for ACE-I/CCB Combination Lotrel: Gauging Improved Control (LOGIC) :  Lotrel: Gauging Improved Control (LOGIC) LOGIC: Background (cont):  LOGIC: Background (cont) LOGIC: Group 1:  LOGIC: Group 1 LOGIC: Change in BP With Lotrel® Group 1: Inadequate BP Control With Norvasc®:  LOGIC: Change in BP With Lotrel® Group 1: Inadequate BP Control With Norvasc® LOGIC: Group 2:  LOGIC: Group 2 LOGIC: Improvement in Edema at Week 4 With Lotrel® Group 2: BP Control but Unacceptable Edema With Norvasc?:  LOGIC: Improvement in Edema at Week 4 With Lotrel® Group 2: BP Control but Unacceptable Edema With Norvasc? LOGIC: Conclusions:  LOGIC: Conclusions Effects of Combination Therapy on Capillary Pressure and Edema:  Effects of Combination Therapy on Capillary Pressure and Edema Slide50:  Glomerular Effects of CCBs and ACE Inhibitors Valentino VA et al. Arch Intern Med. 1991;151:2367-2372. Vivian EM et al. Ann Pharmacother. 2001;35:452-463. Dilation of afferent arteriole only Dilation of both afferent and efferent arteriole  Glomerular pressure  Albumin excretion rate ¯ Glomerular pressure ¯ Albumin excretion rate Efferent arteriole Glomerulus DHPCCB ACE inhibitor Bowman’s capsule Afferent arteriole Efferent arteriole Afferent arteriole Glomerulus Bowman’s capsule Slide51:  216 432 209 422 191 391 131 278 216 432 210 428 193 405 139 290 Incidence of Renal Events and Death: AASK Cumulative incidence (%) No. at risk Amlodipine Ramipril GFR, glomerular filtration rate; ESRD, end-stage renal disease; RR, adjusted risk reduction. *P=0.005 (95% CI, 13-56%); †P=0.007 (95% CI, 14-60%). Agodoa LY et al. JAMA. 2001;285:2719-2728. 3 12 24 36 3 12 24 36 0 Months GFR event, ESRD, or death 0 Months ESRD or death Amlodipine besylate Ramipril RR= 41%† RR= 38%* Slide52:  Change in Proteinuria From Baseline: AASK Months D in UP/Cr (%) -35 0 50 125 230 0 6 24 36 -55 -70 0 6 24 36 UP:Cr, urinary protein:creatinine ratio. AASK Study Group. JAMA. 2001;285:2719-2728. Baseline UP:Cr 0.22 Baseline UP:Cr >0.22 Amlodipine Ramipril 12 12 Months Slide53:  Remember that the glomerulus is a capillary, so anything that makes your feet swell (dhpccb, hydralazine, or minoxidil) can increase glomerular pressures and beget proteinuria and a decline in renal function. That is what happened in the AASK trial. At the same mean BP, Norvasc had more renal failure compared to ramipril. Those previous slides point out the issue of capillary hypertension,which is the cause of the edema. Lotrel does decrease proteinuria even in the face of the DHPCCB so this combination still offers benefit above both Lotensin or Norvasc alone. Amlodipine/Fosinopril Combination Therapy in DM-HTN Patients With Microalbuminuria Effects on Blood Pressure:  Amlodipine/Fosinopril Combination Therapy in DM-HTN Patients With Microalbuminuria Effects on Blood Pressure DM-HTN, concomitant type 2 diabetes and hypertension. Fogari R et al. AJH. 2002;15:1042-1049. 170 160 150 140 130 120 Months SBP mmHg 100 90 80 70 Months DBP mmHg Amlodipine besylate (n=103) Fosinopril (n=102) Combination (n=104) Amlodipine/Fosinopril Combination Therapy in DM-HTN Patients With Microalbuminuria Effects on Microalbuminuria:  30 Amlodipine/Fosinopril Combination Therapy in DM-HTN Patients With Microalbuminuria Effects on Microalbuminuria *P<.05; †P<.01; ‡P<.001 vs. baseline. DM-HTN, concomitant type 2 diabetes and hypertension. Fogari R et al. AJH. 2002;15:1042-1049. 100 90 80 70 60 50 40 20 0 3 6 12 18 24 30 36 42 48 * † † † † † † ‡ † † † † † † * † † * * * * * * * Months Proteinuria mg/24h ASCOT - BPLA Background and Objective :  Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005. ASCOT - BPLA Background and Objective Rationale Insufficient outcome data on newer types of BP-lowering agents, especially in specific combination treatment regimens Less-than-expected CHD prevention using standard therapy Objective To compare the effect on non-fatal MI and fatal CHD of the standard anti-HTN regimen (ß-blocker + diuretic) with a more contemporary regimen (CCB + ACE inhibitor) ASCOT Entry Criteria:  ASCOT Entry Criteria Sever PS et al. J Hypertens 2001;19:1139–1147. | Sever PS et al. Lancet 2003;361:1149–1158. No treated angina or prior MI Age: 40–79 yr Blood pressure Untreated: SBP 160 and/or DBP 100 mm Hg Treated: SBP 140 and/or DBP 90 mm Hg 3 CV risk factors: Smoking  ECG abnormalities LVH  NIDDM Family Hx  PVD Age 55 yr  Hx CVA Male sex  TC/HDL-C 6 Microalbuminuria/proteinuria TG 400 mg/dL TC 250 mg/dL (in lipid-lowering arm) Slide59:  . ASCOT – BPLA - Preliminary results Baseline Characteristics Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005. Slide60:  19,342 patients aged 40–79 with U N T R E A T E D SBP ≥160 mmHg and/or DBP ≥100 mmHg OR T R E A T E D SBP ≥140 mmHg and/or DBP ≥90 mmHg In each arm, patients with total chol of ≤ 6.5 mmol/L randomized to atorvastatin (10 mg) or placebo daily (n=10,297) RANDOMIZATION atenolol 50 mg amlo 5 mg amlo 10 mg atenolol 100 mg amlo10 mg + perindopril4 mg amlo10 mg + peri 8 mg (2 x 4 mg) amlo 10 mg + peri 8 mg (2 x4 mg) + doxa 4 mg amlo 10 mg + peri 8 mg (2 x 4 mg) + doxa 8 mg atenolol 100 mg + BFZ 2.5 mg + K+ atenolol 100 mg + BFZ 2.5 mg + K+ + doxazosin GITS 4 mg atenolol 100 mg + BFZ 1.25 mg + K+ atenolol 100 mg + BFZ 2.5 mg + K+ + doxazosin GITS 8 mg 5 Years or 1,150 Primary Events Blood pressure medication titrated to next step to achieve target blood pressures: No diabetes: <140/90 mmHg Patients with diabetes: <130/80 mmHg Sever PS, for the ASCOT Investigators. J Hypertens. 2001;19:1139–1147. amlo = amlodipine; peri= perindopril doxa = doxazosin GITS (gastrointestinal Transport system); BFZ = bendroflumethiazide ASCOT – BPLA Methods Slide61:  Similar BP lowering good in traditional arm (to 136/78 mm Hg) and in newer therapy arm (to 136/77 mm Hg) by end of study Medication use in “traditional” arm (atenolol 73%, thiazide 67%) and in “newer” therapy arm (amlodipine 78%, perindopril 63%) were comparable Average BP 2.9/1.8 mm Hg higher with ß-blocker/diuretic early in trial, prior to addition of other drugs ASCOT – BPLA Preliminary Results Dalhof, B. Late Breaking Clinical Trials II. ACC Scientific Session 2005. Slide62:  ASCOT-BPLA Secondary Endpoints The area of each square is proportional to the amount of statistical information. *Excludes silent non-fatal MI. Favors amlodipine  perindopril Favors atenolol  thiazide 0.50 0.70 1.00 1.45 Endpoint Non-fatal MI* +fatal CHD Total coronary endpoint Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure 2.00 P Value P = 0.0003 P = 0.0070 P < 0.0001 P = 0.0247 P = 0.0010 P = 0.0003 P = 0.1257 Adapted from Dahlöf B et al. Lancet. 2005;366:895–906. Unadjusted Hazard Ratio (95% CI) Slide63:  0.50 0.70 1.00 1.45 Endpoint Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment 2.00 Favors amlodipine  perindopril Favors atenolol  thiazide The area of each square is proportional to the amount of statistical information. Adapted from Dahlöf B et al. Lancet. 2005;366:895–906. ASCOT-BPLA Tertiary Endpoints P Value P = 0.3089 P = 0.0115 P = 0.8323 P = 0.0001 P = 0.8009 P < 0.0001 P = 0.0187 Unadjusted Hazard Ratio (95% CI) ASCOT-BPLA: Summary:  ASCOT-BPLA: Summary In ASCOT-BPLA, a CCB/ACEi regimen (amlodipine ± perindopril) vs. a β-blocker/thiazide regimen (atenolol ± BFZ) resulted in: Earlier and better blood pressure control Greater reduction in morbidity and mortality Fewer adverse effects: reduction of new-onset diabetes, reduction of peripheral arterial disease reduction of new-onset renal impairment BFZ=bendroflumethiazide. Dahlöf B et al. Lancet. 2005;366:895–906. ASCOT-BPLA Conclusions:  ASCOT-BPLA Conclusions The effective blood-pressure lowering achieved by the amlodipine/ACEi regimen —particularly in the first year — may account for the differential cardiovascular benefits Reaffirm that most hypertensive patients require at least two agents to reach blood pressure targets Dahlöf B et al. Lancet. 2005;366:895–906. Are Beta Blockers Cardioprotective in HTN ?:  Are Beta Blockers Cardioprotective in HTN ? No significant overall cardioprotective effect of beta blokers compared to other drugs Medical Research Council (MRC) propranolol International Prospective Primary Prevention in HTN Trial (IPPPSH) oxprenolol Heart Attack Primary Prevention in HTN Trial (HAPPHY) Atenolol, propranolol, metoprolol CAPPP TRIAL (captopril) Drug Trials (BB):  Drug Trials (BB) Medical Research Council (MRC) propranolol International Prospective Primary Prevention in HTN Trial (IPPPSH) oxprenolol Heart Attack Primary Prevention in HTN Trial (HAPPHY) Atenolol, propranolol, metoprolol CAPPP TRIAL (captopril) Meta-Analysis of 5 antihypertensive therapies (2004):  Meta-Analysis of 5 antihypertensive therapies (2004) Atenolol was associated with higher mortality (1.13.1.02-1.25) CV mortality (1.16,1.00-1.34) Rate of stroke (1.3, 1.12-1.50) HAPPHY MRC UKPDS LIFE ELSA (European Lacipidine Study on Atherosclerosis) SOLACE: Safety of Lotrel® vs. Amlodipine in a Comparative Efficacy Trial:  SOLACE: Safety of Lotrel® vs. Amlodipine in a Comparative Efficacy Trial SOLACE: Study Design:  SOLACE: Study Design SOLACE: Change from Baseline in SBP:  SOLACE: Change from Baseline in SBP SOLACE: Change in SBP Baseline SBP =180 mm Hg :  SOLACE: Change in SBP Baseline SBP =180 mm Hg SELECT: Primary Study Objective:  SELECT: Primary Study Objective SELECT: Study Design ITT Population:  SELECT: Study Design ITT Population SELECT: Change From Baseline in Mean 24-Hour ABPM SBP:  SELECT: Change From Baseline in Mean 24-Hour ABPM SBP SELECT: Change from Baseline in Mean 4-hour ABPM DBP:  SELECT: Change from Baseline in Mean 4-hour ABPM DBP SHIELD: Study Design:  SHIELD: Study Design SHIELD: Time to Target BP (<130/85 mm Hg):  SHIELD: Time to Target BP (<130/85 mm Hg) SHIELD: Conclusions:  SHIELD: Conclusions Fixed-dose amlodipine besylate/benazepril HCl therapy reduced BP to goal (<130/85 mm Hg) faster and to a greater extent than enalapril monotherapy achieved lower BP than ACE inhibitor alone resulted in a significantly greater percentage of patients who achieved and maintained BP goal than enalapril monotherapy, even after the addition of HCTZ to enalapril was well tolerated had no adverse effects on glycemic control or lipid levels ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide. Bakris GL, Weir MR. J Clin Hypertens. 2003 [in press]. LEAAD Conclusions:  LEAAD Conclusions In African American patients with high BP and type 2 diabetes, combination therapy with the amlodipine besylate/benazepril HCl regimen achieved significantly faster control of BP, compared with the enalapril monotherapy regimen The results of LEAAD support a strategy of initiating fixed-dose combination therapy in high-risk patients in whom lower BP goals are indicated Flack JM et al. Am J Hypertens 2004;17(5) part 2:180A. ALERT: Conclusions:  ALERT: Conclusions LVH, left ventricular hypertrophy. Neutel JM et al. Am J Hypertens. 2002;15:166A. Low-dose amlodipine besylate/benazepril HCl demonstrated BP reduction comparable to high-dose amlodipine besylate (10 mg) Compared with high-dose amlodipine besylate (10 mg) and benazepril HCl (40 mg) monotherapies, low-dose amlodipine besylate/benazepril HCl combination therapy showed significantly greater improvement in arterial stiffness and significantly greater regression of LVH These results demonstrate the importance of BP reduction and drug selection for target-organ protection Relative Potency of ACE Inhibitors in Tissue:  Quinaprilat 22.3 Benazeprilat 21.6 Perindoprilat 13.3 Ramiprilat 10.0 Lisinopril 3.4 Fosinoprilat 0.6 Relative Potency of ACE Inhibitors in Tissue Relative tissue potency ACE inhibitor Fabris B et al. Br J Pharmacol. 1990;100:651-655. High tissue affinity Low tissue affinity DIOVAN:  DIOVAN Angiotensin II Escape With Long-term ACEI Therapy:  *P < 0.001 vs placebo. Adapted with permission from Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966–972. Plasma A II levels increase with time, although plasma angiotensin-converting enzyme activity remained suppressed Angiotensin II Escape With Long-term ACEI Therapy Plasma ACE, nmol/mL/min 100 80 60 40 20 0 30 20 10 0 Plasma A II, pg/mL * Placebo 4h 24h 1 2 3 4 5 6 Hospital Months Slide90:  Multiple Pathways of Angiotensin II Production t-PA Cathepsin G Tonin Angiotensinogen Ang I Renin Ang II CAGE Cathepsin G Chymase Antiproliferation Apoptosis Differentiation Vasodilation Hypertrophy/proliferation Vasoconstriction Aldosterone release Antidiuretic hormone release AT1 receptor AT2 receptor ARB site of action ACE inhibitor site of action ACE Degradation products Kinins Clinical Significance of AT1 Receptor Blockade:  Clinical Significance of AT1 Receptor Blockade A II AT2 AT1 receptor blockade A II binding at the AT2 receptor ARB LVH = left ventricular hypertrophy. AT1 The Effect of ARBs on Diabetic Nephropathy:  IDNT IRMA 2 RENAAL MARVAL Primary composite: doubling of serum creatinine/ESRD/ death Time to onset of nephropathy with UAER > 200 g/ min. 30% greater than baseline Primary composite: doubling of serum creatinine/ESRD/ death  UAER Endpoints Results VAL significantly lowered UAER (44%) vs. AML (17%) (P<.001) Risk of primary endpoint lower by 16% (P = .02) with LOS IRB was renoprotective; 5.2% reached endpoint in 300 mg group; 9.7% reached endpoint in 150 mg group vs. 14.9% in PLA (P =.08) Risk of primary endpoint 20% lower with IRB vs. PLA; (P = 0.02); 23% lower vs. AML (P = 0.006) Lewis E, et al. N Engl J Med. 2001. Parving H-H, et al. N Engl J Med. 2001. Brenner BM, et al. N Engl J Med. 2001. Wheeldon NM, Viberti GC, for the MARVAL Trial. Am J Hypertens. 2001. lower doubling of serum creatine, ESRD with IRB no difference in deaths lower doubling of serum creatine, ESRD with LOS; no difference in deaths The Effect of ARBs on Diabetic Nephropathy Slide93:  Cardiovascular Benefits of ARBs Val-HeFT: Study Design and Inclusion Criteria:  Val-HeFT: Study Design and Inclusion Criteria Randomized to Receiving background therapy 5,010 patients  18 years; EF < 40%; NYHA II – IV; LVIDD > 2.9 cm/m2 ACEIs (93%), diuretics (86%), digoxin (67%), beta blockers (36%) Valsartan 40 mg BID titrated to 160 mg BID Cohn JN, et al. N Engl J Med. 2001;345:1667–1675. Val-HeFT: Effect of Valsartan on Primary Endpoints*:  Val-HeFT: Effect of Valsartan on Primary Endpoints* Valsartan reduced overall HF morbidity by 13% (P = 0.009)† patients were also receiving other prescribed HF therapies: 93% on ACEIs, 36% on BBs, 86% on diuretics, 67% on digoxin Overall mortality was similar in the 2 groups targeted maintenance dose: valsartan 160 mg BID (starting dose 40 mg BID) — 84% of patients achieved target dose no evidence of further clinical benefit when valsartan added to adequate dose of ACEI. Overall results largely driven by the 7% of patients not on ACEI *Morbidity defined as all-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators. Cohn JN, et al. N Engl J Med. 2001;345:1667–1675. ACE-I Comparator MI Trial:  ACE-I Comparator MI Trial MI Trials with Mortality Benefit Early Use Long-Term GISSI 3 lisinopril SAVE captopril ISIS 4 captopril AIRE ramipril Chinese-Cap captopril TRACE trandolapril Captopril—most extensively studied with survival benefits in both early initiation and long-term trials Two prior direct ARB-ACE-I comparisons to captopril (50 mg tid) showed a trend for fewer deaths and major CV events with captopril therapy. CHARM Trial Program:  CHARM Trial Program (McMurray J, et al. Presented at ESC 2000. Total N = 7,500 Duration = 42 mo. Aims:  Aims VALIANT was designed as a mortality trial in high-risk MI patients (SAVE, AIRE, TRACE) who derived particular benefits from an ACE inhibitor. To determine whether: the ARB valsartan was superior to captopril in improving survival and with equal statistical power the addition of the ARB valsartan to captopril was superior to the proven dose of captopril in improving survival If valsartan was not superior to captopril, a non-inferiority analysis was prespecified to determine whether valsartan could be considered “as effective as” captopril Slide100:  Primary Endpoint: All-Cause Mortality Secondary Endpoints: CV Death, MI, or HF Other Endpoints: Safety and Tolerability Captopril 50 mg tid (n = 4909) Valsartan 160 mg bid (n = 4909) Captopril 50 mg tid + Valsartan 80 mg bid (n = 4885) Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible (either clinical/radiologic signs of HF or LV systolic dysfunction) Major Exclusion Criteria: — Serum creatinine > 2.5 mg/dL — BP < 100 mm Hg — Prior intolerance of an ARB or ACE-I — Nonconsent double-blind active-controlled median duration: 24.7 months event-driven Study Drug Dose Titration:  Study Drug Dose Titration Am Heart J. 2000;140:727–734. Mortality by Treatment:  0 0.05 0.1 0.15 0.2 0.25 0.3 0 6 12 18 24 30 36 Probability of Event Mortality by Treatment Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349 Valsartan 4909 4464 4272 4007 2648 1437 357 Months Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 Captopril 4909 4428 4241 4018 2635 1432 364 Valsartan + Cap 4885 4414 4265 3994 2648 1435 382 All-Cause Mortality: Non-Inferiority Analyses:  All-Cause Mortality: Non-Inferiority Analyses 0.8 1 1.2 Hazard Ratio (97.5% CI) 1.13 P-value (noninferiority) noninferiority margin Favors Valsartan Favors Captopril Mortality in SAVE, TRACE, AIRE, and VALIANT:  Mortality in SAVE, TRACE, AIRE, and VALIANT Hazard Ratio for Mortality Favors Active Drug Favors Placebo Valsartan preserves 99.6% of mortality benefit of captopril. Conclusion:  Conclusion In patients with MI complicated by heart failure, left ventricular dysfunction or both: Valsartan is as effective as a proven dose of captopril in reducing the risk of: Death CV death or nonfatal MI or heart failure admission Combining valsartan with a proven dose of captopril produced no further reduction in mortality—and more adverse drug events. Implications: In these patients, valsartan is a clinically effective alternative to an ACE inhibitor. Patients With CRD and HTN Have Minimal Changes in Serum Creatinine With ACEI or ARB Therapy:  Weeks 2.9 2.7 2.5 2.3 2.1 1.9 1.7 1.5 1.3 1.1 0.9 0.7 Serum Creatinine (mg/dL) Baseline 1 2 3 4 A B C ACEI or ARB Started Bakris GL, Weir M. Arch Intern Med. 2000;160(5):685-693. Reprinted by permission, American Medical Association. Patients With CRD and HTN Have Minimal Changes in Serum Creatinine With ACEI or ARB Therapy www.hypertensiononline.org Rationale for Diuretic/ARB Combination:  Rationale for Diuretic/ARB Combination SUMMARY:  SUMMARY Blood Pressure Control is Paramount Target Organ Damage ~ AII Expression at the Tissue Level AII intervention is the “pharmacological balm” Doses of ARB or ACEI needed for TOD impact may exceed dose needed for BP control Follow a TOD parameter rather than BP alone THE END:  THE END Additional Trandolapril Studies Effects on Proteinuria:  Additional Trandolapril Studies Effects on Proteinuria Proteinuria baseline and endpoint expressed in mg/d. -27% -33% -62% -70 -50 -30 -10 Verapamil n=11 Trandolapril n=12 Trandolapril + Verapamil n=14 Changes from Baseline (%) Proteinuria Mean arterial pressure Baseline = 604 Endpoint = 421 Baseline = 616 Endpoint = 399 Baseline = 672 Endpoint = 234 Bakris et al. Kidney Int. 1998;54:1283-1289. N=37 2-week placebo run-in 52 weeks’ active treatment Mean daily doses: T alone 5.5 mg T in combination 2.9 mg V alone 314.8 mg V in combination 219.0 mg

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