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1. Peut-on aller encore plus loin avec les antagonistes de lAngiotensine II ? Antoine Sarkis, MD
Associate Professor of Cardiology
Hotel Dieu de France Hospital
3. Ang II: Influence on structure, function, and atherosclerosis
In addition to its effects on BP, Ang II, through a variety of direct and indirect mechanisms, can substantially affect structure and remodeling of the CV tree, leading to increased risk of atherosclerosis.1
In addition to its effects on BP, Ang II, through a variety of direct and indirect mechanisms, can substantially affect structure and remodeling of the CV tree, leading to increased risk of atherosclerosis.1
4. Ang II effect in target organ damage In summary, RAAS activation is implicated in the altered structure and function of several organ systems. These effects are mediated by Ang II, the principal effector molecule of the RAAS.
Renin converts angiotensinogen to Ang I, which in turn is converted to Ang II by ACE.
Intervention at multiple targets in this system has favorable effects on target organ structure and function.
In summary, RAAS activation is implicated in the altered structure and function of several organ systems. These effects are mediated by Ang II, the principal effector molecule of the RAAS.
Renin converts angiotensinogen to Ang I, which in turn is converted to Ang II by ACE.
Intervention at multiple targets in this system has favorable effects on target organ structure and function.
5. Angiotensinogen is transformed by Renin into Ang I, which is transformed by Angiotensin Converting Enzyme (ACE) into Ang II.
Ang II has a direct effect by activating different Angiotensin receptors (AT1, AT2, ATn), as well as an indirect effect through its action on Aldosterone and anti-diuretic hormone,
Beside acting on Ang I, ACE is also responsible for the degradation of Bradykinin (which acts on endothelial B2 receptors) into inactive peptidesAngiotensinogen is transformed by Renin into Ang I, which is transformed by Angiotensin Converting Enzyme (ACE) into Ang II.
Ang II has a direct effect by activating different Angiotensin receptors (AT1, AT2, ATn), as well as an indirect effect through its action on Aldosterone and anti-diuretic hormone,
Beside acting on Ang I, ACE is also responsible for the degradation of Bradykinin (which acts on endothelial B2 receptors) into inactive peptides
6. ACEIs by inhibiting the ACE enzyme, will have a dual mode of action:
First they block the transformation of AngI into AngII, thus all the AT receptors will be blocked or in more precise words there will be only little AngII available to activate them.
Second, ACEIs will stop the degradation of Bradykinin into inactive peptides, thus higher amounts of Bradykinin will be availableACEIs by inhibiting the ACE enzyme, will have a dual mode of action:
First they block the transformation of AngI into AngII, thus all the AT receptors will be blocked or in more precise words there will be only little AngII available to activate them.
Second, ACEIs will stop the degradation of Bradykinin into inactive peptides, thus higher amounts of Bradykinin will be available
7. While ARBs only and selectively block AT1 receptors, so more AngII will be available to activate AT2, and at the same time AT2 receptors will be upregulated.
On the other hand, ARBs dont exert any effect on the Bradykinin pathway
This selective AT1 blockade is at the source of the ARBs dilemma, due to the uncertainity about the different roles of different AT receptors, mainly AT2 While ARBs only and selectively block AT1 receptors, so more AngII will be available to activate AT2, and at the same time AT2 receptors will be upregulated.
On the other hand, ARBs dont exert any effect on the Bradykinin pathway
This selective AT1 blockade is at the source of the ARBs dilemma, due to the uncertainity about the different roles of different AT receptors, mainly AT2
8. Escape phenomena The RAS plays a key role in the regulation of several physiologic functions such as systemic BP, electrolyte and fluid balance, and blood volume.25 Angiotensinogen, produced primarily in the liver, is transformed to angiotensin I by renin. Angiotensin I is cleaved into angiotensin II by both ACE and non-ACE pathways. ACE acts by cleaving the C-terminal dipeptide from biologically inactive angiotensin I and bradykinin, thus affecting the RAS and kallikrein-kinin systems.25 Angiotensin I is converted to the physiologically active octapeptide angiotensin II by ACE.26 ACE catalyzes the breakdown of bradykinin to inactive peptides.
The physiologic functions of RAS are mediated via angiotensin II, a very potent vasoactive substance.26 ACE regulates the balance between the vasoconstrictive and salt-retentive properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin.25
When angiotensin II binds with the angiotensin type 1 (AT1) receptor, it causes vasoconstriction, cell growth, sodium and fluid retention, and sympathetic activationall of which play a part in hypertension and its sequelae.27
The RAS plays a key role in the regulation of several physiologic functions such as systemic BP, electrolyte and fluid balance, and blood volume.25 Angiotensinogen, produced primarily in the liver, is transformed to angiotensin I by renin. Angiotensin I is cleaved into angiotensin II by both ACE and non-ACE pathways. ACE acts by cleaving the C-terminal dipeptide from biologically inactive angiotensin I and bradykinin, thus affecting the RAS and kallikrein-kinin systems.25 Angiotensin I is converted to the physiologically active octapeptide angiotensin II by ACE.26 ACE catalyzes the breakdown of bradykinin to inactive peptides.
The physiologic functions of RAS are mediated via angiotensin II, a very potent vasoactive substance.26 ACE regulates the balance between the vasoconstrictive and salt-retentive properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin.25
When angiotensin II binds with the angiotensin type 1 (AT1) receptor, it causes vasoconstriction, cell growth, sodium and fluid retention, and sympathetic activationall of which play a part in hypertension and its sequelae.27
9. Angiotensin II Receptor Blockers (ARBs) Treatment of congestive heart failure.
Angiotensin II inhibitors
Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan.Treatment of congestive heart failure.
Angiotensin II inhibitors
Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan.
10. Potential advantages of ARBs
11. The presence of AT1 and AT2 receptors has been documented in various tissues. The function of the AT2 receptors is currently under investigation; however, A II stimulation of the AT2 receptor is believed to counterbalance deleterious effects of AT1 receptor stimulation on the blood vessels, kidneys, and adrenals.1
Effects of AT1 receptor stimulation include vasoconstriction, cell growth and proliferation, angiogenesis, renal sodium reabsorption, secretion of aldosterone and vasopressin, and sympathetic activation.2
Effects of AT2 receptor stimulation include vasodilation, antiproliferation, apoptosis, differentiation, and regeneration.2
References:
1. Siragy HM. The role of the AT2 receptor in hypertension. Am J Hypertens. 2000;13:62S67S.
2. Siragy H. Angiotensin II receptor blockers: review of the binding characteristics. Am J
Cardiol. 1999;84:3S8S.
The presence of AT1 and AT2 receptors has been documented in various tissues. The function of the AT2 receptors is currently under investigation; however, A II stimulation of the AT2 receptor is believed to counterbalance deleterious effects of AT1 receptor stimulation on the blood vessels, kidneys, and adrenals.1
Effects of AT1 receptor stimulation include vasoconstriction, cell growth and proliferation, angiogenesis, renal sodium reabsorption, secretion of aldosterone and vasopressin, and sympathetic activation.2
Effects of AT2 receptor stimulation include vasodilation, antiproliferation, apoptosis, differentiation, and regeneration.2
References:
1. Siragy HM. The role of the AT2 receptor in hypertension. Am J Hypertens. 2000;13:62S67S.
2. Siragy H. Angiotensin II receptor blockers: review of the binding characteristics. Am J
Cardiol. 1999;84:3S8S.
12. Postulated role of AT2R and MMP-1 in plaque destabilization AT1R blockade with ARBs lead to elevated levels of Ang II and upregulation of AT2R in atherosclerotic plaque.
Ang II, via AT2R, stimulates monocyte production of matrix metalloproteinase-1 (MMP-1), one of a family of MMPs that are produced by monocytes/macrophages and other cells.1 MMP-1 is a collagenase that cleaves fibrillar collagens.
Degradation of the fibrous cap by increased MMP-1 levels may eventually lead to mechanical failure of the plaque, contact between blood and the plaque contents, and formation of an occlusive thrombus.AT1R blockade with ARBs lead to elevated levels of Ang II and upregulation of AT2R in atherosclerotic plaque.
Ang II, via AT2R, stimulates monocyte production of matrix metalloproteinase-1 (MMP-1), one of a family of MMPs that are produced by monocytes/macrophages and other cells.1 MMP-1 is a collagenase that cleaves fibrillar collagens.
Degradation of the fibrous cap by increased MMP-1 levels may eventually lead to mechanical failure of the plaque, contact between blood and the plaque contents, and formation of an occlusive thrombus.
13. This article was published in the section of Controversies in Cardiovascular Medicine, it was prepared by a direct request from Circulation without any interference from any pharmaceutical company.
In fact this article is divided into 2 parts:
One review the evidence indicating that ARBs increase the risk of MI
The second one the review the evidence that ARBs doesnt increase the risk of MI
The article addresses the different aspects of ARBs from pharmacology and mode of action to clinical evidenceThis article was published in the section of Controversies in Cardiovascular Medicine, it was prepared by a direct request from Circulation without any interference from any pharmaceutical company.
In fact this article is divided into 2 parts:
One review the evidence indicating that ARBs increase the risk of MI
The second one the review the evidence that ARBs doesnt increase the risk of MI
The article addresses the different aspects of ARBs from pharmacology and mode of action to clinical evidence
14. ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD The Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) conducted a meta-regression analysis of 21 randomized trials (N = 137,356) that compared ACEI versus ARB.
The BPLTTC concluded there were no differences in risk reduction between the two classes with respect to stroke and heart failure. However, there was a significant risk reduction in favor of ACEI with respect to MI and CV death (RRR 15%, P = 0.001).
Compared with BP lowering alone, ACEIs were associated with a 9% RRR and ARBs were associated with a 7% relative increase in CHD risk.The Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC) conducted a meta-regression analysis of 21 randomized trials (N = 137,356) that compared ACEI versus ARB.
The BPLTTC concluded there were no differences in risk reduction between the two classes with respect to stroke and heart failure. However, there was a significant risk reduction in favor of ACEI with respect to MI and CV death (RRR 15%, P = 0.001).
Compared with BP lowering alone, ACEIs were associated with a 9% RRR and ARBs were associated with a 7% relative increase in CHD risk.
15. And in the conclusion of their part of the articles entitled ARBs dont increase the risk of MI, they wrote:
It appears reasonable to conclude that ARBs.And in the conclusion of their part of the articles entitled ARBs dont increase the risk of MI, they wrote:
It appears reasonable to conclude that ARBs.
16. Clinical trials of ARBs in HTN: CV outcomes The LIFE (Losartan Intervention For Endpoint reduction) study was a double-blind study comparing the effects of losartan with atenolol in hypertensive patients with LV hypertrophy (N = 9193). Mean follow-up was 4.8 years.1
BP reductions were similar in the losartan and atenolol groups (-30.2/16.6 mm Hg vs -29.1/16.8 mm Hg, respectively).
Compared with atenolol, the losartan group had a 13% reduction in primary outcome (CV death, MI, and stroke) (P = 0.0021), which was driven by a 25% reduction in stroke.
Rates of CV death and MI were similar in the losartan and atenolol groups.
The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study tested the hypothesis that in hypertensive patients at high CV risk (N = 15,425) and with the same level of BP control, a valsartan-based regimen would reduce cardiac mortality and morbidity more than an amlodipine-based regimen. Mean follow-up was 4.2 years.2
BP control was more pronounced with amlodipine, especially in the early months of the study.
For the primary outcome (composite of CV mortality and morbidity), there was no difference between the two treatment groups, but the trend favored amlodipine at 3 and 6 months.
The LIFE (Losartan Intervention For Endpoint reduction) study was a double-blind study comparing the effects of losartan with atenolol in hypertensive patients with LV hypertrophy (N = 9193). Mean follow-up was 4.8 years.1
BP reductions were similar in the losartan and atenolol groups(-30.2/16.6 mm Hg vs -29.1/16.8 mm Hg, respectively).
Compared with atenolol, the losartan group had a 13% reduction in primary outcome (CV death, MI, and stroke) (P = 0.0021), which was driven by a 25% reduction in stroke.
Rates of CV death and MI were similar in the losartan and atenolol groups.
The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study tested the hypothesis that in hypertensive patients at high CV risk (N = 15,425) and with the same level of BP control, a valsartan-based regimen would reduce cardiac mortality and morbidity more than an amlodipine-based regimen. Mean follow-up was 4.2 years.2
BP control was more pronounced with amlodipine, especially in the early months of the study.
For the primary outcome (composite of CV mortality and morbidity), there was no difference between the two treatment groups, but the trend favored amlodipine at 3 and 6 months.
17. Algorithm for Treatment of Hypertension (JNC 7) JAMA, May 2003
18. 2003 ESH/ESC Hypertension Guidelines
19. Choosing drugs for patients newly diagnosed with hypertension BHS Guidelines (June 2006)
20. Hypertension and Diabetes Recommendations of the American Diabetic Association
21. Conditions favoring the use of ARBs Type 2 diabetic nephropathy
Diabetic microalbuminuria
Proteinuria
Left ventricular hypertrpphy
ACE-I induced cough
22. Specific considerations about Candesartan Pharmacological properties
Delaying new onset of hypertension in pre-hypertensive patients
Preventing diabetes
End Organ protective effects (CHF)
23. Pharmacological properties 1. Candesartan binds unsurmountably to AT1 receptor
2. Longest lasting AT1-receptor binding ?T/ P Ratio almost 100%
In the latest JNC 7:
Candesartan 8-32 mg Once daily
Losartan 25-100 mg Once to Twice daily
Valsartan 80-320 mg Once to Twice daily
JNC 7, Hypertension, 2003
24. Use in pre-hypertensive patients? TROPHY hypothesis The TRial Of Preventing HYpertension (TROPHY) is an investigator-initiated trial.
Aim: To examine whether early treatment of high-normal blood pressure values (according to JNC VI) with 16 mg Candesartan would prevent or postpone the development of stage 1 hypertension.
25. TROPHY study design
26. TROPHY: Reduction in new-onset hypertension
27. Adipocyte and vasculature interactions Adipose tissue is now recognized as a major endocrine and secretory organ, releasing a wide range of metabolically important protein factors and signals collectively called adipokinesin addition to fatty acids and other lipid molecules.
Most adipokines are secreted at higher than normal levels in obesity and the metabolic syndrome; adiponectin is an exception, as its secretion is decreased in these states.
Low levels of adiponectin are associated with endothelial cell dysfunction.1 Whereas low adiponectin levels are found in CAD and type 2 diabetes, high adiponectin levels predicted reduced coronary risk in men in long-term epidemiologic studies.2
There is a growing list of adipokines involved in inflammation (eg, TNF-?, IL-6, leptin) and in the acute-phase response (eg, PAI-1).3
Increased levels of several adipokines are implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (TNF-?, IL-6, resistin).2
Adipose tissue is now recognized as a major endocrine and secretory organ, releasing a wide range of metabolically important protein factors and signals collectively called adipokinesin addition to fatty acids and other lipid molecules.
Most adipokines are secreted at higher than normal levels in obesity and the metabolic syndrome; adiponectin is an exception, as its secretion is decreased in these states.
Low levels of adiponectin are associated with endothelial cell dysfunction.1 Whereas low adiponectin levels are found in CAD and type 2 diabetes, high adiponectin levels predicted reduced coronary risk in men in long-term epidemiologic studies.2
There is a growing list of adipokines involved in inflammation (eg, TNF-?, IL-6, leptin) and in the acute-phase response (eg, PAI-1).3
Increased levels of several adipokines are implicated in hypertension (angiotensinogen), impaired fibrinolysis (PAI-1) and insulin resistance (TNF-?, IL-6, resistin).2
28. RAAS blockade increases adiponectin This study examined the association between insulin sensitivity and adiponectin concentrations in 30 patients with essential hypertension, including patients who were insulin resistant (n = 12) and noninsulin resistant (n = 18).1
Insulin sensitivity, BMI, and high-density-lipoprotein cholesterol (HDL-C) were independently correlated with serum adiponectin concentrations.
Adiponectin levels were negatively correlated with insulin sensitivity and BMI and positively correlated with HDL-C levels.
The study also examined the effect of RAAS blockade on adiponectin concentrations in patients with essential hypertension.
Patients were treated for 2 weeks with the ACE inhibitor temocaptril 4 mg (n = 9) or AT1 receptor blocker candesartan 8 mg (n = 7).
Insulin sensitivity and adiponectin concentrations were significantly increased by both drug classes.
There was a significant correlation between changes in insulin resistance in changes in adiponectin (r = 0.59, P < 0.05).
Results suggest that RAAS blockade increases serum adiponectin concentrations with improvement in insulin sensitivity. This study examined the association between insulin sensitivity and adiponectin concentrations in 30 patients with essential hypertension, including patients who were insulin resistant (n = 12) and noninsulin resistant (n = 18).1
Insulin sensitivity, BMI, and high-density-lipoprotein cholesterol (HDL-C) were independently correlated with serum adiponectin concentrations.
Adiponectin levels were negatively correlated with insulin sensitivity and BMI and positively correlated with HDL-C levels.
The study also examined the effect of RAAS blockade on adiponectin concentrations in patients with essential hypertension.
Patients were treated for 2 weeks with the ACE inhibitor temocaptril 4 mg (n = 9) or AT1 receptor blocker candesartan 8 mg (n = 7).
Insulin sensitivity and adiponectin concentrations were significantly increased by both drug classes.
There was a significant correlation between changes in insulin resistance in changes in adiponectin (r = 0.59, P < 0.05).
Results suggest that RAAS blockade increases serum adiponectin concentrations with improvement in insulin sensitivity.
29. Candesartan in preventing Diabetes development
30. ALPINE Study Design
31. ALPINE studyNew onset of diabetes
32. Development of new diabetes CHARM study
33. Possible mechanisms involved in the prevention of diabetes
35. End Organ Protective effects of Candesartan Congestive Heart failure
36. Renin-Angiotensin-Aldosterone System in CHF
RAAS is activated early in the course of heart failure and plays an important role in the progression of the syndrome
37. ACE-I Indications Symptomatic heart failure (stage C)
Asymptomatic ventricular dysfunction with LVEF <35-40 % (stage B)
Patients with recent or remote history of MI regardless of EF or presence of HF
38. HF: Mortality Remains High ACEI
Risk reduction 35% (mortality and hospitalizations)1
-blockers
Risk reduction 38% (mortality and hospitalizations)2
Spironolactone
Mortality reduction 23%
Several large clinical trials have shown ACE inhibitor treatments to reduce mortality in HF patients with mild, moderate or severe heart failure.
The benefits from ACE inhibitors appear to be independent of age, sex, use of diuretics, aspirin and beta-blockers.
Based on the clinical studies, ACE inhibitors are recommended as first-choice treatment for heart failure.
Despite the reduction in mortality with ACE inhibitor therapy, mortality rates remain unacceptably high. Mortality in large clinical trials is close to 40% over a four-year period.Several large clinical trials have shown ACE inhibitor treatments to reduce mortality in HF patients with mild, moderate or severe heart failure.
The benefits from ACE inhibitors appear to be independent of age, sex, use of diuretics, aspirin and beta-blockers.
Based on the clinical studies, ACE inhibitors are recommended as first-choice treatment for heart failure.
Despite the reduction in mortality with ACE inhibitor therapy, mortality rates remain unacceptably high. Mortality in large clinical trials is close to 40% over a four-year period.
39. Substitute or adjunctive therapy to ACE inhibitors ?
40. Comparative trial: ELITE II The recommended treatment of HF due to left ventricular systolic dysfunction (ejection fraction, <0.35 to 0.40) ranges from monotherapy with ACEIs in patients with the mildest manifestations to the use of a combination of ACEI, digoxin, diuretic(s), and hydralazine HCl or isosorbide dinitrate for patients with severe HF.35 The efficacy of ACEIs in the treatment of HF is well established. However, some physicians do not prescribe these agents due to safety concerns surrounding the accumulation of bradykinin associated with these agents.36 Therefore, clinical studies with ARBs in HF were initiated in an effort to find out if similar efficacy was observed with better tolerability.
In 1997, the results of a 48-week study in HF patients demonstrated a 46% risk reduction in mortality with losartan therapy (an ARB) compared to captopril (an ACEI).36 However, these results were analyzed with caution because mortality was a secondary endpoint of the study and the number of events in this initial trial were small.36 Therefore, a larger study, including over 3,000 patients with HF, randomized patients to losartan or captopril and evaluated death from any cause as the primary endpoint.36 After a median follow-up period of 1.5 years, no differences in all-cause mortality, sudden death or resuscitated arrest, or all-cause mortality or hospital admission were observed between the two treatment groups.36 Interestingly, losartan therapy was associated with significantly fewer discontinuations due to adverse events attributed to study drug or due to cough compared to captopril (P<.001).36 Worsening HF was reported in 25% of patients in each group and the frequency of discontinuations did not differ for worsening of HF.36
Slide Reference
Pitt B, Poole-Wilson PA, Segal R, et al, on behalf of the ELITE II investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trialthe Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-1587.
The recommended treatment of HF due to left ventricular systolic dysfunction (ejection fraction, <0.35 to 0.40) ranges from monotherapy with ACEIs in patients with the mildest manifestations to the use of a combination of ACEI, digoxin, diuretic(s), and hydralazine HCl or isosorbide dinitrate for patients with severe HF.35 The efficacy of ACEIs in the treatment of HF is well established. However, some physicians do not prescribe these agents due to safety concerns surrounding the accumulation of bradykinin associated with these agents.36 Therefore, clinical studies with ARBs in HF were initiated in an effort to find out if similar efficacy was observed with better tolerability.
In 1997, the results of a 48-week study in HF patients demonstrated a 46% risk reduction in mortality with losartan therapy (an ARB) compared to captopril (an ACEI).36 However, these results were analyzed with caution because mortality was a secondary endpoint of the study and the number of events in this initial trial were small.36 Therefore, a larger study, including over 3,000 patients with HF, randomized patients to losartan or captopril and evaluated death from any cause as the primary endpoint.36 After a median follow-up period of 1.5 years, no differences in all-cause mortality, sudden death or resuscitated arrest, or all-cause mortality or hospital admission were observed between the two treatment groups.36 Interestingly, losartan therapy was associated with significantly fewer discontinuations due to adverse events attributed to study drug or due to cough compared to captopril (P<.001).36 Worsening HF was reported in 25% of patients in each group and the frequency of discontinuations did not differ for worsening of HF.36
Slide Reference
Pitt B, Poole-Wilson PA, Segal R, et al, on behalf of the ELITE II investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trialthe Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-1587.
41. Add-on trial: Val-HeFT. Valsartan 160 mg Bid vs placebo on top of standard therapy
Over 5,000 patients with chronic heart failure defined as NYHA class II (62%), III (36%), and IV (2%) with an ejection fraction of <40% and left ventricular diastolic transverse diameter (LVIDD) >2.0 cm/m2 were randomized to receive valsartan 40 mg twice daily titrated to 160 mg twice daily or placebo.38
At the time of randomization, 93% of patients were receiving an ACEI, 86% a diuretic, 67% digoxin, and 35% were receiving a beta-blocker.38
In the overall population, Val-HeFT showed a significant benefit on the primary endpoint combined morbidity and mortality, which was reduced by 13.2% (p=0.009), but a neutral effect on all-cause mortality.
Over 5,000 patients with chronic heart failure defined as NYHA class II (62%), III (36%), and IV (2%) with an ejection fraction of <40% and left ventricular diastolic transverse diameter (LVIDD) >2.0 cm/m2 were randomized to receive valsartan 40 mg twice daily titrated to 160 mg twice daily or placebo.38
At the time of randomization, 93% of patients were receiving an ACEI, 86% a diuretic, 67% digoxin, and 35% were receiving a beta-blocker.38
In the overall population, Val-HeFT showed a significant benefit on the primary endpoint combined morbidity and mortality, which was reduced by 13.2% (p=0.009), but a neutral effect on all-cause mortality.
42. CHARM Program
43. CHARM Alternative trial
44. CHARM Added Trial
45. CHARM Program Mortality and morbidity
46. CHARM LVEF ?40% (CHARM-Alternative and CHARM-Added) Before starting the CHARM Programme, it was also specified that outcomes in patients with low ejection fraction would be analysed, that is in CHARM-Alternative and Added combined. These are the type of patients that have usually been studied in previous heart failure trials, and so the data from the low EF population of CHARM would be most comparable with that from previous outcome studies.
In the two CHARM Low ejection fraction trials combined, representing more than 4500 patients, candesartan treatment significantly reduced all-cause death by 12% (p=0.018), as well as cardiovascular death by 16% (p=0.005). This is a clear-cut benefit of candesartan on fatal outcomes in classical, low-ejection fraction heart failure.Before starting the CHARM Programme, it was also specified that outcomes in patients with low ejection fraction would be analysed, that is in CHARM-Alternative and Added combined. These are the type of patients that have usually been studied in previous heart failure trials, and so the data from the low EF population of CHARM would be most comparable with that from previous outcome studies.
In the two CHARM Low ejection fraction trials combined, representing more than 4500 patients, candesartan treatment significantly reduced all-cause death by 12% (p=0.018), as well as cardiovascular death by 16% (p=0.005). This is a clear-cut benefit of candesartan on fatal outcomes in classical, low-ejection fraction heart failure.
47. FDA approved candesartan cilexetil on top of ACE inhibitor for HF NYHA class II-IV heart failure
Dose: initial dose of 4 mg once daily to a target dose of 32 mg once daily, achieved by doubling the dose at approximately two-week intervals, as tolerated FDA approves candesartan cilexetil on top of ACE inhibitor for HF May 19, 2005 Shelley Wood
Rockville, MD - The FDA has approved the use of candesartan cilexetil (Atacand, AstraZeneca), an angiotensin-receptor blocker, for use with an ACE inhibitor in the treatment of NYHA class 2-4 heart failure (HF), the company announced today. The approval was based on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-Added (CHARM-Added) trial, which showed that the addition of candesartan produced a 15% relative-risk reduction in cardiovascular death or HF hospitalizations.
The FDA's stamp of approval comes within three months of its advisory panel's unanimous vote recommending approval, as reported by heartwire.
At that time, committee member Dr Jonathan Sackner-Bernstein (North Shore University Hospital, Manhasset, NY) concluded that CHARM-Added provided "convincing evidence" that the ARB provided "something extra" over ACE inhibition.
"The benefit [of candesartan] was sufficient in its magnitude and clinical relevance for the committee to recommend that its use be broadened, despite the potential risks of hypotension and azotemia," Sackner-Bernstein told heartwire.
The FDA had previously granted market approval for candesartan to be used in patients with systolic heart failure on the basis of CHARM-Alternative, which enrolled only patients with HF and systolic dysfunction who could not tolerate ACE-inhibitor therapy.
The dosage of candesartan approved today to be used on top of ACE-inhibitor therapy specifies a recommended initial dose of 4 mg once daily to a target dose of 32 mg once daily, achieved by doubling the dose at approximately two-week intervals, as tolerated.
FDA approves candesartan cilexetil on top of ACE inhibitor for HF May 19, 2005 Shelley Wood
Rockville, MD - The FDA has approved the use of candesartan cilexetil (Atacand, AstraZeneca), an angiotensin-receptor blocker, for use with an ACE inhibitor in the treatment of NYHA class 2-4 heart failure (HF), the company announced today. The approval was based on the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-Added (CHARM-Added) trial, which showed that the addition of candesartan produced a 15% relative-risk reduction in cardiovascular death or HF hospitalizations.
The FDA's stamp of approval comes within three months of its advisory panel's unanimous vote recommending approval, as reported by heartwire.
At that time, committee member Dr Jonathan Sackner-Bernstein (North Shore University Hospital, Manhasset, NY) concluded that CHARM-Added provided "convincing evidence" that the ARB provided "something extra" over ACE inhibition.
"The benefit [of candesartan] was sufficient in its magnitude and clinical relevance for the committee to recommend that its use be broadened, despite the potential risks of hypotension and azotemia," Sackner-Bernstein told heartwire.
The FDA had previously granted market approval for candesartan to be used in patients with systolic heart failure on the basis of CHARM-Alternative, which enrolled only patients with HF and systolic dysfunction who could not tolerate ACE-inhibitor therapy.
The dosage of candesartan approved today to be used on top of ACE-inhibitor therapy specifies a recommended initial dose of 4 mg once daily to a target dose of 32 mg once daily, achieved by doubling the dose at approximately two-week intervals, as tolerated.
48. ARB Indications in CHF
Patients intolerant to ACE-Inhibitors:
(Class I recommendation in stage C, class IIa in stage B, class I in stage B post MI)
Use of ARB instead of ACE-I in stage C heart failure:
Class IIa recommendation (reasonable, should be considered)
On top of ACE I and B Blockers in patients who remain symptomatic: optional, because of discrepancy in guidelines:
Class I (ESC, CCS), IIa (HFSA), and IIb (ACC/AHA)
49. CHARM-Overall Non-fatal MI
50. Clinical trials continue with ARBs
51. ONTARGET: Study design The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) randomized 25,620 high-risk patients to telmisartan 80 mg, ramipril 10 mg, or their combination. Eligible subjects were =55 years of age with coronary, cerebrovascular, or peripheral vascular disease, or with diabetes plus evidence of end-organ damage.
The primary end point is a composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for congestive heart failure. New-onset diabetes is one of the secondary end points. Patients will be followed for up to 5.5 years. Recruitment ended in 2003.The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) randomized 25,620 high-risk patients to telmisartan 80 mg, ramipril 10 mg, or their combination. Eligible subjects were =55 years of age with coronary, cerebrovascular, or peripheral vascular disease, or with diabetes plus evidence of end-organ damage.
The primary end point is a composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for congestive heart failure. New-onset diabetes is one of the secondary end points. Patients will be followed for up to 5.5 years. Recruitment ended in 2003.
52. Diabetic retinopathy is the most common cause of blindness in people aged 30-69 in developed countries
Laser photocoagulation reduces the risk of blindness, but is performed only when advanced vascular damage is present
Only current established treatment involves careful glycaemic control
strict glycaemic control reduces both onset and progression of retinopathy Diabetic retinopathy
53. Beneficial effect of ACE-inhibition 3 small studies, non-significant results, positive tendency (Larsen et al 1990, Chase et al 1993, Ravid et al 1993).
EUCLID, n = 354, Lisinopril 10-20 mg or placebo, 2 year follow-up Progression reduced by 50% (p=0.02) Incidence reduced by 31% (n.s.) (Chaturvedi et al 1998)
54. Study question Does blockade of the RAS system with Candesartan cilexetil prevent incidence and progression of retinopathy in type 1 and type 2 diabetes?
56. DIRECT Design I. Type 1 diabetic patients without diabetic retinopathy
Endpoint: Development of retinopathy
II. Type 1 diabetic patients with diabetic retinopathy
Endpoint: Progression of retinopathy
III. Type 2 diabetic patients with diabetic retinopathy
Endpoint: Progression of retinopathy
Pooled populations of all three studies
Endpoint: Incidence of microalbuminuria
57. In conclusion The controversial dilemma between ACE-I and ARBs is not settled
ARBs have suffered from their introduction late after ACE-I were well established
However a placebo-like tolerability has extended their indications in daily practice irrespective of guidelines
Candesartan is a potent ARB with solid data in end organ protection
Need for earlier intervention in the natural history of HTN? (targeting subclinical organ damage)
