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Core Curriculum

• Progress and Promise in RAAS Blockade


 

Core001.ppt

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Slide 1 Abbreviations:ACEI = angiotensin-converting enzyme inhibitor ARB = angiotensin II receptor blocker Despite significant advances in prevention and treatment over the past 50 years, cardiovascular disease (CVD) remains the leading cause of death in the United States for both women and men. CVD continues to impose a substantial medical and economic burden on society. A meta-analysis of 61 prospective studies with over 12 million subject-years revealed that blood pressure (BP) throughout middle and old age is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg. An analysis of data on ambulatory BP monitoring from 7458 subjects (enrolled in prospective studies in 6 countries) found that night-time BP independently predicted total, CV, and non-CV mortality, as well as nonfatal outcomes, regardless of treatment status. The human and economic costs of hypertension (HTN) are staggering. HTN, ie, a BP reading of 140/90 mm Hg or higher, is associated with 69% of all first myocardial infarctions (MIs), 77% of first strokes, and 74% of cases of congestive heart failure (CHF). More than 90% of heart failure cases are preceded by HTN. A study of more than 57,000 HTN patients aged 35 years or older in a large managed-care organization, found that 56% of these individuals also had other risk factors for CVD that included diabetes, hyperlipidemia, and obesity, ie, a body mass index (BMI) of 30 kg/m2 or greater. INTERHEART, a global case-control study of risk factors for acute MI, was conducted in 52 countries on every continent with ~15,000 cases and controls matched for age and gender.
 

The slides in this section examine mechanisms and new understanding of modulation of the RAAS.

Download Core002.ppt (12 slides - 2.3MB)

The slides in this section examine mechanisms and new understanding of modulation of the RAAS. This slide summarizes the pathophysiologic continuum that underlies the CVD continuum (which has been expanded since its inception to include other areas such as cerebrovascular disease, peripheral vascular disease, and renal disease). The RAAS has been characterized in great detail. As the elements of the enzymatic cascade representing the RAAS have been progressively elucidated, our understanding of the proteins, peptides, enzymes, and receptors of the RAAS has grown increasingly complex. The important biologically-active component of the RAAS is angiotensin II, which is believed to be central to many of the pathologic changes that result in CVD and renal morbidity and mortality. ACEIs block ACE-mediated cleavage of angiotensin I to angiotensin II. Schmieder et al showed that targeting the RAAS in patients with type 2 diabetes mellitus (T2DM) and hypertension with ACEIs and ARBs, produced similar effects on renal endothelial function as indicated by increased nitric oxide (NO) activity. ARBs differ pharmacologically in their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. Among the ARBs, telmisartan has the longest duration of action with a 24-hour elimination half-life as compared with 11 to 15 hours for irbesartan, the ARB with the next longest half-life. A subset of ARBs (eg, telmisartan), has the ability to selectively modulate PPAR-gamma pathways, as well as angiotensin II pathways. In transcription reporter assays, both irbesartan and telmisartan induced transcriptional activity of PPAR-gamma; however, in contrast to the thiazolidinedione pioglitazone, the ARBs telmisartan and irbesartan are only partial PPAR-gamma agonists. ARBs were tested at a concentration of 5 mmol/L, which is near the highest plasma concentration attained after usual oral dosing. Compared with the thiazolidinediones, a subset of ARBs (telmisartan and irbesartan) act as selective PPAR-gamma modulators with a distinctive gene expression profile.
 

This section will summarize the results of major trials that have provided insight into the disease process and powerfully demonstrate that blocking the RAAS impacts CVD and renal outcomes.

Download Core003.ppt (7 slides - 1.4MB)

This section will summarize the results of major trials that have provided insight into the disease process and powerfully demonstrate that blocking the RAAS impacts CVD and renal outcomes. This diagram summarizes the effect of ACEIs on hypertension, restenosis,  atherosclerosis, and aortic aneurysm, as established in clinical trials. Over the past 2 decades, outcomes trials have demonstrated benefits of ACE inhibition in a wide range of patients with CVD. The effect of ACE inhibition on CV morbidity and mortality has been examined in more than 31,000 patients with stable vascular disease without LV dysfunction, in the HOPE, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), Prevention of Events With ACE Inhibition (PEACE), and QUinapril Ischemic Event Trial (QUIET) trials. Dagenais et al conducted a combined analysis of the HOPE, EUROPA, and PEACE trials (N = 29,805), which indicated that ACE inhibition has a significant benefit on all-cause mortality in patients with stable vascular disease without LV dysfunction. In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, the use of ramipril (up to 15 mg per day) was studied in 5269 low-risk patients without CVD, but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance. Slide 7
 

Core004.ppt

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Slide 1 Initially, ARBs were developed as antihypertensive agents, but subsequently, a series of major trials have demonstrated the benefits of ARBs across the spectrum of CV and renal disease. Although it is now well established that ACEIs can reduce CV risk, attention is increasingly being focused on ARBs because of their mechanism of action, ie, obviating angiotensin II escape, and allowing continued activation of the protective AT2 receptor could theoretically provide more complete RAAS inhibition. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) performed a meta-analysis of 29 hypertension trials that compared the effects of various antihypertensive regimens based on different drug classes. In the Valsartan-Managing BP Aggressively and Evaluation Reductions in hs-CRP (Val-MARC) study, valsartan reduced high sensitivity C-reactive protein (hs-CRP) in a manner independent of BP reduction. The Framingham Heart Study, The Multiple Risk Factor Intervention Total (MRFIT), and other studies indicate that prehypertension is a strong predictor of excessive CV risk. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of 3 parallel, independent, integrated, randomized, double-blind, placebo-controlled, clinical trials comparing candesartan with placebo in 3 distinct but complementary populations of patients with symptomatic HF. Median follow-up was 37.7 months. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigators compared the effects of the ARB valsartan, the ACEI captopril, and a combination of the 2 on mortality among patients with MI complicated by LV systolic dysfunction, HF, or both. The study enrolled 14,808 patients during a median follow-up of 24.7 months. In summary, evidence from clinical trials of ARBs show a benefit in post-MI patients with LV dysfunction, but as yet no conclusive evidence on benefits in patients with chronic stable disease. Despite a similar reduction in BP in the losartan and atenolol groups, the losartan group had a significant reduction in the primary endpoint, a composite of CV mortality, stroke, and MI. The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study, tested the hypothesis that in hypertensive stroke patients, for the same level of BP control, an ARB (eprosartan)-based regimen is more effective than a calcium channel blocker (CCB; nitrendipine)-based regimen in reducing cerebrovascular and CV morbidity and mortality. A post hoc analysis of the Study on Cognition and Prognosis in the Elderly (SCOPE), a blood-pressure-lowering trial, assessed cognitive outcomes in patients with lower versus higher cognitive function at baseline. The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is the largest secondary stroke prevention trial to date involving more than 20,000 patients from 695 sites in 35 countries or regions. Individuals eligible for randomization are aged 50 years or more who have had an ischemic stroke within <120 days, and are stable on entering the study. During a mean follow-up of 2.5 years, mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group. The Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) trial demonstrated that ARBs reduce end-stage renal disease in hypertensive patients with T2DM. The AMADEO  study compared the effects of telmisartan vs losartan on proteinuria in patients with T2DM, overt nephropathy, and hypertension.
 

Core005.ppt

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Slide 1 The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study compared the ARB losartan with the beta-blocker atenolol in 9193 patients with HTN (BP 160-200/95-115 mm Hg). This study found that compared with once-daily losartan 50 mg, once-daily telmisartan 80 mg improved metabolic parameters in patients with metabolic syndrome, including glucose tolerance and insulin sensitivity. Abuissa et al conducted a meta-analysis of 12 randomized trials (N = 116,220) of ACEIs (5 trials) and ARBs (7 trials), that reported the incidence of new-onset T2DM. There were 72,333 patients without T2DM at baseline. Reduction of CVD risk by the RAAS blockade is caused by BP lowering, but it also involves additional antiatherosclerotic effects mediated by anti-inflammatory, antiproliferative, and oxidative stress-lowering properties.
 

Core006.ppt

Download Core006.ppt (38 slides - 6.3MB)

Slide 1 Although ACEIs and ARBs exert protective effects against CVD and renal damage, the difference in their mechanisms may have important clinical implications. Dual blockade of the RAAS combines the biochemical consequences of ACE inhibition and ARBs. Doulton et al conducted a meta-analysis to examine evidence for a greater decline in BP when combing an ACEI and ARB for the treatment of HTN. Doulton et al also found that the combination of an ACEI and an ARB reduced ambulatory systolic BP by 3.8 mm Hg compared with ARB monotherapy. A meta-analysis of randomized trials compared the effect of monotherapy with ACEI and ARB with the combination of ACEIs and ARBs on proteinuria in patients with microalbuminuria and proteinuria, with or without diabetes. The Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study randomly assigned 250 subjects with T2DM and early nephropathy to receive either the ARB telmisartan (80 mg daily) or the ACEI enalapril (20 mg daily). The Valsartan Heart Failure Trial (Val-HeFT) compared the additive effects of valsartan on top of standard treatment in 5010 patients with CHF. Although mortality was unaffected, valsartan clearly reduced hospital admissions for worsening of CHF (valsartan 13.8% vs placebo 18.2%; relative risk [RR] 0.76, P < 0.001). Suzuki et al assessed the effects of an ACEI, an ARB, and an ACEI and ARB combination, on the regression of LV hypertrophy in diabetic patients on dialysis therapy. A meta-analysis of clinical trials, all randomized, examining the prevention of atrial fibrillation (AF), shows a 25% relative risk reduction with ACEIs. The safety profile of combination ARB and ACEI therapy in patients with symptomatic LV dysfunction was assessed in a meta-analysis of 4 randomized clinical trials with 17,337 patients. There have been some reports that the use of ARBs might increase a patient’s risk of MI. The meta-analysis illustrated here explored the influence of ARBs on MI, analyzing all the major international, randomized trials using ARBs compared with another active drug or placebo. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was designed to determine if the combination of the ARB telmisartan and the ACEI ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril in high-risk patients. Seven substudies are embedded in the main trials: The ONTARGET study compared an ACEI vs an ARB vs a combination of both in high-risk individuals similar to those in the HOPE trial, ie, aged 55 years or older with a previous coronary artery, peripheral artery, or cerebrovascular event, or diabetes with evidence of target organ damage. By design, the patients enrolled in ONTARGET were comparable to those in HOPE; ie, they were at high risk for a CV event. Use of aspirin was comparable in both trials. The primary outcome occurred in 16.5%, 16.7%, and 16.3% of patients in the ramipril, telmisartan, and combination groups, respectively. The margin to determine noninferiority was based on the results of the HOPE trial. In that trial, the hazard ratio for the composite outcome used in ONTARGET (CV death, MI, stroke, or hospitalization for heart failure) was 0.775. However, for ONTARGET the value used was the 40th percentile (0.794), which translates into an excess risk for placebo vs ramipril of 1.26. Thus, an upper CI <1.13 ensured that telmisartan retained at least 50% of the effect of ramipril. The slide graphically illustrates the results discussed in the previous slide. Comparisons of key subgroups showed similar results for the combination vs ramipril as observed for the overall population. In this prespecified analysis of renal outcomes, the primary outcome was the first occurrence of dialysis, doubling of serum creatinine, or death. In the overall population, the hazard ratio for the primary renal outcome for telmisartan vs ramipril was 1.00, 95% CI 0.92-1.09. In the overall population, the HR for the primary renal outcome for ramipril vs ramipril plus telmisartan was 1.09, 95% CI 1.01-1.18, P = 0.037. At 2 years follow-up, estimated glomerular filtration rate (eGFR, expressed as mL/min per 1.73 m[2]) decreased less with ramipril (-1.96) than with telmisartan (-3.05) or with combination therapy (-5.12; P < 0.0001 for both telmisartan and combination vs ramipril). Study drug was discontinued in 23.7% and 21.0% of the ramipril and telmisartan groups, respectively.(1) However, at any time point, the discontinuation rate tended to be lower in the telmisartan group. Compared with telmisartan, more patients discontinued ramipril because of cough or angioedema. The slide summarizes the most important reasons for discontinuation in the ramipril and combination groups. The study investigators concluded that telmisartan was noninferior to ramipril and was better tolerated. Based on the ONTARGET results, telmisartan appears to be an equally effective alternative to ramipril, with better tolerability. The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) was a placebo-controlled evaluation of telmisartan 80 mg in patients who were intolerant to ACEIs. ACEI intolerance was defined as previous discontinuation by a physician, with a specific documented cause. As with ONTARGET, by design, the patients enrolled in TRANSCEND were comparable to those in HOPE; ie, they were at high risk for a CV event. Use of aspirin was comparable in both trials. The primary outcome occurred in 15.7% and 17.0% of the telmisartan and placebo groups, respectively (hazard ratio 0.92, 95% CI 0.81-1.05, P = 0.216. Consistent with the primary outcome, there was no statistically significant between-group difference in event rate for the individual components of this composite outcome. When the data were combined with PRoFESS and events classified as occurring either before or after 6 months, there was a significant reduction in the primary outcome events that occurred after 6 months: 10.3% (telmisartan) vs 11.7% (placebo), P < 0.001. Telmisartan was well tolerated in this population of high-risk, ACEI-intolerant patients. Combination of an ACEI and ARB is associated with greater lowering of blood pressure than monotherapy alone.
 

The slides in this section provide practical information for clinical practice relative to the use of ACEI and ARB in patients.

Download Core007.ppt (16 slides - 3.0MB)

The slides in this section provide practical information for clinical practice relative to the use of ACEI and ARB in patients. Slide 2 Slide 3 Slide 4 Slide 5 Adoption of individual lifestyle modifications have demonstrated significant reductions in systolic blood pressure (SBP); adopting 2 or more modifications has a cumulative effect. This slide provides a BP classification for adults 18 years of age or older. The American Heart Association (AHA) has recently issued a scientific statement on the treatment of hypertension in the prevention and management of ischemic heart disease, that recommends aggressive BP lowering. Slide 9 Slide 10 Abbreviation: This slide summarizes current AHA/ACC guidelines for use of ACEIs and ARBs for secondary prevention in patients with coronary and other atherosclerotic vascular disease. Compelling indications for specific antihypertensive therapies involve high-risk conditions that can be direct outcomes of hypertension (HF, ischemic heart disease, chronic kidney disease, or recurrent stroke) or commonly associated with hypertension (ie, diabetes, high coronary disease risk). Among survivors of ischemic stroke or TIA, antihypertensive treatment is recommended for the prevention of recurrent stroke and other vascular events after the hyperacute period (Class I, level of evidence A). ACEIs are recommended for prevention of HF in patients at high risk due to vascular disease or with T2DM and another major risk factor, or with T2DM who smoke or have microalbuminuria (Level of evidence A). RAAS modulation is a cornerstone of management strategies to reduce CV risk and there is considerable opportunity for expanded use of ACEIs and ARBs in high-risk patients.
PNP08.pdf (1.7MB)PNP08.pdf (1.7MB)
 

PNP08.ppt

Download PNP08.ppt (102 slides - 18.6MB)

Slide 1 Abbreviations:ACEI = angiotensin-converting enzyme inhibitor ARB = angiotensin II receptor blocker Despite significant advances in prevention and treatment over the past 50 years, cardiovascular disease (CVD) remains the leading cause of death in the United States for both women and men. CVD continues to impose a substantial medical and economic burden on society. A meta-analysis of 61 prospective studies with over 12 million subject-years revealed that blood pressure (BP) throughout middle and old age is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg. An analysis of data on ambulatory BP monitoring from 7458 subjects (enrolled in prospective studies in 6 countries) found that night-time BP independently predicted total, CV, and non-CV mortality, as well as nonfatal outcomes, regardless of treatment status. The human and economic costs of hypertension (HTN) are staggering. HTN, ie, a BP reading of 140/90 mm Hg or higher, is associated with 69% of all first myocardial infarctions (MIs), 77% of first strokes, and 74% of cases of congestive heart failure (CHF). More than 90% of heart failure cases are preceded by HTN. A study of more than 57,000 HTN patients aged 35 years or older in a large managed-care organization, found that 56% of these individuals also had other risk factors for CVD that included diabetes, hyperlipidemia, and obesity, ie, a body mass index (BMI) of 30 kg/m2 or greater. INTERHEART, a global case-control study of risk factors for acute MI, was conducted in 52 countries on every continent with ~15,000 cases and controls matched for age and gender. The slides in this section examine mechanisms and new understanding of modulation of the RAAS. This slide summarizes the pathophysiologic continuum that underlies the CVD continuum (which has been expanded since its inception to include other areas such as cerebrovascular disease, peripheral vascular disease, and renal disease). The RAAS has been characterized in great detail. As the elements of the enzymatic cascade representing the RAAS have been progressively elucidated, our understanding of the proteins, peptides, enzymes, and receptors of the RAAS has grown increasingly complex. The important biologically-active component of the RAAS is angiotensin II, which is believed to be central to many of the pathologic changes that result in CVD and renal morbidity and mortality. ACEIs block ACE-mediated cleavage of angiotensin I to angiotensin II. Schmieder et al showed that targeting the RAAS in patients with type 2 diabetes mellitus (T2DM) and hypertension with ACEIs and ARBs, produced similar effects on renal endothelial function as indicated by increased nitric oxide (NO) activity. ARBs differ pharmacologically in their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. Among the ARBs, telmisartan has the longest duration of action with a 24-hour elimination half-life as compared with 11 to 15 hours for irbesartan, the ARB with the next longest half-life. A subset of ARBs (eg, telmisartan), has the ability to selectively modulate PPAR-gamma pathways, as well as angiotensin II pathways. In transcription reporter assays, both irbesartan and telmisartan induced transcriptional activity of PPAR-gamma; however, in contrast to the thiazolidinedione pioglitazone, the ARBs telmisartan and irbesartan are only partial PPAR-gamma agonists. ARBs were tested at a concentration of 5 mmol/L, which is near the highest plasma concentration attained after usual oral dosing. Compared with the thiazolidinediones, a subset of ARBs (telmisartan and irbesartan) act as selective PPAR-gamma modulators with a distinctive gene expression profile. This section will summarize the results of major trials that have provided insight into the disease process and powerfully demonstrate that blocking the RAAS impacts CVD and renal outcomes. This diagram summarizes the effect of ACEIs on hypertension, restenosis,  atherosclerosis, and aortic aneurysm, as established in clinical trials. Over the past 2 decades, outcomes trials have demonstrated benefits of ACE inhibition in a wide range of patients with CVD. The effect of ACE inhibition on CV morbidity and mortality has been examined in more than 31,000 patients with stable vascular disease without LV dysfunction, in the HOPE, European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), Prevention of Events With ACE Inhibition (PEACE), and QUinapril Ischemic Event Trial (QUIET) trials. Dagenais et al conducted a combined analysis of the HOPE, EUROPA, and PEACE trials (N = 29,805), which indicated that ACE inhibition has a significant benefit on all-cause mortality in patients with stable vascular disease without LV dysfunction. In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, the use of ramipril (up to 15 mg per day) was studied in 5269 low-risk patients without CVD, but with impaired fasting glucose levels (after an 8-hour fast) or impaired glucose tolerance. Slide 28 Initially, ARBs were developed as antihypertensive agents, but subsequently, a series of major trials have demonstrated the benefits of ARBs across the spectrum of CV and renal disease. Although it is now well established that ACEIs can reduce CV risk, attention is increasingly being focused on ARBs because of their mechanism of action, ie, obviating angiotensin II escape, and allowing continued activation of the protective AT2 receptor could theoretically provide more complete RAAS inhibition. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) performed a meta-analysis of 29 hypertension trials that compared the effects of various antihypertensive regimens based on different drug classes. In the Valsartan-Managing BP Aggressively and Evaluation Reductions in hs-CRP (Val-MARC) study, valsartan reduced high sensitivity C-reactive protein (hs-CRP) in a manner independent of BP reduction. The Framingham Heart Study, The Multiple Risk Factor Intervention Total (MRFIT), and other studies indicate that prehypertension is a strong predictor of excessive CV risk. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program consisted of 3 parallel, independent, integrated, randomized, double-blind, placebo-controlled, clinical trials comparing candesartan with placebo in 3 distinct but complementary populations of patients with symptomatic HF. Median follow-up was 37.7 months. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigators compared the effects of the ARB valsartan, the ACEI captopril, and a combination of the 2 on mortality among patients with MI complicated by LV systolic dysfunction, HF, or both. The study enrolled 14,808 patients during a median follow-up of 24.7 months. In summary, evidence from clinical trials of ARBs show a benefit in post-MI patients with LV dysfunction, but as yet no conclusive evidence on benefits in patients with chronic stable disease. Despite a similar reduction in BP in the losartan and atenolol groups, the losartan group had a significant reduction in the primary endpoint, a composite of CV mortality, stroke, and MI. The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study, tested the hypothesis that in hypertensive stroke patients, for the same level of BP control, an ARB (eprosartan)-based regimen is more effective than a calcium channel blocker (CCB; nitrendipine)-based regimen in reducing cerebrovascular and CV morbidity and mortality. A post hoc analysis of the Study on Cognition and Prognosis in the Elderly (SCOPE), a blood-pressure-lowering trial, assessed cognitive outcomes in patients with lower versus higher cognitive function at baseline. The ongoing PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial is the largest secondary stroke prevention trial to date involving more than 20,000 patients from 695 sites in 35 countries or regions. Individuals eligible for randomization are aged 50 years or more who have had an ischemic stroke within <120 days, and are stable on entering the study. During a mean follow-up of 2.5 years, mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group. The Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) trial demonstrated that ARBs reduce end-stage renal disease in hypertensive patients with T2DM. The AMADEO  study compared the effects of telmisartan vs losartan on proteinuria in patients with T2DM, overt nephropathy, and hypertension. Slide 44 The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study compared the ARB losartan with the beta-blocker atenolol in 9193 patients with HTN (BP 160-200/95-115 mm Hg). This study found that compared with once-daily losartan 50 mg, once-daily telmisartan 80 mg improved metabolic parameters in patients with metabolic syndrome, including glucose tolerance and insulin sensitivity. Abuissa et al conducted a meta-analysis of 12 randomized trials (N = 116,220) of ACEIs (5 trials) and ARBs (7 trials), that reported the incidence of new-onset T2DM. There were 72,333 patients without T2DM at baseline. Reduction of CVD risk by the RAAS blockade is caused by BP lowering, but it also involves additional antiatherosclerotic effects mediated by anti-inflammatory, antiproliferative, and oxidative stress-lowering properties. Slide 49 Although ACEIs and ARBs exert protective effects against CVD and renal damage, the difference in their mechanisms may have important clinical implications. Dual blockade of the RAAS combines the biochemical consequences of ACE inhibition and ARBs. Doulton et al conducted a meta-analysis to examine evidence for a greater decline in BP when combing an ACEI and ARB for the treatment of HTN. Doulton et al also found that the combination of an ACEI and an ARB reduced ambulatory systolic BP by 3.8 mm Hg compared with ARB monotherapy. A meta-analysis of randomized trials compared the effect of monotherapy with ACEI and ARB with the combination of ACEIs and ARBs on proteinuria in patients with microalbuminuria and proteinuria, with or without diabetes. The Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study randomly assigned 250 subjects with T2DM and early nephropathy to receive either the ARB telmisartan (80 mg daily) or the ACEI enalapril (20 mg daily). The Valsartan Heart Failure Trial (Val-HeFT) compared the additive effects of valsartan on top of standard treatment in 5010 patients with CHF. Although mortality was unaffected, valsartan clearly reduced hospital admissions for worsening of CHF (valsartan 13.8% vs placebo 18.2%; relative risk [RR] 0.76, P < 0.001). Suzuki et al assessed the effects of an ACEI, an ARB, and an ACEI and ARB combination, on the regression of LV hypertrophy in diabetic patients on dialysis therapy. A meta-analysis of clinical trials, all randomized, examining the prevention of atrial fibrillation (AF), shows a 25% relative risk reduction with ACEIs. The safety profile of combination ARB and ACEI therapy in patients with symptomatic LV dysfunction was assessed in a meta-analysis of 4 randomized clinical trials with 17,337 patients. There have been some reports that the use of ARBs might increase a patient’s risk of MI. The meta-analysis illustrated here explored the influence of ARBs on MI, analyzing all the major international, randomized trials using ARBs compared with another active drug or placebo. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was designed to determine if the combination of the ARB telmisartan and the ACEI ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril in high-risk patients. Seven substudies are embedded in the main trials: The ONTARGET study compared an ACEI vs an ARB vs a combination of both in high-risk individuals similar to those in the HOPE trial, ie, aged 55 years or older with a previous coronary artery, peripheral artery, or cerebrovascular event, or diabetes with evidence of target organ damage. By design, the patients enrolled in ONTARGET were comparable to those in HOPE; ie, they were at high risk for a CV event. Use of aspirin was comparable in both trials. The primary outcome occurred in 16.5%, 16.7%, and 16.3% of patients in the ramipril, telmisartan, and combination groups, respectively. The margin to determine noninferiority was based on the results of the HOPE trial. In that trial, the hazard ratio for the composite outcome used in ONTARGET (CV death, MI, stroke, or hospitalization for heart failure) was 0.775. However, for ONTARGET the value used was the 40th percentile (0.794), which translates into an excess risk for placebo vs ramipril of 1.26. Thus, an upper CI <1.13 ensured that telmisartan retained at least 50% of the effect of ramipril. The slide graphically illustrates the results discussed in the previous slide. Comparisons of key subgroups showed similar results for the combination vs ramipril as observed for the overall population. In this prespecified analysis of renal outcomes, the primary outcome was the first occurrence of dialysis, doubling of serum creatinine, or death. In the overall population, the hazard ratio for the primary renal outcome for telmisartan vs ramipril was 1.00, 95% CI 0.92-1.09. In the overall population, the HR for the primary renal outcome for ramipril vs ramipril plus telmisartan was 1.09, 95% CI 1.01-1.18, P = 0.037. At 2 years follow-up, estimated glomerular filtration rate (eGFR, expressed as mL/min per 1.73 m[2]) decreased less with ramipril (-1.96) than with telmisartan (-3.05) or with combination therapy (-5.12; P < 0.0001 for both telmisartan and combination vs ramipril). Study drug was discontinued in 23.7% and 21.0% of the ramipril and telmisartan groups, respectively.(1) However, at any time point, the discontinuation rate tended to be lower in the telmisartan group. Compared with telmisartan, more patients discontinued ramipril because of cough or angioedema. The slide summarizes the most important reasons for discontinuation in the ramipril and combination groups. The study investigators concluded that telmisartan was noninferior to ramipril and was better tolerated. Based on the ONTARGET results, telmisartan appears to be an equally effective alternative to ramipril, with better tolerability. The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) was a placebo-controlled evaluation of telmisartan 80 mg in patients who were intolerant to ACEIs. ACEI intolerance was defined as previous discontinuation by a physician, with a specific documented cause. As with ONTARGET, by design, the patients enrolled in TRANSCEND were comparable to those in HOPE; ie, they were at high risk for a CV event. Use of aspirin was comparable in both trials. The primary outcome occurred in 15.7% and 17.0% of the telmisartan and placebo groups, respectively (hazard ratio 0.92, 95% CI 0.81-1.05, P = 0.216. Consistent with the primary outcome, there was no statistically significant between-group difference in event rate for the individual components of this composite outcome. When the data were combined with PRoFESS and events classified as occurring either before or after 6 months, there was a significant reduction in the primary outcome events that occurred after 6 months: 10.3% (telmisartan) vs 11.7% (placebo), P < 0.001. Telmisartan was well tolerated in this population of high-risk, ACEI-intolerant patients. Combination of an ACEI and ARB is associated with greater lowering of blood pressure than monotherapy alone. The slides in this section provide practical information for clinical practice relative to the use of ACEI and ARB in patients. Slide 88 Slide 89 Slide 90 Slide 91 Adoption of individual lifestyle modifications have demonstrated significant reductions in systolic blood pressure (SBP); adopting 2 or more modifications has a cumulative effect. This slide provides a BP classification for adults 18 years of age or older. The American Heart Association (AHA) has recently issued a scientific statement on the treatment of hypertension in the prevention and management of ischemic heart disease, that recommends aggressive BP lowering. Slide 95 Slide 96 Abbreviation: This slide summarizes current AHA/ACC guidelines for use of ACEIs and ARBs for secondary prevention in patients with coronary and other atherosclerotic vascular disease. Compelling indications for specific antihypertensive therapies involve high-risk conditions that can be direct outcomes of hypertension (HF, ischemic heart disease, chronic kidney disease, or recurrent stroke) or commonly associated with hypertension (ie, diabetes, high coronary disease risk). Among survivors of ischemic stroke or TIA, antihypertensive treatment is recommended for the prevention of recurrent stroke and other vascular events after the hyperacute period (Class I, level of evidence A). ACEIs are recommended for prevention of HF in patients at high risk due to vascular disease or with T2DM and another major risk factor, or with T2DM who smoke or have microalbuminuria (Level of evidence A). RAAS modulation is a cornerstone of management strategies to reduce CV risk and there is considerable opportunity for expanded use of ACEIs and ARBs in high-risk patients.
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Core Curriculum

Advancing Our Understanding of RAAS Modulation in High-Risk Patients

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RAAS Modulation: Novel Strategies for Reducing Cardiovascular Risk

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Impact of vascular biology on cardiovascular disease, risk prevention, and treatment Section IV - Update: RAAS manipulation and cardiovascular risk--Hope for Peace?

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