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3 acc prevention blood pressure

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  • The National Health and Nutritional Examination Survey (NHANES) III was a large U.S. survey designed to estimate the prevalence of selected diseases and risk factors. The NHANES III sample was selected from 81 counties between 1988 and 1994. The prevalence of hypertension in a representative sample from NHANES III demonstrates that approximately 25% of the U.S. adult population has hypertension and its prevalence increases steadily with advancing age.
  • A total of 1,298 participants from the Framingham Heart Study that were between 55 and 65 years of age and free of hypertension at baseline (1976-1998) were included in the study cohort. Data from long-term follow-up indicates that the lifetime risk of developing hypertension is about 90 percent. The residual life-time risk for developing hypertension (depicted above) was estimated for participants who reached the age of 65 free of hypertension.
  • The prevalence of favorable blood pressure status (using only systolic and diastolic blood pressures) for 4 NHANES periods is shown here. The age-adjusted estimates for the 4 time periods were 21.6%, 28.8%, 48.9%, and 43.7%, respectively.
  • JNC VII classification of hypertension is based on a mean of two appropriately performed readings as described above on two separate office visits. Blood pressure is classified as normal (<120/80 mm Hg), pre-hypertension (120-139/80-89 mm Hg), stage 1 hypertension (140-159/90-99 mm Hg), or stage 2 hypertension (>160/100 mm Hg).
  • Secondary causes of hypertension are rare but require specific treatment when identified.
  • Resistant hypertension can be difficult to treat. This stepwise algorithm can be a helpful approach to manage these patients.
  • In this algorithm, the diagnosis of resistant hypertension should be confirmed and pseudoresistance excluded. Reversible lifestyle factors that may be contributing should next be identified. Prescription and non-prescription medications should be reviewed as some may be causal. Screening for secondary causes of hypertension should then be pursued. Pharmacologic therapy should include a diuretic, possibly an aldosterone antagonist, and agents with different mechanisms of action. Potent vasodilators may even be necessary. If the patient remains hypertensive, consideration should be given towards referring to a specialist.
  • This slide represents data from a collaborative meta-analysis of individual participant data from separate prospective studies. Throughout middle and older age, blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold, at least to a blood pressure of 115/75 mm Hg.
  • The effect of elevated blood pressure on risk of cardiovascular and renal disease has been documented in both observational, epidemiologic studies and clinical trials. This slide represents data from prospective observational studies and randomized controlled trials, quantifying the cardiovascular risk associated with elevations of systolic blood pressure. Based on pooled data from randomized controlled trials, an average reduction of systolic blood pressure by 12 to 13 mm Hg over 4 years was associated with a 21% reduction in coronary heart disease, a 37% reduction in stroke, a 25% reduction in total cardiovascular mortality, and a 13% reduction in all-cause mortality. These data indicate that systolic blood pressure represents an independent and strong predictor of risk for cardiovascular and renal disease.
    Overall: Reducing systolic blood pressure reduces CHD, stroke, CV and all-cause mortality.
  • Most patients need at least two medications to adequately control their blood pressure.
  • The objective of the ALLHAT trial was to evaluate whether therapy with a calcium channel blocker (amlodipine) or an ACE inhibitor (lisinopril) could lower the incidence of CHD events compared to therapy with a diuretic (chlorthalidone). The primary outcome (by an intention to treat analysis) was fatal coronary heart disease or nonfatal myocardial infarction. Over a mean follow-up of 5 years, there was no difference with regard to the incidence of the primary end point or all cause mortality among the treatment arms. Systolic blood pressure was significantly higher in the amlodipine and lisinopril groups and diastolic blood pressure was significantly lower in the amlodipine group.
    Secondary outcomes demonstrated a higher rate of heart failure hospitalization with amlodipine compared to chlorthalidone and higher rates of combined CVD, stroke, and heart failure with lisinopril compared to chlorthalidone.
    Overall: Calcium channel blockers, ACE-inhibitors, and thiazide diuretics are equivalent in their ability to reduce CVD events in hypertensive patients.
  • In the LIFE trial, treatment with once daily losartan (compared to atenolol) in adults with essential hypertension and electrocardiographic evidence of left ventricular hypertrophy resulted in a significant decrease in the primary composite endpoint of death, MI, or stroke without a significant blood pressure difference between the two arms. This difference was driven predominantly by a statistically significant decrease in stroke, with no statistically significant difference in death from cardiovascular disease and myocardial infarction. There were also fewer new cases of diabetes mellitus in the losartan arm.
    Overall: In the LIFE trial, an ARB was more effective than a beta blocker in reducing CV risk in hypertensive patients with evidence of LVH.
  • The goal of the ASCOT-BPLA study was to compare two antihypertensive regimens, one the combination of a diuretic and beta-blocker and the other the combination of a calcium channel blocker and ACE inhibitor, in patients with hypertension and at least 3 additional cardiovascular risk factors. The primary end point (by an intention to treat analysis) was the incidence of non-fatal myocardial infarction (including silent myocardial infarction) and fatal coronary heart disease.
    The study was stopped prematurely after 5.5 years of median follow-up. There was no statistically significant difference between the two treatment regimens with respect to the primary end point, nor the incidence of fatal and non-fatal stroke, total cardiovascular events and procedures, and all-cause mortality. Among patients receiving the calcium channel blocker and ACE inhibitor regimen, however, there was a lower incidence of diabetes mellitus.
  • In the ASCOT-BPLA study, the amlodopine-based regimen did appear more efficacious in lowering several secondary endpoints including nonfatal MI plus fatal CHD (silent myocardial infarctions were excluded in this analysis), total coronary endpoints, total CV events and procedures, all-cause mortality, cardiovascular mortality, and fatal and nonfatal stroke. There was no difference in fatal and nonfatal heart failure.
  • The ACCOMPLISH trial sought to evaluate the effect of two antihypertensive treatment regimens (one the combination of benazepril and HCTZ and the other the combination of benazepril and amlodipine) in high-risk hypertensive patients. The trial was stopped early (pre-specified stopping rule) because the blood pressure regimen of benazepril/amlodipine showed superiority to benazepril/HCTZ in reducing the primary endpoint of CV death, myocardial infarction, hospitalization for angina, sudden cardiac arrest, and coronary revascularization. For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio for benazaepril/amlodipine was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril–amlodipine group and 132.5/74.4 mm Hg in the benazepril–hydrochlorothiazide group.
  • The HYVET trial enrolled 3845 patients from Europe, China, Australasia, and Tunisia who were 80 years of age or older and had a sustained systolic blood pressure of 160 mm Hg or more. Patients were randomly assigned to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo. The angiotensin-converting–enzyme inhibitor perindopril (2 or 4 mg), or matching placebo, was added if necessary to achieve the target blood pressure of 150/80 mm Hg. The primary end point was fatal or nonfatal stroke.
    At 2 years, 25.8%, 23.9%, and 49.5% of patients in the active-treatment group were receiving indapamide alone, indapamide and perindopril (2 mg), and indapamide and perindopril (4 mg), respectively; 14.2%, 13.4%, and 71.8% of patients in the placebo group, respectively, were receiving the corresponding placebos.
    At 2 years, the mean blood pressure while sitting was 15.0/6.1 mm Hg lower in the active-treatment group than in the placebo group. In an intention-to-treat analysis, active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% confidence interval [CI], –1 to 51; P=0.06), a 39% reduction in the rate of death from stroke (95% CI, 1 to 62; P=0.05), a 21% reduction in the rate of death from any cause (95% CI, 4 to 35; P=0.02), a 23% reduction in the rate of death from cardiovascular causes (95% CI, –1 to 40; P=0.06), and a 64% reduction in the rate of heart failure (95% CI, 42 to 78; P<0.001). Fewer serious adverse events were also reported in the active-treatment group (358, vs. 448 in the placebo group; P=0.001).
  • The goal of the INVEST study was to compare morbidity and mortality in a randomized, open label, blinded end point study of patients with hypertension and coronary artery disease treated with a calcium antagonist strategy (CAS) or a non–calcium antagonist strategy (NCAS). The CAS consisted of sustained release verapamil and the NCAS consisted of atenolol. By the end of the study, approximately half of the patients in each group were also taking trandolapril and hydrochlorothiazide to achieve blood pressure goals according to JNC VI. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment.
    The primary outcome was first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke. At 24 months, there were no statistical differences between the treatment strategies and the primary outcome. A total of 72% of CAS and 71% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg. Overall, the treatment strategy of verapamil-trandolapril was as clinically effective as the atenolol-hydrochlorothiazide strategy in hypertensive patients with coronary artery disease.
    Overall: In CAD patients with hypertension, multiple agents will likely be needed to control BP. Starting with a calcium channel blocker versus a beta blocker does not impact the composite event rate of death, MI and stroke.
  • The VALUE trial sought to investigate differing effects of valsartan and amlodipine on cardiac morbidity and mortality in patients with hypertension given the same level of blood pressure control. The primary end point was a composite of cardiac mortality and morbidity.
    Amlodipine resulted in a greater reduction in blood pressure after one month and one year compared to valsartan. Despite this, there were no differences in the primary composite endpoint between the two treatments. There were, however, fewer cases of new onset diabetes mellitus in the valsartan arm.
    Overall: Valsartan and amlodipine are equally efficacious in reducing CVD risk in hypertensive patients.
  • The goal of the CAMELOT trial was to compare the effect of amlodipine or enalapril vs. placebo on cardiovascular events in patients with angiographically documented coronary artery disease. The primary outcome was a composite of adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral arterial disease.
    There was a significant decrease in blood pressure in both treatment arms as compared to placebo. A significant decrease in the primary end point was noted in the amlodipine arm as compared to placebo. A small non-significant decrease in the primary end point was noted in the enalapril arm as compared to placebo; however, there was no significant difference noted between the amlodipine and enalapril arms.
    Overall: Amlodipine, but not enalapril, reduced the incidence of a composite CVD endpoint as compared to placebo in hypertensive patients with known CAD.
  • The importance of reducing diastolic BP in patients with diabetes mellitus was demonstrated in the Hypertension Optimal Treatment (HOT) trial. In the HOT trial, 18,790 patients with hypertension and a diastolic BP between 100 and 115 mm Hg were randomized to 1 of 3 target diastolic BP groups: 90 mm Hg, 85 mm Hg, or 80 mm Hg. A subgroup of 1501 patients had DM at baseline. A 5-step treatment regimen that started with felodipine was used to lower BP. At the study end, 78% of patients were still taking felodipine, usually with an angiotensin converting enzyme inhibitor (41%) or a -blocker (28%).
    The incidence of major CV events (MI, stroke, CV mortality) did not differ significantly among the 3 target BP groups in patients who did not have diabetes. Events per 1000 patient-years were 9.9, 10.0, and 9.3 for the 90 mm Hg, 85 mm Hg, or 80 mm Hg groups, respectively. In patients with diabetes mellitus, however, there was a 51% reduction in major CV events in the target group 80 mm compared with target group 90 mm (P for trend = .005). Events per 1000 patient-years were 24.4, 18.6, and 11.9 (P=0.005 for trend) for those with diabetes in the 90 mm Hg, 85 mm Hg, or 80 mm Hg groups, respectively.
  • Cardio-SIS was a multicenter, randomized open-label trial undertaken in Italy. A total of 1111 non-diabetic patients (age 55 and older) with a systolic blood pressure of 150 mm Hg or greater were randomly assigned to a target systolic blood pressure of less than 140 mm Hg (usual control; n=553) or less than 130 mm Hg (tight control; n=558). All patients had at least one additional cardiac risk factor. The blood pressure medicines used for the study were left to clinician discretion.
    The primary study outcome was the prevalence of ECG evidence of left ventricular hypertrophy at 2 years using the modified Cornell criteria, left ventricular strain, or a Romhilt-Estes score of 5 or more. The main pre-specified secondary outcome was a composite of all-cause mortality, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, transient ischemic attack, congestive heart failure of New York Heart Association class III or IV requiring admission to the hospital, angina pectoris with objective evidence of myocardial ischemia, new-onset atrial fibrillation, coronary revascularization, aortic dissection, occlusive peripheral arterial disease, and renal failure requiring dialysis.
    Patients in the tight control group had lower systolic blood pressure [between-group difference 3.8 mm Hg systolic [95% CI 2.4–5.2], p<0.0001; and 1.5 mm Hg diastolic [0.6–2.4]; p=0.041], a lower incidence of LVH [11.4% vs. 17.0%, OR 0.63, p=0.013], and a lower incidence of the composite secondary endpoint [4.8% vs. 9.3%, OR 0.50, p=0.003]. Adverse events were similar in the two groups.
    The use of diuretics and angiotensin receptor blockers were higher in the tight control group. Overall, the total number of clinical events were small and were driven by a reduction in coronary revascularization and new onset atrial fibrillation.
  • In this substudy of the original INVEST study, 6400 patients with diabetes and CAD were randomized to two blood-pressure lowering strategies including long acting verapamil or atenolol. Additional BP lowering could be achieved through the addition of trandolopril and HCTZ. The target was a blood pressure of less than 130/85 mm Hg.
    In the current analysis, patients were categorized according to the degree of blood-pressure control actually achieved. Patients with a systolic blood pressure of 140 mm Hg or higher were classified as "not controlled." Those with a systolic blood pressure below 130 mm Hg were classified as "tight control" and those with a systolic blood pressure between 130 and 140 mm Hg were classified as "usual control.“
    During the follow-up period, patients in the uncontrolled group had nearly a 50% higher combined risk of death, MI, or stroke when compared with the usual-control group. Those in the tight-control group had a similar risk to those in the usual-control group in terms of the combined end point; however, further analysis showed an increase in the risk of all-cause death in the tight-control group when compared with the usual-control group. This increase became apparent about 30 months into the study and persisted for an additional five years of follow-up.
  • In the ACCORD BP trial, 4,733 diabetic patients were randomized, in a non-blinded fashion, to an intensive BP-lowering regimen with a target systolic BP goal of <120 mm Hg—with patients on average taking three and a half antihypertensives—or standard BP lowering, where the goal was <140 mm Hg. The primary composite outcome was nonfatal MI, nonfatal stroke, or death from cardiovascular causes, and the mean follow-up was 4.7 years.
    After one year, the mean systolic pressure was 119.3 mm Hg in the intensive-BP-lowering group and 133.5 mm Hg in the standard group. There was no significant difference in the primary end point between the groups. There was also no difference between the groups in terms of pre-specified secondary end points (except stroke), including the primary outcome plus revascularization or nonfatal heart failure; major coronary disease events; and fatal or nonfatal heart failure.
    There was a significant difference in stroke (41% relative risk reduction) between the intensive and standard BP-lowering arms.
    Those assigned to the intensive-therapy group were more likely to suffer adverse events due to antihypertensive therapy—3.3% compared with 1.3% in the standard-therapy group (p<0.001).
  • Compelling indications refer to treatments that have demonstrated efficacy for a particular patient population in large randomized controlled trials.
  • The lifestyle modifications outlined above have proven efficacy in the prevention and treatment of hypertension and are recommended for all pre-hypertensive and hypertensive patients. Lifestyle modifications are complementary to pharmacotherapy and the combination of lifestyle modifications can be additive.
  • Compelling indications refer to treatments that have demonstrated efficacy for a particular patient population in large randomized controlled trials.
  • The JNC VII treatment algorithm provides a framework to assist physicians in the treatment of hypertensive patients.
  • Angiotensin I converting enzyme (ACE) is involved in the production of angiotensin II and the inactivation of bradykinin. The conversion of angiotensin I to angiotensin II is an important component of the renin-angiotensin system, which regulates sodium/potassium balance and blood pressure/volume homeostasis. Angiotensin II stimulates vasoconstriction, aldosterone secretion, increased sympathetic tone, and vascular remodeling. Increased levels of bradykinin occur with use of an ACE inhibitor and are responsible for the cough that sometimes occurs.
  • The HOPE trial sought to evaluate the effect of ramipril in patients at high risk for cardiovascular events without left ventricular systolic dysfunction or heart failure. The primary outcome was a composite of MI, stroke, or death from cardiovascular causes. A total of 14% of patients taking ramipril reached the primary end point, as compared with 18% of patients assigned to receive placebo (RR 0.78; 0.70-0.86; P<0.001).
    Treatment with ramipril reduced the rates of death from cardiovascular causes (6%, vs. 8%; RR 0.74; P<0.001), MI (10% vs. 12%; RR 0.80; P<0.001), stroke (3.4% vs. 5%; RR 0.68; P<0.001), death from any cause (10% vs. 12%; RR 0.84; P=0.005), revascularization procedures (16% vs. 18%;RR 0.85; P=0.002), cardiac arrest (0.8% vs. 1.3%; RR 0.63; P=0.03), heart failure (9% vs. 11.5%; RR 0.77; P<0.001), and complications related to diabetes (6% vs. 8%; RR 0.84; P=0.03).
    Overall: Compared to placebo, ramipril was associated with a significant reduction in the rates of death, MI, and stroke in high-risk patients that were not known to have left ventricular systolic dysfunction or heart failure.
  • The EUROPA trial randomized 12,218 patients with stable coronary heart disease and no apparent heart failure to perindopril or placebo. After 4.2 years, perindopril resulted in a 20% relative risk reduction in the primary endpoint of cardiovascular death, myocardial infarction, or cardiac arrest (95% CI 9–29, p=0.0003), with consistent benefit in all pre-specified subgroups and secondary end points.
    Overall: Compared to placebo, perindopril was associated with a significant reduction in the rates of CV death, MI, and cardiac arrest in patients with stable coronary heart disease that were not known to have left ventricular systolic dysfunction.
  • The PEACE trial was designed to test whether patients with stable coronary artery disease and normal or near normal left ventricular systolic function derive therapeutic benefit from the addition of an ACE inhibitor to conventional therapy.
    The incidence of the primary end point (death from cardiovascular causes, myocardial infarction, or coronary revascularization) was 21.9% in the trandolapril group, as compared with 22.5% in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent CI, 0.88 to 1.06; P=0.43) over a median follow-up period of 5 years.
    Overall: Unlike ramipril and perindopril; trandolapril failed to show a significant reduction in death from cardiovascular causes, myocardial infarction, or coronary revascularization in patients with stable CAD and normal or near normal left ventricular systolic function.
  • This slide demonstrates that the incidence of MI, cardiac death, or stroke in the PEACE trial was lower than that observed in the HOPE trial. This likely reflects a greater percentage of patients receiving contemporary risk reducing therapies (70% in PEACE received lipid lowering therapy as compared to 29% in HOPE) and may explain why trandolapril, unlike ramipril, failed to show a significant reduction in CVD events.
  • This slide represents a meta-analysis of 7 trials demonstrating the beneficial effects of ACE inhibitors in reducing overall mortality (OR, 0.86; 95% confidence interval, 0.79-0.93), myocardial infarction (OR, 0.82; 95% confidence interval, 0.75-0.89), cardiovascular mortality (OR, 0.81; 95% confidence interval, 0.73-0.90), and stroke (OR, 0.77; 95% confidence interval, 0.66-0.88) in patients with coronary artery disease and preserved left ventricular systolic function as compared to placebo.
  • In these three placebo-controlled trials of patients with left ventricular systolic dysfunction and/or heart failure after a myocardial infarction (n=5966), treatment with an ACE inhibitor resulted in a reduction in mortality (odds ratio 0.74 [95% Cl 0.66–0.83]), readmission for heart failure (OR 0.73 [0.63–0.85]), re-infarction (OR 0.80 [0.69-0.94]), and a composite of these events (OR 0.75 [0.67–0.83]; all p<0.001).
    The benefits were observed early and persisted long term. The benefits occurred independent of age, sex, and baseline use of diuretics, aspirin, and β-blockers. Although there was a trend towards greater reduction in the risk of death or readmission for heart failure in patients with a lower ejection fraction, the benefit extended over the range of ejection fractions examined.
    Overall: ACE inhibitors lower rates of mortality, myocardial infarction, and hospital admission for heart failure in patients with left-ventricular systolic dysfunction and/or heart failure following a MI.
  • Angiotensin II is a potent vasoconstrictor that stimulates norepinephrine release and sympathetic stimulation. Angiotensin receptor blockers act directly on the AT I receptor. This permits Angiotensin II to bind to the AT II receptor, leading to favorable effects of vasodilatation and possible slowing of atherosclerosis.
  • This arm of the CHARM trial sought to evaluate whether candesartan, an angiotensin receptor blocker, could improve outcomes in patients intolerant of ACE inhibitors. The primary outcome (by an intention to treat analysis) was a composite of cardiovascular death or hospitalization for CHF.
    The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%).
    During a median follow-up of 34 months, 33% of patients in the candesartan group and 40% in the placebo group had cardiovascular death or hospitalization for CHF (unadjusted hazard ratio 0.77 [95% CI 0.67–0.89], p=0.0004; covariate adjusted 0.70 [0.60–0.81], p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospitalizations for CHF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups.
    Overall: Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.
  • The VALIANT study sought to compare the effect of an angiotensin receptor blocker (valsartan), to an ACE inhibitor (captopril), and the combination of the two on mortality in patients with post-infarction heart failure or left ventricular systolic dysfunction.
    During a median follow-up of 24.7 months, there was no difference in all cause mortality between the three groups. The upper limit of the one-sided 97.5% confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for non-inferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001).
    The valsartan plus captopril group had the most drug-related adverse events. Among patients on only a single agent, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group.
    Overall: Valsartan was as effective as captopril in patients with heart failure or reduced left ventricular systolic function after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.
  • This arm of the CHARM trial sought to determine whether the addition of an angiotensin receptor blocker to an ACE inhibitor would improve clinical outcomes as compared to use of an ACE inhibitor alone. Patients were randomly assigned to candesartan (target dose 32 mg once daily) or placebo. At baseline, 55% of patients were also treated with beta blockers and 17% with an aldosterone blocker.
    The primary outcome of the study (by intention to treat analysis) was a composite of cardiovascular death or hospitalization for CHF. The median follow-up was 41 months. A total of 38% patients in the candesartan group and 42% in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.85 [95% CI 0.75–0.96], p=0.011; covariate adjusted p=0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as, the total number of hospitalizations for CHF. The benefits of candesartan were similar in all prespecified subgroups, including patients receiving β-blockers.
    Overall: Unlike in the VALIANT trial (and the more recent OnTarget trial), the addition of an angiotensin receptor blocker to background therapy with an ACE inhibitor produced further reductions in cardiovascular events in patients with CHF and reduced left-ventricular systolic function.
  • The ONTARGET trial randomized 25,620 high risk patients (known cardiovascular disease or diabetes) to ramipril (an ACE inhibitor), telmisartan (an angiotensin receptor blocker), or both for 56 months. The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. The main secondary outcome was death from cardiovascular causes, myocardial infarction, or stroke, which was used as the primary outcome in the Heart Outcomes Prevention Evaluation (HOPE) trial. There was no difference in outcomes between the groups randomized to ramipril or telmisartan alone.
  • In this analysis of the ONTARGET trial, there was no difference in the primary endpoint among those randomized to ramipril, telmisartan, or their combination (even after adjustment for the same differences in blood pressure). Patients randomized to combination therapy had greater rates of renal impairment.
  • The TRANSCEND trial randomized 5,926 high risk patients intolerant to ACE inhibitors to telmisartan 80 mg/day (n=2954) or placebo (n=2972) for an average of 56 months. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 [SD 19.6/12.0] mm Hg). A total of 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio 0.92, 95% CI 0.81-1.05, p=0.216). One of the secondary outcomes -- a composite of cardiovascular death, myocardial infarction, or stroke -- occurred in 384 (13.0%) patients on telmisartan compared with 440 (14.8%) on placebo (0.87, 0.76-1.00, p=0.048 unadjusted; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome).
    Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21.6%] vs 705 [23.8%]; p=0.055), with the most common reason for permanent discontinuation being hypotensive symptoms (29 [0.98%] in the telmisartan group vs 16 [0.54%] in the placebo group).
    Overall: Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of the study, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke (the primary endpoint in HOPE).
  • Betablockers bind to beta-adrenergic receptors in the vasculature, cardiac myocytes, conduction system, and cardiac nodal tissue. These receptors primarily bind norepinephrine. Betablockers inhibit inotropy, chronotropy and dromotropy (conduction velocity) in the heart. Nonselective beta-blockers also block vasoconstriction (through 1 blockade) and vasodilation (through beta2 blockade) in the periphery.
  • The majority of large randomized clinical trials comparing beta blockers to placebo in post-MI patients show a reduction in mortality and reinfarction.
  • Multiple trials have shown beta blockers to be effective in reducing death in the acute and chronic treatment of patients following a myocardial infarction.
    Overall: Beta blockers represent standard therapy for the secondary prevention of cardiovascular disease.
  • The majority of large randomized clinical trials comparing beta blockers to placebo in patients with heart failure and/or left ventricular systolic dysfunction show a significant decrease in all cause mortality.
  • Transcript

    • 1. The Evidence for Current Cardiovascular Disease Prevention Guidelines: Blood Pressure Control American College of Cardiology Evidence Initiative Subcommittee Best Practice Quality and Guidelines and Prevention Committee
    • 2. Classification of Recommendations and Levels of Evidence *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. †In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.
    • 3. Icons Representing the Classification and Evidence Levels for Recommendations I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III
    • 4. Evidence for Current Cardiovascular Disease Prevention Guidelines Blood Pressure Evidence
    • 5. Hypertension* Prevalence (%) High Blood Pressure*: Prevalence Increases with Age National Health and Nutrition Examination Survey (NHANES) III 66% 72% 51% 38% 18% 3% 18-29 9% 30-39 40-49 50-59 60-69 70-79 80+ Age The prevalence of high blood pressure increases with age *Hypertension defined as blood pressure >140/90 mmHg or treatment Source: JNC-VI. Arch Intern Med 1997;157:2413-2446
    • 6. High Blood Pressure*: Prevalence in Different Patient Groups National Health and Nutrition Examination Survey (NHANES) *High blood pressure defined as blood pressure ≥140/90 mmHg or treatment Source: Yoon SS et al. NCHS Data Brief 2012;107:1-7
    • 7. High Blood Pressure: Lifetime Risk* Risk of hypertension (%) Framingham Heart Study Men Women Years *Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg starting at age 55-65 years Source: Vasan RS et al. JAMA 2002; 287:1003-1010
    • 8. Blood pressure age-adjusted percentage Change in Blood Pressure Levels in the United States Over Time National Health and Nutrition Examination Survey (NHANES) Source: Ford ES et al. Figure 2b, Circulation 2009;120:1181-1188
    • 9. Evidence for Current Cardiovascular Disease Prevention Guidelines Blood Pressure Treatment Evidence and Guidelines
    • 10. JNC VII Guidelines: Measurement of Blood Pressure Method Brief Description In-office Two readings, 5 minutes apart, sitting in chair Confirm elevated reading in contralateral arm Ambulatory BP monitoring Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep indicates increased CVD risk Self-measurement Provides information on response to treatment. May help improve adherence to treatment and evaluate “white-coat” HTN BP=Blood pressure, CVD=Cardiovascular disease, HTN=Hypertension Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 11. JNC VII Guidelines: Causes of Secondary Hypertension Medical Conditions Drugs Chronic kidney disease NSAIDs Primary hyperaldosteronism Oral contraceptives Renovascular disease Adrenal steroids Chronic steroid therapy Sympathomimetics Cushing’s syndrome Cyclosporine or tacrolimus Pheochromocytoma Erythropoietin Aortic coarctation Ephedra, mu huang, bitter orange Thyroid or parathyroid disease Cocaine or amphetamines Sleep apnea Alcohol NSAIDs=Non-steroidal anti-inflammatory drugs Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 12. Resistant Hypertension Diagnostic and Treatment Algorithm Confirm Treatment Resistance Office BP >140/90 or 130/80 mm Hg in patients with DM or chronic kidney disease and Patient prescribed 3 or more antihypertensive medications at optimal doses, including if possible a diuretic or Office BP at goal but patient requiring 4 or more antihypertensive medications Exclude Pseudoresistance Identify/Reverse Contributing Lifestyle Factors Obesity Physical inactivity Excessive alcohol ingestion High salt, low fiber diet Discontinue/Minimize Interfering Substances Non-steroidal anti-inflammatory agents Sympathomimetics (diet pills, decongestants) Stimulants Oral contraceptives Licorice Ephedra Is patient adherent with prescribed reigmen? Obtain home, work, or ambulatory BP readings to exclude white coat effect BP=Blood pressure, DM=Diabetes mellitus Source: Calhoun DA et al. Circulation 2008;117:e510-526
    • 13. Resistant Hypertension (Continued) Diagnostic and Treatment Algorithm Screen for Secondary Causes of Hypertension Obstructive sleep apnea (snoring, witnessed apena, excessive daytime sleepiness) Primary aldosteronism (elevated aldosterone/renin ratio) Chronic kidney disease (CrCl <30 ml/min) Renal artery stenosis (young female, known atherosclerotic disease, worsening renal function) Pheochromocytoma (episodic hypertension, palpitations, diaphoresis, headache) Cushing’s syndrome (moon facies, central obesity, abdominal striae, inter-scapular fat deposition) Aortic coarctation (differential in brachial or femoral pulses, systolic bruit) Pharmacologic Treatment Maximize diuretic therapy, including possible addition of mineralocorticoid receptor antagonist Combine agents with different mechanisms of action Use loop diuretics in patients with chronic kidney disease and/or those receiving potent vasodilators (e.g., minoxidil) Refer to Specialist Refer to appropriate specialist for known or suspected secondary cause(s) of hypertension Refer to hypertension specialist if blood pressure remains uncontrolled after 6 months of treatment CrCl=Creatinine clearance Source: Calhoun DA et al. Circulation 2008;117:e510-526
    • 14. 256 Age at Risk (Y) 80-89 128 70-79 64 60-69 32 50-59 16 40-49 8 4 2 1 0 120 140 160 180 Usual Systolic BP (mm Hg) 256 Ischemic Heart Disease Mortality (Floating absolute risk) Ischemic Heart Disease Mortality (Floating absolute risk) High Blood Pressure Evidence: Increased Risk with Increased Levels disease mortality and blood pressure Ischemic heart Age at Risk (Y) 80-89 128 70-79 64 60-69 32 50-59 16 40-49 8 4 2 1 0 70 80 90 100 110 Usual Diastolic BP (mm Hg) BP=Blood pressure Source: Prospective Studies Collaboration. Lancet 2002;360:1903-1913
    • 15. High Blood Pressure Evidence: Risk of CHD with Treatment Veterans Administration, 1967 Veterans Administration, 1970 Hypertension Stroke Study, 1974 USPHS Study, 1977 EWPHE Study, 1985 Coope and Warrender, 1986 SHEP Study, 1991 STOP-Hypertension Study, 1991 MRC Study, 1992 Syst-Eur Study, 1997 0.79 (0.69 to 0.90) Total 0 2.0 0.5 1.5 1.0 Better than placebo Worse than placebo CHD=Coronary heart disease Source: He J et al. Am Heart J 1999;138:211-219
    • 16. High Blood Pressure Evidence: Number of Medications Needed Trial (SBP Achieved) UKPDS (144 mm Hg) ABCD (127 mm Hg) MDRD (132 mm Hg) HOT (138 mm Hg) AASK (127 mm Hg) 1 1.5 2 2.5 3 3.5 4 Number of BP Meds AASK=African American Study of Kidney Disease and Hypertension, ABCD=Appropriate Blood Pressure Control in Diabetes, BP=Blood pressure, HOT=Hypertension Optimal Treatment, MDRD=Modification of Dietary Protein in Renal Disease, SBP=Systolic blood pressure, UKPDS=UK Prospective Diabetes Study Source: Abbott K et al. J Clin Pharmacology 2004;44:431-438
    • 17. Blood Pressure Lowering Therapy Evidence: Primary Prevention Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 33,357 patients with HTN and >1 CHD risk factor randomized to chlorthalidone, amlodipine, or lisinopril for 5 years Rate of MI or fatal CHD .20 Chlorthalidone Amlodipine Lisinopril .16 .12 RR (95% CI) P-value A/C 0.98 (0.90-1.07) 0.65 L/C (0.91-1.08) 0.81 .08 .04 0 0 1 2 3 4 Years to CHD Event 0.99 5 6 7 All three BP lowering agents provide similar efficacy BP=Blood pressure, CHD=Coronary heart disease, HTN=Hypertension, MI=Myocardial infarction Source: ALLHAT Investigators. JAMA 2002;288:2981-2997
    • 18. Blood Pressure Lowering Therapy Evidence: Primary Prevention Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study Proportion with CV death, MI, or stroke (%) 9,193 high-risk hypertensive* patients with LVH randomized to losartan (100 mg) or atenolol (100 mg) for 5 years 16 12 Atenolol Losartan 8 4 13% RRR, P=0.021 0 0 6 12 18 24 30 36 42 48 54 60 66 Study Month An ARB provides greater efficacy in patients with LVH *Defined by SBP=160-200 mmHg or DBP=95-115 mmHg ARB=Angiotensin receptor blocker, CV=Cardiovascular, DBP=Diastolic blood pressure, LVH=Left ventricular hypertrophy, MI=Myocardial infarction, SBP=Systolic blood pressure Source: Dahlöf B et al. Lancet 2002;359:995-1003
    • 19. Blood Pressure Lowering Therapy Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) Nonfatal MI and fatal CHD (%) 19,342 high-risk hypertensive patients with 3 additional CV risk factors randomized to amlodipine (10 mg) & perindopril (8 mg) or atenolol (100 mg) & bendroflumethiazide (2.5 mg) for 5.5 years 6 Atenolol-based regimen 4 Amlodipine-based regimen 2 RRR=10%, P=0.1052 0 0 1 2 3 4 5 Time since randomization (years) 6 Both BP lowering regimens provide similar efficacy BP=Blood pressure, CV=Cardiovascular, CHD=Coronary heart disease, MI=Myocardial infarction Source: Dahlöf B et al. Lancet 2005;366:895-906
    • 20. Blood Pressure Lowering Therapy Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) Secondary endpoints Nonfatal MI + fatal CHD Total coronary endpoint Total CV events/procedures All-cause mortality CV mortality Fatal/nonfatal stroke Fatal/nonfatal HF Amlodipinebased rate/1000 patient years 7.4 14.6 27.4 13.9 4.9 6.2 2.5 Atenolol-based rate/1000 patient years Amlodipinebased better Atenololbased better 8.5 16.8 32.8 15.5 6.5 8.1 3.0 P <0.05 <0.01 <0.0001 <0.05 0.001 <0.001 NS 0.50 0.70 1.00 1.45 2.00 An amlodopine-based regimen appears to reduce the rate of other CV events CHD=Coronary heart disease, CV=Cardiovascular, HF=Heart failure, MI=Myocardial infarction Source: Dahlöf B et al. Lancet 2005;366:895-906
    • 21. Blood Pressure Lowering Therapy Evidence: Primary Prevention Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) Composite of CV death, MI, stroke, hospitalization for angina, sudden cardiac arrest, and coronary revascularization (%) 11,506 high-risk hypertensive patients randomized to benazepril (40 mg) and amlodipine (10 mg) or benazepril (40 mg) and HCTZ (25 mg) for 36 months* 0.16 0.14 0.12 Benazepril/HCTZ 0.10 0.08 Benazepril/Amlodipine 0.06 0.04 0.02 0.00 20% RRR, HR=0.80, P=0.0002 0 200 400 600 800 1000 1200 1400 An amlodipine-based regimen provides greater benefit *The study was prematurely stopped CV=Cardiovascular, MI=Myocardial infarction Source: Jamerson K et al. NEJM 2008;359:2417-2428
    • 22. Blood Pressure Lowering Therapy Evidence: Primary Prevention Hypertension in the Very Elderly (HYVET) Trial Rate/1000 patient years (%) 3,845 patients >80 years with SBP >160 mm Hg randomized to treatment to indapamide (1.5 mg) and perindopril (2-4 mg if needed) vs. placebo for 2 years P=0.02 P<0.001 Indapamide + perindopril Placebo P=0.06 P=0.05 P<0.001 (Primary end point) Blood pressure control in patients >80 years of age provides benefit CV=Cardiovascular, CVA=Cerebrovascular accident Source: Beckett NS et al. NEJM 2008;358:1887-1898
    • 23. Blood Pressure Lowering Therapy Evidence: Secondary Prevention International Verapamil-Trandolapril Study (INVEST) Incidence of all cause death, nonfatal MI, or nonfatal stroke 22,576 patients with HTN and CAD randomized to a BP lowering strategy with verapamil SR (240 mg) or atenolol (50 mg) for 2.7 years Calcium antagonist strategy (CAS)* Non-calcium antagonist strategy (NCAS)* 20 15 10 5 RR=0.98, P=0.57 0 0 6 12 18 24 30 36 42 48 54 60 Months Both a CAS and NCAS provide similar efficacy *Trandolapril (up to 4 mg) was added in those with diabetes mellitus, chronic kidney disease, or heart failure BP=Blood pressure, CAS=Calcium antagonist strategy, HTN=Hypertension, MI=Myocardial infarction, NCAS=Non-calcium antagonist strategy Source: Pepine CJ et al. JAMA 2003;290:2805-2816
    • 24. Blood Pressure Lowering Therapy Evidence: Secondary Prevention Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial 15,245 patients with untreated HTN and high CV risk randomized to a BP lowering strategy with valsartan (160 mg) or amlodipine (10 mg) for 4.2 years Primary cardiac composite endpoint Cardiac mortality Cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes 0.5 1 2 Favors valsartan Favors amlodipine Both blood pressure lowering regimens provide similar efficacy BP=Blood pressure, CV=Cardiovascular, HTN=Hypertension Source: Julius S et al. Lancet 2004;363:2022-2031
    • 25. Blood Pressure Lowering Therapy Evidence: Secondary Prevention Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) Trial CV event rate* 1,991 patients with CAD and a DBP <100 mmHg randomized to amlodipine (10 mg), enalapril (20 mg), or placebo for 2 years 0.25 130/78 124/77 125/77 Placebo Enalapril Amlodipine 0.20 0.15 Follow-up BP (mmHg) 0.10 0.05 0 0 6 12 18 24 Months Treatment with amlodipine results in reduced CV events *Includes CV death, myocardial infarction, cardiac arrest, coronary revascularization, hospitalization for heart failure or angina pectoris, stroke, transient ischemic attack, development of peripheral arterial disease BP=Blood pressure, CAD=Coronary artery disease, CV=Cardiovascular, DBP=Diastolic blood pressure Source: Nissen S et al. JAMA 2004;292:2217-2226
    • 26. Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control Hypertension Optimal Treatment (HOT) Study 18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg Patients without Diabetes Diastolic BP goal Major CV events per 1000 patient-years Patients with Diabetes Diastolic BP goal More intensive blood pressure control provides greater benefit in diabetics BP=Blood pressure, CV=Cardiovascular Source: Hansson L et al. Lancet 1998;351:1755-1762
    • 27. Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control Cardio-SIS Trial 1,111 patients >55 years with SBP >150 mm Hg randomized to treatment to achieve usual BP control (SBP <140 mm Hg) or intensive BP control (SBP <130 mm Hg) 21 17.0 14 11.4 7 0 Usual Control P=0.003 15 Composite of CV events* (%) Incidence of LVH (%) P=0.013 Tight Control 10 9.4 4.8 5 0 Usual Control Tight Control More intensive blood pressure control provides greater benefit *Composite of death, MI, CVA, TIA, CHF, angina, new AF, revascularization, aortic dissection, PAD, and ESRD AF=Atrial fibrillation, ESRD=End stage renal disease, CHF=Congestive heart failure, CVA=Cerebrovascular accident, LVH=Left ventricular hypertrophy, MI=Myocardial infarction, PAD=Peripheral artery disease, SBP=Systolic blood pressure, TIA=Transient ischemic attack Source: Verdecchia P et al. Lancet 2009;374:525-533
    • 28. Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Control International Verapamil-Trandolapril Study (INVEST)—DM Substudy 6,400 diabetic patients from the INVEST study grouped by tight (<130 mm Hg), usual (>130 to <140 mm Hg), or uncontrolled (>140 mm Hg) blood pressure HR=1.15, p=0.036 Tight BP control is not associated with reduced adverse CV events BP=Blood pressure, CV=Cardiovascular Source: Cooper-DeHoff RM et al. JAMA 2010;304:61-68
    • 29. Blood Pressure Lowering Therapy Evidence: Effect of Intensive Blood Pressure Controlto Control Cardiovascular Risk in Diabetes (ACCORD) Action Blood Pressure Trial 4,733 diabetic patients randomized to intensive BP control (target SBP <120 mm Hg) or standard BP control (target SBP <140 mm Hg) for 4.7 years 20 15 10 5 0 Patients with Events (%) HR=0.88 95% CI (0.73-1.06) Total stroke Patients with Events (%) Nonfatal MI, nonfatal stroke, or CV death 20 HR=0.59 95% CI (0.39-0.89) 15 10 5 0 0 1 2 3 4 5 6 7 Years Post-Randomization 8 0 1 2 3 4 5 6 7 8 Years Post-Randomization Intensive BP control in DM does not reduce a composite of adverse CV events, but does reduce the rate of stroke BP=Blood pressure, DM=Diabetes mellitus, HR=Hazard ratio, SBP=Systolic blood pressure ACCORD study group. NEJM 2010;362:1575-1585
    • 30. JNC VII Guidelines: Management and Treatment Initial drug therapy BP classification SBP* mmHg DBP* mmHg Lifestyle modification Without compelling indications With compelling indications <120 and <80 Encourage Prehypertension 120–139 or 80–89 Yes No antihypertensive drug indicated. Stage 1 Hypertension 140–159 or 90–99 Yes Stage 2 Hypertension >160 or >100 Yes Thiazide-type diuretics for most. May consider ACE-I, ARB, BB, CCB, or combination Drug(s) for compelling of these. indications.‡ 2-drug combination for most† Other antihypertensive (usually thiazide-type diuretic drugs (as needed). and ACE-I or ARB or BB or CCB). Normal Drug(s) for compelling indications.‡ *Treatment determined by highest blood pressure category Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension ‡ Treat patients with chronic kidney disease or diabetes mellitus to blood pressure goal of <130/80 mmHg † ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=Beta-blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 31. JNC VII Guidelines: Lifestyle Modifications for BP Control Modification Recommendation Approximate SBP Reduction Range Weight reduction Maintain normal body weight (BMI=18.525) 5-20 mmHg/10 kg weight lost DASH eating plan Diet rich in fruits, vegetables, low fat dairy and reduced in fat 8-14 mmHg Restrict sodium intake <2.4 grams of sodium per day 2-8 mmHg Physical activity Regular aerobic exercise for at least 30 minutes most days of the week 4-10 mmHg Moderate alcohol <2 drinks/day for men and <1 drink/day for women 2-4 mmHg BMI=Body mass index, BP=Blood pressure, SBP=Systolic blood pressure Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 32. JNC VII Guidelines: Compelling Indications for Drug Classes Compelling Indication Initial Therapy Options Clinical-Trial Basis Heart Failure Diuretic, BB, ACE-I, ARB, Aldo ANT MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES Post-MI BB, ACE-I, Aldo ANT ACC/AHA Post-MI Guidelines, BHAT, SAVE, Capricorn, EPHESUS High CAD Risk Diuretic, BB, ACE-I, CCB ALLHAT, HOPE, ANBP2, LIFE, CONVINCE Diabetes Mellitus Diuretic, BB, ACE-I, ARB, CCB NKF-ADA Guideline, UKPDS, ALLHAT Chronic Kidney Disease ACE-I, ARB NKF Guidelines, Captopril Trial, RENAAL, IDNT, REIN, AASK Recurrent Stroke Prevention Diuretic, ACE-I PROGRESS ACE-I=Angiotensin converting enzyme inhibitor, Aldo ANT=Aldosterone antagonist, ARB=Angiotensin receptor blocker, BB=Beta-blocker, CAD=Coronary artery disease, CCB=Calcium channel blocker, MI=Myocardial infarction Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 33. JNC VII Guidelines: Blood Pressure Treatment Algorithm Lifestyle modifications Not at goal BP (<140/90 mm Hg) (<130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) Initial drug choices WITHOUT compelling indications Stage 1 hypertension (SBP 140–159 mm Hg or DBP 90–99 mm Hg): Thiazide-type diuretic for most. May consider ACEI, ARB, BB, CCB, or combo. WITH compelling indications Stage 2 hypertension (SBP ≥160 or DBP ≥100 mm Hg): Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Drugs for compelling indications: Other antihypertensive drugs (diuretic, ACEI, ARB, BB, CCB) as needed. Not at goal BP Optimize dosages or add additional drugs until goal BP is achieved. Consider consultation with hypertension specialist. ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=Beta-blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure Source: Chobanian AV et al. JAMA 2003;289:2560-2572
    • 34. Blood Pressure Recommendations Primary and Secondary Prevention I IIa IIb III Counsel regarding the need for lifestyle modification: weight control; increased physical activity; alcohol moderation; sodium reduction; and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products. Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    • 35. AHA Primary Prevention of CV Disease in DM Blood Pressure Recommendations Primary Prevention • BP should be measured at every routine visit. Patients with a SBP >130 mm Hg or DBP >80 mm Hg should have BP confirmed on a separate day. • Patients should be treated to a SBP <130 mm Hg and a DBP <80 mm Hg. • Patients with a SBP of 130-139 mm Hg or a DBP of 80-89 mm Hg should initiate lifestyle modification* alone for a maximum of 3 months. If, after these efforts, targets are not achieved, treatment with pharmacological agents should be initiated. *Includes weight control, increased physical activity, alcohol moderation, sodium reduction, and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products AHA=American Heart Association, BP=Blood pressure, CV=Cardiovascular, DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure Source: Buse JB et al. Circulation 2007;115:114-126
    • 36. AHA Primary Prevention of CV Disease in DM Blood Pressure Recommendations (Continued) Primary Prevention • Multiple-drug therapy is generally required to achieve BP targets. • In elderly hypertensive patients, BP should be lowered gradually to avoid complications. • Orthostatic measurement of BP should be performed when clinically indicated. • Patients not achieving target BP despite multiple-drug therapy should be referred to a physician specializing in the care of patients with hypertension. AHA=American Heart Association, BP=Blood pressure, CV=Cardiovascular, DM=Diabetes Mellitus Source: Buse JB et al. Circulation 2007;115:114-126
    • 37. ADA Blood Pressure Recommendations for Patients with Diabetes Mellitus Primary Prevention • BP should be measured at every routine DM visit. Patients found to have a SBP >130 mm Hg or a DBP >80 mm Hg should have BP confirmed on a separate day. A repeat SBP >130 mm Hg or a repeat DBP >80 mm Hg confirms a diagnosis of hypertension. • Patients with DM should be treated to a SBP <130 mm Hg. • Patients with DM should be treated to a DBP <80 mm Hg. • Patients with a SBP 130-139 mm Hg or a DBP 80-89 mm Hg may be given lifestyle therapy alone for a maximum of 3 months, and then if targets are not achieved, patients should have pharmacologic agents added. ADA=American Diabetes Association, BP=Blood pressure, DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
    • 38. ADA Blood Pressure Recommendations for Patients with Diabetes Mellitus (Continued) Primary Prevention • Patients with more severe hypertension (SBP >140 mm Hg or DBP >90 mm Hg) at diagnosis or follow-up should receive pharmacologic therapy in addition to lifestyle therapy. • Lifestyle therapy for hypertension consists of weight loss if overweight, DASH-style dietary pattern including reducing sodium and increasing potassium intake, moderation of alcohol intake, and increased physical activity. ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, BP=Blood pressure, DBP=Diastolic blood pressure, DM=Diabetes mellitus, GFR=Glomerular filtration rate, SBP=Systolic blood pressure Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
    • 39. ADA Blood Pressure Recommendations for Patients with Diabetes Mellitus (Continued) Primary Prevention • Pharmacologic therapy for patients with DM and hypertension should be paired with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. If needed to achieve BP targets, a thiazide diuretic should be added to those with an estimated GFR >30 ml/min and a loop diuretic with an estimated GFR <30 ml/min. • Multiple drug therapy (two or more agents at maximal doses) is generally required to achieve BP targets. ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus, GFR=Glomerular filtrate rate Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
    • 40. Blood Pressure Recommendations Secondary Prevention I IIa IIb III Use of an ACE inhibitor and/or beta-blocker in those with BP >140/90 mmHg*. Other drugs should be added in order to achieve the desired BP. *A BP >130/80 mmHg should be used for individuals with CKD or DM ACE=Angiotensin converting enzyme, BP=Blood pressure, CKD=Chronic kidney disease, DM=Diabetes mellitus Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    • 41. Evidence for Current Cardiovascular Disease Prevention Guidelines Angiotensin Converting Enzyme Inhibitor Evidence and Guidelines
    • 42. ACE Inhibitor: Mechanism of Action Angiotensin II ACE Inactive Fragments Inhibitor Angiotensin I Bradykinin Renin Angiotensinogen Sympathetic Vasopressin Aldosterone Vasoconstriction Kininase II Kininogen Kallikrein tPA Vasodilation Prostaglandins ACE=Angiotensin converting enzyme
    • 43. ACE Inhibitor Evidence: Secondary Prevention Heart Outcomes Prevention and Evaluation (HOPE) Study CV death, MI, or stroke (%) 9,297 patients with DM or vascular disease plus an additional CV risk factor, but without HF or known LVSD randomized to ramipril (10 mg) or placebo for 5 years 0.20 Placebo 0.15 0.10 Ramipril 0.05 0.00 22% RRR, P<0.001 0 500 1000 1500 Days of Follow-Up An ACE inhibitor provides benefit in high-risk individuals ACE=Angiotensin converting enzyme, DM=Diabetes mellitus, CV=Cardiovascular, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction Source: HOPE Investigators. NEJM 2000;342:145-153
    • 44. ACE Inhibitor Evidence: Secondary Prevention on Reduction of Cardiac Events with Perindopril European Trial in Stable Coronary Artery Disease (EUROPA) 12,218 patients with CAD and presumed normal LV function randomized to perindopril (8 mg) or placebo for 4 years Cardiovascular death (0.86; 0.72-1.03) Non-fatal MI (0.78; 0.20-0.90) Cardiac arrest (0.54; 0.20-1.47) Combined endpoint (0.80; 0.71-0.91) 0 0.5 Favors Perindopril 1 2 1.5 Favors Placebo An ACE inhibitor provides benefit in intermediate-risk individuals ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction Source: EUROPA Investigators. Lancet 2003;362:782-788
    • 45. ACE Inhibitor Evidence: Secondary Prevention of Events with Angiotensin Converting Enzyme Prevention Inhibition (PEACE) Trial 8,290 patients with stable CAD and normal LV function randomized to trandolapril (4 mg) or placebo for 5 years Primary End Point (%)* 30 Placebo Trandolapril 25 20 15 10 5 0 0 1 2 3 4 5 6 Years After Randomization An ACE inhibitor does not provide benefit in lower-risk individuals *Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, LV=Left ventricular Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
    • 46. ACE Inhibitor Evidence: Secondary Prevention Comparison between the HOPE and PEACE trials MI, Cardiac death, or Stroke (%) HOPE, placebo HOPE, active drug (ramipril) PEACE, placebo Years Patients enrolled in the PEACE trial were lower risk* *Reflects better blood pressure control, revascularization, and use of other risk-reducing medications (i.e., antiplatelet therapy, beta-blocker, lipid-lowering medication) CHD=Coronary heart disease, MI=Myocardial infarction Source: The PEACE Trial Investigators. NEJM 2004;351:2058-2068
    • 47. ACE Inhibitor Evidence: Secondary Prevention Meta-Analysis of the HOPE, EUROPA, and PEACE Trials* Clinical Trial N HOPE 9,297 Deaths RR of Mortality 1051 HR=0.84 P=0.005 EUROPA 12,218 795 HR=0.89 P=0.10 PEACE 8,290 633 HR=0.89 P=0.13 33,960 >3000 HR=0.86 P<0.001 All Trials 0.4 0.6 0.8 ACE-I Better 1.0 1.2 1.4 1.6 Placebo Better *7 RCTs, 33,960 randomized patients, and 4.4 years of mean follow-up. Other findings include a CV mortality HR=0.81, MI HR=0.82, and stroke HR=0.77 ACE-I=Angiotensin converting enzyme inhihbitor, MI=Myocardial infarction Sources: Danchin N et al. Arch Intern Med 2006;166:787-796 The HOPE Trial Investigators. NEJM 2000;342:145-153 The EUROPA Study. Lancet 2003; 362: 782-788 The PEACE Trial Investigators. NEJM 2004;351:2058-2068
    • 48. ACE Inhibitor Evidence: Secondary Prevention TRACE AIRE Radionuclide EF <40% Probability of Event SAVE Clinical and/or radiographic signs of HF Echocardiogram EF <35% 0.4 0.35 Placebo 0.3 ACE-I 0.25 0.2 0.15 0.1 0.05 0 OR 0.74 (0.66–0.83) 0 1 2 3 4 Years An ACE-I provides substantial benefit in post-MI LVSD ACE-I=Angiotensin converting enzyme inhibitor, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio Source: Flather MD et al. Lancet 2000;355:1575–1581
    • 49. ACE Inhibitor Recommendations Secondary Prevention I IIa IIb III An ACE inhibitor should be started and continued indefinitely in all patients with left ventricular ejection fraction <40% and in those with hypertension, DM, or CKD, unless contraindicated I IIa IIb III An ACE inhibitor in all other patients ACE=Angiotensin converting enzyme, CKD=Chronic kidney disease, DM=Diabetes mellitus, LVSD=Left ventricular systolic dysfunction Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    • 50. AHA Primary Prevention of CV Disease in DM Blood Pressure Recommendations Primary Prevention • Patients with a SBP >140 mm Hg or DBP >90 mm Hg should receive drug therapy in addition to lifestyle and behavioral therapy. • All patients with hypertension should be treated with a regimen that includes an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. Other drug classes* that have been demonstrated to reduce CVD events should be added as needed to achieve BP targets. • If ACE inhibitors, ARBs, or diuretics are used, renal function and serum potassium levels should be monitored within the first 3 months. If stable, follow-up could occur every 6 months. *Includes beta-blockers, thiazide diuretics, and calcium channel blockers ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, BP=Blood pressure, CV=Cardiovascular, CVD=Cardiovascular disease, DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure Source: Buse JB et al. Circulation 2007;115:114-126
    • 51. ADA Blood Pressure Recommendations for Patients with Diabetes Mellitus (Continued) Primary Prevention • If an ACE inhibitor, ARB, or diuretic is used, kidney function and serum potassium levels should be closely monitored. • In pregnant patients with DM and chronic hypertension, BP target goals of 110-129/65-79 mm Hg are suggested in the interest of long-term maternal health and minimizing impaired fetal growth. • An ACE inhibitor and ARB are contraindicated during pregnancy. ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
    • 52. Evidence for Current Cardiovascular Disease Prevention Guidelines Angiotensin Receptor Blocker Evidence and Guidelines
    • 53. Angiotensin Receptor Blocker: Mechanism of Action Renin Angiotensinogen Other Pathways AT I Receptor Blocker ATI Angiotensin I Angiotensin II Receptors ACE AT II Receptor Blocker ATII Vasoconstriction Proliferative Vasodilation Action Antiproliferative Action
    • 54. Angiotensin Receptor Blocker Evidence: Secondary Prevention Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial 2,028 patients with symptomatic HF, LVSD (EF <40%), and intolerance to ACE inhibitor randomized to candesartan (32 mg) or placebo for 34 months CV Death or Hospitalization for HF 50 Placebo 40 30 Candesartan 20 10 HR 0.77 p=0.0004 0 0 1 2 Years 3 An ARB provides benefit in those intolerant of an ACE inhibitor ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, CV=Cardiovascular, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction Source: Granger CB et al. Lancet 2003;362:772-777
    • 55. Angiotensin Receptor Blocker Evidence: Secondary Prevention Valsartan in Acute Myocardial Infarction Trial (VALIANT) 14,703 patients with post-MI HF or LVSD (EF <0.40) randomized to captopril (50 mg tid), valsartan (160 mg bid), or captopril (50 mg tid) plus valsartan (80 mg bid) for 2 years All Cause Mortality 0.4 Captopril Valsartan Valsartan and Captopril 0.3 0.2 0.1 0.0 Valsartan vs. Captopril: HR = 1.00; P = 0.982 Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726 0 6 12 18 24 30 36 Months An ARB provides similar efficacy to an ACE inhibitor in Post-MI LVSD ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction Source: Pfeffer M et al. NEJM 2003;349:1893-1906
    • 56. Angiotensin Receptor Blocker Evidence: Secondary Prevention Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) Added Trial 2,548 patients with symptomatic HF and LVSD (EF <40%) randomized to candesartan (32 mg) or placebo in addition to an ACE inhibitor for 34 months CV Death or Hospitalization for HF 50 40 Placebo 30 Candesartan 20 10 HR 0.85, p=0.011 0 0 1 2 Years 3 Addition of an ARB to an ACE inhibitor may provide benefit in those with LVSD ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction Source: McMurray JJ et al. Lancet 2003;362:767-771
    • 57. Angiotensin Receptor Blocker Evidence: Secondary Prevention Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) Non-inferiority Margin 25,620 patients with CVD or DM randomized to ramipril (10 mg), telmisartan (80 mg), or a combination of both for 56 months Primary Composite (p = 0.003) CV Death / MI / Stroke / Hospitalization for Heart Failure CV Death / MI / Stroke (HOPE Composite) (p = <0.001) Telmisartan better 0.8 Ramipril better 0.9 1.0 1.1 1.2 RR (95% CI) An ARB provides similar efficacy to an ACE-I in high risk patients ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, CVD=Cardiovascular disease, DM=Diabetes mellitus, MI=Myocardial infarction Source: ON TARGET Investigators. NEJM 2008;358:1547-1559
    • 58. Angiotensin Receptor Blocker Evidence: Secondary Prevention Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) 25,620 patients with CVD or DM randomized to ramipril (10 mg), telmisartan (80 mg), or a combination of both for 56 months CV Death, MI, Stroke, or Hospitalization for Heart Failure 0.20 Telmisartan plus ramipril* Telmisartan 0.15 Ramipril 0.10 *Dual RAS blockade leads to greater renal impairment HR=1.33 (p<0.001) 0.05 0.00 0 1 2 3 Follow-up (years) 4 5 Dual RAS blockade provides no additional benefit but leads to greater renal impairment CVD=Cardiovascular disease, DM=Diabetes mellitus, MI=Myocardial infarction, RAS=Renin angiotensin system Source: ON TARGET Investigators. NEJM 2008;358-1547-1559
    • 59. Angiotensin Receptor Blocker Evidence: Secondary Prevention Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) 5,926 high risk patients intolerant to ACE inhibitors randomized to telmisartan (80 mg) or placebo for 56 months Percent of patients P=0.055 P=0.216 P=0.048 * An ARB is well tolerated in those unable to take an ACE inhibitor *Primary endpoint is a composite of CV death, MI, stroke or heart failure hospitalization ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, CV=Cardiovascular, MI=Myocardial infarction Source: TRANSCEND Investigators. Lancet. 2008;372:1174-83
    • 60. Angiotensin Receptor Blocker Recommendations Secondary Prevention I IIa IIb III An ARB in patients who have HF or who have had a MI with left ventricular ejection fraction <40% and who are ACE-inhibitor intolerant I IIa IIb III An ARB in other patients who are intolerant of an ACE inhibitor I IIa IIb III Use of an ARB in combination with an ACE inhibitor is not well established in those with systolic heart failure ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, HF=Heart failure, MI=Myocardial infarction Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    • 61. AHA Primary Prevention of CV Disease in DM Blood Pressure Recommendations Primary Prevention • Patients with a SBP >140 mm Hg or DBP >90 mm Hg should receive drug therapy in addition to lifestyle and behavioral therapy. • All patients with hypertension should be treated with a regimen that includes an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted. Other drug classes* that have been demonstrated to reduce CVD events should be added as needed to achieve BP targets. • If ACE inhibitors, ARBs, or diuretics are used, renal function and serum potassium levels should be monitored within the first 3 months. If stable, follow-up could occur every 6 months. *Includes beta-blockers, thiazide diuretics, and calcium channel blockers ACE=Angiotensin converting enzyme, ARB=Angiotensin receptor blocker, BP=Blood pressure, CV=Cardiovascular, CVD=Cardiovascular disease, DBP=Diastolic blood pressure, DM=Diabetes mellitus, SBP=Systolic blood pressure Source: Buse JB et al. Circulation 2007;115:114-126
    • 62. ADA Blood Pressure Recommendations for Patients with Diabetes Mellitus (Continued) Primary Prevention • If an ACE inhibitor, ARB, or diuretic is used, kidney function and serum potassium levels should be closely monitored. • In pregnant patients with DM and chronic hypertension, BP target goals of 110-129/65-79 mm Hg are suggested in the interest of long-term maternal health and minimizing impaired fetal growth. • An ACE inhibitor and ARB are contraindicated during pregnancy. ACE=Angiotensin converting enzyme, ADA=American Diabetes Association, ARB=Angiotensin receptor blocker, BP=Blood pressure, DM=Diabetes mellitus Source: American Diabetes Association. Diabetes Care 2010;33:S11-61
    • 63. Evidence for Current Cardiovascular Disease Prevention Guidelines Beta-blocker Evidence and Guidelines
    • 64. Beta-blocker: Targets and Receptor Selectivity Heart Inotropy Chronotropy Dromotropy + + + _ a2 b1 b2 a1 M2 β1 selective blocker β non-selective blocker β non-selective blocker with α1 blocking activity Parasympathetic Nerve Terminal NE _ _ Blood Vessel a2 _ NE a2 NE + M2 b2 Vasoconstriction a1 Vasoconstriction b2 Vasodilation M2 Vasodilation Sympathetic Nerve Terminal ACh Sympathetic Cholinergic Nerve Terminal a=Alpha receptor, Ach=Acetylcholine, b=Beta receptor, M=Muscarinic receptor, NE=Norepinephrine Source: Klabunde, RE (ed) Cardiovascular Physiology Concepts LWW 2001
    • 65. Beta-blocker Evidence: Secondary Prevention Placebo-controlled post-MI trials* using oral beta-blockers Study Patients (N) Treatment Groups Duration of Follow-Up Effect on Mortality Effect on Reinfarction Göteborg Study† 1,395 Metoprolol tartrate 3 months ↓ 36% (P<.03) P=NS Timolol Trial (Norwegian) 1,884 Timolol 17 months ↓ 39% (P=.003) ↓ 28% (P=.0005) Lopressor Intervention Trial 2,395 Metoprolol tartrate 12 months P=NS NA Beta-blocker Heart Attack Trial 3,837 Propranolol 25 months ↓ 26% (P<.005) P=NS CAPRICORN Trial 1,959 Carvedilol 15 months ↓ 23% (P=.03) ↓ 40% (P=.01) † *Includes the largest trials performed to date Patients received IV followed by oral metoprolol MI=Myocardial infarction, NA=Not applicable, NS=Not significant
    • 66. Beta-blocker Evidence: Secondary Prevention Summary of secondary prevention trials of beta-blocker therapy Phase of Treatment Total # Patients RR (95% CI) Acute treatment 28,970 0.87 (0.77-0.98) Secondary prevention 24,298 0.77 (0.70-0.84) Overall 53,268 0.81 (0.75-0.87) 0.5 1.0 RR of death Beta-blocker Placebo better better 2.0 CI=Confidence interval, RR=Relative risk Source: Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
    • 67. Beta-blocker Evidence: Benefit in HF and/or LVSD Study Drug HF Severity Patients (n) Follow-up Mean Dosage Effects on Outcomes CIBIS Bisoprolol* ModerateSevere 641 1.9 Years 3.8 mg/day All cause mortality (p=NS) CIBIS-II Bisoprolol* ModerateSevere 2,647 1.3 Years 7.5 mg/day All cause mortality ↓34% (P<0.0001) BEST Bucindolol* ModerateSevere 2,708 2.0 Years 152 mg/day All cause mortality (p=NS) MERIT-HF Metoprolol succinate# MildModerate 3,991 1.0 Years 159 mg/day All cause mortality ↓34% (P=0.0062) MDC Metoprolol tartrate* MildModerate 383 1.0 Years 108 mg/day Death or Need for TX (P=NS) CAPRICORN Carvedilol Mild 1,989 1.3 Years 40 mg/day All cause mortality ↓23% (P =0.03) US Carvedilol Carvedilol MildModerate 1,094 0.5 Years 45 mg/day All-cause mortality† ↓65% (P=.0001) COPERNICUS Carvedilol Severe 2,289 0.9 Years 37 mg/day All-cause mortality ↓35% (P =0.0014) SENIORS Nebivolol Moderate 2,128 3.0 Years 7.7 mg/day All-cause mortality or CV hospitalization ↓14% (P =0.039) *Not an approved indication, † Not a planned end point # Not approved for severe HF/mortality reduction alone HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NS=Not significant, TX=Transplant
    • 68. Beta-Blocker Recommendations Secondary Prevention I IIa IIb III Beta-blocker should be used in all patients with LVSD (ejection fraction <40%) with HF or prior MI, unless contraindicated*. (Use should be limited to carvedilol, metoprolol succinate, or bisoprolol, which have been shown to reduce mortality.) I IIa IIb III Beta-blocker for 3 years in all patients with normal left ventricular function who have had a MI or ACS I IIa IIb III Beta-blocker beyond 3 years as chronic therapy in all patients with normal left ventricular function who have had a MI or ACS *Relative contraindications include asthma, chronic obstructive pulmonary disease, insulin dependent diabetes mellitus, severe peripheral arterial disease, and a PR interval >0.24 seconds ACS=Acute coronary syndrome, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction Source: Smith SC Jr. et al. JACC 2011;58:2432-2446
    • 69. Beta-Blocker Recommendations (Continued) I IIa IIb III Secondary Prevention Beta-blocker in patients with LVSD (ejection fraction <40%) without HF or prior MI I IIa IIb III Beta-blocker as chronic therapy for all other patients with coronary or other vascular disease HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction Source: Smith SC Jr. et al. JACC 2011;58:2432-2446

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