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Abstract

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

Identification and management of cardiovascular (CV) risk factors are essential to help prevent CV disease and slow its progression. Long-term epidemiologic data show that hypertension is associated with a two- to four-fold increase in CV morbidity and mortality; moreover, antihypertensive therapy has been proven to significantly reduce the risk of CV events. Clinical trial data also suggest that different antihypertensive agents generally provide similar reductions in CV risks and outcomes. Beta blockers have historically played an integral role in hypertension treatment, particularly among patients at high CV risk; however, a recent meta-analysis, based primarily on the use of atenolol, found that β blockers may provide less clinical benefit as initial therapy than other classes of antihypertensive agents. Beta blockers are heterogeneous, and atenolol data may not be representative of other β blockers. Newer β blockers, which provide both cardioselective β2-adrenergic receptor blockade and endothelium-dependent vasodilation, may prove to be more effective in reducing CV morbidity and mortality. Intensive strategies to control global CV risk have been shown to significantly reduce CV events. The challenge remains to develop effective risk assessment tools to identify at-risk patients who often go undetected.

The primary goal of antihypertensive therapy is to prevent cardiovascular (CV) complications.1 Current research has therefore focused on prevention of early CV disease (CVD) through detection of patients at risk and through control of their CV risk factors.2 Increasing evidence has also suggested that CV risk factors are not only precipitators but continuous pathogenic components at every stage of the progression of CVD.3 Therefore, control of elevated blood pressure (BP) and other CV risk factors is essential for prevention of CVD.

CV risk factors such as increased age, smoking, physical inactivity, obesity, dyslipidemia, hypertension, and glucose intolerance, which are strongly associated, combine and interact with inherited genetic factors to form a risk burden.3 CVD results when the risk burden overwhelms endogenous, physiologic defense mechanisms against atherogenesis. In the current disease model of CVD, risk factors stimulate increased activity of inflammatory enzymes such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate, as well as nitric oxide (NO) synthase, which can become “uncoupled” under conditions of oxidative stress to produce peroxynitrite, a reactive oxygen species, rather than vasodilating NO.3 The resulting increase in oxidative stress causes endothelial dysfunction, thus impairing the essential endogenous vasodilatory, antioxidant, and antithrombotic actions of the endothelium.3 Endothelial dysfunction and loss of vascular homeostasis then leads to pathogenic functional and structural alterations, including increased vasoconstriction and inflammation, platelet aggregation and adhesion, atherosclerotic plaque formation, and vascular remodeling.3 These changes promote the clinical sequelae of overt CVD, such as ischemic heart disease, myocardial infarction (MI) and stroke, target organ remodeling and dysfunction, target organ failure, and death.3 Based on this progressive syndrome, an effective strategy to manage global CV risk must include early therapy to control both clinical risk factors, such as obesity and hypertension, and more occult factors, such as endothelial dysfunction.

The continuous role of hypertension through all stages of CVD has been clearly illustrated by a prospective longitudinal analysis of 36-year follow-up data from the Framingham Heart Study.4 This analysis showed that the presence of hypertension in both men and women caused a two- to four-fold increased risk in virtually all major CV outcomes, including coronary heart disease (CHD), stroke, peripheral artery disease, and heart failure (HF) (Figure 1).4 Conversely, meta-analyses of randomized clinical trials prove that long-term antihypertensive therapy achieves reductions of 35%–40% in stroke, 20%–25% in MI, and >50% in the incidence of HF.5 While the benefits of lowering BP with antihypertensive therapy are clear, the optimal strategies for antihypertensive treatment have been a topic of ongoing research and controversy.

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Figure 1. A prospective longitudinal analysis of 36-year follow-up data from the Framingham Heart Study showed that the presence of hypertension among both men and women 35–64 years of age caused two- to four-fold increased risks in major cardiovascular outcomes, including coronary heart disease, stroke, peripheral artery disease, and heart failure. Reproduced with permission from JAMA. 1996;275:1571–1576.4

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OVERVIEW OF HYPERTENSION TREATMENT

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

The treatment of hypertension has evolved with the proliferation of many classes of antihypertensive agents over the past 30 years. This trend is well documented by the recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) in its hypertension treatment guidelines that have been issued every few years beginning in 1977. The first report, JNC I, recommended stepped-care treatment using a diuretic, with addition of methyldopa, reserpine, or propranolol as needed; JNC II, in 1980, revised this as stepped-care treatment using diuretic and adrenergic-inhibiting agents.6,7 The JNC III through VI reports recommended first-step therapy with either thiazide diuretics or β blockers.8–11 Beginning with JNC IV in 1988, angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) were also recommended as secondary options for drug therapy.9 In JNC VI, angiotensin II receptor blockers (ARBs) were recommended for renal and cardiac target organ protection in patients intolerant of ACE inhibitors.11

In 2003, the JNC 7 report recommended thiazide diuretics as initial therapy for most patients, while noting that ARBs, ACE inhibitors, β blockers, or CCBs could also be considered as options for first-step drug treatment.1 The JNC 7 report also recommended combination drug therapy for initial treatment of stage 2 hypertension (systolic BP [SBP] ≥160 mm Hg/diastolic BP [DBP] ≥100 mm Hg) in most patients.1 It is important to note that despite ongoing debate over the comparative efficacy of different antihypertensive agents and the optimal initial drug therapy for hypertension, major studies have shown that most hypertensive patients require combination therapy with two or more drugs to reach their recommended BP goal.12–14

Thiazide diuretics were among the first effective antihypertensive drug therapies to be developed and have long served as a cornerstone of hypertension treatment.15 The most prominent concern of thiazide-type diuretics is their tendency to cause metabolic effects such as increases in blood glucose, total cholesterol, and low-density lipoprotein cholesterol, which could potentially adversely affect CV outcomes, particularly among patients with diabetes mellitus.16 In the Systolic Hypertension in the Elderly Program (SHEP) study,16 however, which was conducted in 4736 men and women aged 60 years and older at baseline with isolated systolic hypertension, treatment with the thiazide diuretic chlorthalidone achieved 5-year relative risk reductions (RRRs) of 34% in major CV events among both diabetic and nondiabetic patients, compared with placebo. Indeed, absolute risk reductions with chlorthalidone were twice as great in diabetic compared with nondiabetic patients, reflecting the higher CV risks among those with diabetes.16

Thiazide-type diuretics were recommended by JNC 7 as preferred first-line agents for hypertension based primarily on the results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),13 conducted in 33,357 patients aged 55 years and older with hypertension and at least one other risk factor for CHD. In ALLHAT, there were no significant differences among antihypertensive therapy regimens based on initial therapy with chlorthalidone, the CCB amlodipine, or the ACE inhibitor lisinopril for the primary composite outcome of fatal CHD or nonfatal MI.13 However, chlorthalidone appeared to reduce the risk of the secondary outcomes of HF, stroke, and combined CVD to a significantly greater degree than lisinopril, and HF to a significantly greater degree than amlodipine.13

The results of ALLHAT are generally consistent with previous large-scale trials that compared newer antihypertensive agents, primarily ACE inhibitors and CCBs, with conventional therapy with diuretics or β blockers.5 An analysis of pooled data from these trials preceding ALLHAT—including the Swedish Trial in Old Patients with Hypertension 2 (STOP-2), United Kingdom Prospective Diabetes Study (UKPDS), and the Captopril Prevention Project (CAPPP) in a total of more than 16,000 patients—showed that diuretic or β-blocker therapy and ACE inhibitors had very similar effects on stroke, CV outcomes, and total mortality (Figure 2).5 Similarly, a pooled analysis of trials comparing CCBs with diuretic or β-blocker therapy—including the International Nifedipine GITS Intervention as a Goal in Hypertension Treatment (INSIGHT), National Interventional Cooperative Study in Elderly Hypertensives (NICH-ES), STOP-2, Nordic Diltiazem (NORDIL), and the Verapamil in Hypertension and Atherosclerosis Study (VHAS) in a total of more than 23,000 patients—found that the two treatment strategies had similar effects on most CV outcomes, with possible advantages with CCBs in reducing stroke risks and with diuretic/β-blocker therapy in preventing CHD and HF events.5

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Figure 2. An analysis was conducted of pooled data from major trials comparing the effects of angiotensin-converting enzyme inhibitors (ACEIs) with “conventional” therapy consisting of either diuretics or β blockers, including the Swedish Trial in Old Patients with Hypertension 2 (STOP-2), the United Kingdom Prospective Diabetes Study (UKPDS), and the Captopril Prevention Project (CAPPP). The analysis showed that diuretic or β-blocker therapy and ACEI therapy had very similar effects on stroke, cardiovascular (CV) outcomes, and total mortality. CI=confidence interval; CHD=coronary heart disease; HF=heart failure. Adapted from Lancet. 2000;356:1955–1964.5

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Overall, the results of multiple trials demonstrate that antihypertensive agents significantly reduce CV morbidity and mortality, compared with placebo. When antihypertensive agents from different drug classes have been compared head-to-head in outcomes trials, they have generally demonstrated reductions in the risk of CV events. Differences that have been observed between therapies, often in secondary outcomes, may be attributable to differences in BP reduction achieved during the course of some trials.

THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

Substantial data in a broad range of patient populations and risk groups have established that β blockers significantly reduce CV morbidity and mortality in patients with hypertension and concomitant conditions.1 Based on these data, the JNC 7 report recommends β blockers as preferred agents in patients with post-MI, high CHD risk, diabetes, or HE1 However, doubts have been raised about the efficacy of β blockers as initial therapy in older patients.17 These concerns are largely based on trials involving the β blocker atenolol, which is still one of the most widely prescribed antihypertensive agents in the United States.18 In the Medical Research Council trial of hypertension treatment, for example, 4396 hypertensive patients between 65 and 74 years of age were randomized to treatment with atenolol 50 mg once daily, the thiazide diuretic hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg once daily, or placebo. After a mean follow-up of 5.8 years, the diuretic treatment had significantly reduced risks of stroke, CHD, all CVD events, and death, while atenolol treatment showed no significant reductions in these end points, compared with placebo despite similar BP reduction.

In addition, a meta-analysis was conducted of 13 randomized, controlled trials involving a total of 105,951 patients that compared β blockers with other antihypertensive drugs, and seven other studies involving 27,433 patients comparing β blockers with placebo or no treatment.19 This analysis found that the relative risk of stroke was 16% higher with β blockers compared with other antihypertensive agents (p=0.009). Similar risk reductions were observed, however, between β blockers and other antihypertensive agents in MI and total mortality. The vast majority of patients in these trials had received atenolol as β-blocker therapy.19 Indeed, atenolol alone was associated with a 26% higher risk of stroke compared with other antihypertensive agents (n=56,301; p<0.001).

The single large trial that is most often cited to support the use of atenolol is the UKPDS study,20 in which an atenolol-based regimen was as effective as one based on the ACE inhibitor captopril in reducing CV risk in hypertensive patients with type 2 diabetes mellitus. However, atenolol was dosed at twice daily in that study, rather than once daily as in most other trials.20,21 Atenolol was also dosed twice daily in the International Verapamil SR/Trandolapril Study (INVEST),22 in which atenolol was as effective as verapamil SR in reducing the primary composite CHD morbidity and mortality end point, in patients with hypertension and CHD. Therefore, the effects of atenolol on CV outcomes may vary significantly according to the dosage used and, based on its variable half-life, if given more than once daily.

These variables cast considerable doubt on whether the sum of trial data with atenolol can be used as an accurate representation of the effects of other β blockers on CV outcomes. In addition, the β-blocker class is perhaps the most heterogeneous of all the antihypertensive drug classes. Beta blockers vary in important pharmacologic properties, including β12-adrenergic receptor selectivity and vasodilator effects. The β1 receptor is the primary adrenergic receptor of norepinephrine present in human CV tissues; norepinephrine has an affinity for the β1 receptor 20 times that for the β2 and 10 times that for α1 receptors.23 High selectivity for the β1 receptor theoretically has the advantages of focusing blockade on cardiac tissue, thereby limiting respiratory adverse events resulting from blockade of β2 receptors in the lungs. A recent comparison of the β12 selectivity ratio among commonly used β blockers showed that nebivolol has the highest β1 selectivity of available β blockers, which was more than three times higher than the next most β1-selective agent, bisoprolol (Figure 3).24

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Figure 3. The magnitude of the β12 selectivity ratio was compared among commonly used β blockers. Nebivolol demonstrated a 321-fold higher affinity for human cardiac β2- vs. β2-adrenergic receptors compared with other β blockers.

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NEBIVOLOL: A VASODILATING β BLOCKER

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

Nebivolol has demonstrated a dual mechanism of action. In addition to its highly selective blockade of the β1 receptor, this agent promotes vasodilation through stimulation of the l-arginine/NO pathway.25–29 Nebivolol is among the β blockers that are distinguished by their vasodilating action, including labetalol, bucindolol, and carvedilol, in contrast to the traditional, nonvasodilating β blockers such as atenolol.30 Nebivolol is the only β blocker clearly documented to provide vasodilation through stimulation of endothelial NO activity.30

Nebivolol is effective for once-daily dosing, with a time-to-peak plasma concentration of 0.5–2.0 hours, and elimination half-lives for the unchanged compound averaging approximately 10 hours.31 In clinical trials, nebivolol has demonstrated dose-dependent antihypertensive efficacy, similar to that of other β blockers and other antihypertensive drug classes.31,32 In one dose-ranging study, for example, 509 patients with essential hypertension (DBP ≥95 mm Hg) were randomized in double-blind fashion to placebo or nebivolol 0.5, 1.0, 2.5, 5, or 10 mg once daily for 1 month.32 After 4 weeks, nebivolol at the three highest doses of 2.5, 5, and 10 mg had significantly reduced supine DBP at trough drug level, generally in a dose-dependent manner. Similarly, at peak plasma drug level, BP was significantly reduced in a dose-dependent manner (Figure 4). There were no appreciable differences in the antihypertensive efficacy of nebivolol between trough and peak drug levels. This medication also had similar efficacy among black and nonblack patients.

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Figure 4. In a randomized, double-blind, placebo-controlled, dose-ranging study in 509 patients with essential hypertension (diastolic blood pressure [DBP] ≥95 mm Hg), 4 weeks of therapy with nebivolol at the three highest doses of 2.5, 5, and 10 mg, significantly reduced supine DBP, generally in a dose-dependent manner, compared with placebo. SBP=systolic blood pressure; *BP measured at peak drug levels (2 hours after administration).

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In addition, nebivolol has demonstrated a favorable hemodynamic profile in comparison to conventional β blockers. In one study, nebivolol and atenolol produced similar reductions in DBP and SBP, but heart rate was reduced to a greater degree with atenolol, while nebivolol significantly increased mean stroke volume (Figure 5),33 produced a small increase in cardiac output, a significant decrease in peripheral resistance, a significant increase in left ventricular (LV) end-diastolic volume, and a small decrease in LV end-systolic volume (Figure 5). In comparison, atenolol was associated with a large decrease in cardiac output, an increase in peripheral resistance, a smaller increase in LV end-diastolic volume, and an increase in LV end-systolic volume (Figure 5).

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Figure 5. In a double-blind, randomized, prospective, 2-week study, nebivolol had favorable effects compared with atenolol on systolic and diastolic left ventricular function in 25 patients with essential hypertension. Nebivolol and atenolol produced similar reductions in blood pressure, and heart rate was reduced with both agents, although to a greater degree with atenolol. Nebivolol significantly increased mean stroke volume, compared with a small increase with atenolol, and also caused a small increase in cardiac output and decreases in peripheral resistance and left ventricular end-systolic volume. In contrast, atenolol was associated with a decrease in cardiac output and increases in peripheral vascular resistance and left ventricular end-systolic volume. bpm=beats per minute. Reproduced with permission from Am J Cardiol. 2003;92:344–348.33

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These findings suggest that the BP reduction observed with atenolol might be dependent on the reduced cardiac output as a result of a marked reduction in heart rate, while the antihypertensive effect of nebivolol may be related to the reduction in peripheral resistance.33 As previously noted, β blockers are recommended as the preferred agents in hypertensive patients with overt cardiac disease, such as post-MI and HE, based on their well-documented cardioprotective effects.1 Nebivolol, which combines highly selective β-blockade with endothelium-dependent vasodilation, offers some promise in patients with CVD, including those with HE34,35

Nebivolol in HF

The understanding of HF has evolved significantly over the past 20 years, moving from a treatment paradigm based almost entirely on symptomatology, or hemodynamic factors, to a model that incorporates such vital elements as neurohormonal activation, primarily of the renin-angiotensin and sympathetic nervous systems, and cardiac remodeling.34,36 Treatment of HF has, correspondingly, expanded from the use of conventional therapies aimed at improving hemodynamic status and symptoms, such as diuretics and digoxin, to include neurohormonal activation suppressants, including ACE inhibitors, ARBs, and β blockers as well as diuretics.34,36 The β blockers bisoprolol, carvedilol, and extended-release metoprolol have each demonstrated similar 35% reductions in mortality among patients with HF when added to conventional therapy in large, randomized, controlled studies.37–39

The large trials involving bisoprolol, carvedilol, and metoprolol included patients with an average age of 63 and excluded patients with an LV ejection fraction (LVEF) >40%.40 This is in sharp contrast to epidemiologic data indicating that the average age of patients newly diagnosed with HF is 76 years41 and that up to 50% of all HF patients older than 70 years have preserved ejection fractions of >40%, or diastolic HF.42,43

The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS)40 included elderly patients with a history of HF independent of LVEF (mean age of 76 years; mean ejection fraction of 36%). After a mean follow-up of 21 months, the primary outcome had occurred in 332 patients (31.1%) in the group treated with nebivolol, compared with 375 patients (35.3%) given placebo, representing a significant 14% RRR with nebivolol (p=0.039) (Figure 6). In a subgroup of patients similar to the patient populations enrolled in the previous large-scale β-blocker trials in HF (75 years or younger and with an LVEF <35%), nebivolol was associated with a 27% RRR in the primary composite outcome and a 38% RRR for total mortality—results comparable to those observed with bisoprolol, carvedilol, and metoprolol.37–39 The results of SENIORS thus extends the benefits of β-blockade to a patient population more representative of a community-based HF population.

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Figure 6. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial, patients aged 70 years and older (n=2128) who had been hospitalized with a diagnosis of heart failure within the past 12 months, irrespective of left ventricular ejection fraction (LVEF), or an LVEF of <35% within the past 6 months, were randomized in double-blind fashion to nebivolol, titrated from 1.25 mg daily to 10 mg once daily (n=1067), or placebo (n=1061). After a mean follow-up of 21 months, the primary composite outcome (all-cause mortality or cardiovascular hospital admission) occurred in 332 patients (31.1%) in the nebivolol group, compared with 375 patients (35.3%) given placebo (p=0.039). Adapted from Eur Heart J. 2005;26:215–225.40

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FOCUS ON CV RISK FACTORS

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

The need to treat CV risk factors early and aggressively has recently come under investigation. The benefits of intensive treatment of global CV risk in high-risk patients was evaluated in the Steno-2 study,44 which compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on CV and microvascular events among 160 patients with type 2 diabetes mellitus and microalbuminuria. In this open-label, parallel-group, long-term study, 80 patients were randomized to receive conventional therapy and another 80 patients to an intensive regimen of step-wise lifestyle modification and pharmacologic treatment, including strict dietary intervention and exercise; ACE inhibitor treatment equivalent to captopril 50 mg twice daily; or if ACE inhibitor treatment was contraindicated, an ARB equivalent to losartan 50 mg twice daily, irrespective of the BP level; addition of other antihypertensive agents as needed to meet the BP goal of <130/80 mm Hg; daily vitamin and mineral supplements; and aspirin 150 mg daily. The primary end point was a composite of CV death, nonfatal MI, nonfatal stroke, revascularization, and amputation. Effects on risk factors such as BP, glucose, and lipid levels were also tracked.

After a mean follow-up of 7.8 years, the intensive, multifactorial approach achieved incremental mean reductions of 11/4 mm Hg in BP, 34 mg/dL in glucose, 34 mg/dL in low-density lipoprotein, and reduced urine microalbumin by 50 mg/d, compared with conventional care.44 A significantly greater percentage of patients in the intensive group, compared with the conventional group, reached the goal levels of <175 mg/dL in total cholesterol and <130 mm Hg for SBP. Higher percentages of patients in the intensive therapy group also reached the goals for glycosylated hemoglobin (<6.5%), triglycerides (<150 mg/dL), and DBP (<80 mm Hg), although these differences were not statistically significant when compared with the conventional group. Importantly, the intensive, multifactorial approach was associated with significant RRRs of 61% for diabetic nephropathy (p=0.003), 58% for retinopathy (p=0.02), and 63% for autonomic neuropathy (p=0.002), compared with conventional therapy. As for the primary outcome, a total of 85 CV and microvascular events occurred among 35 patients (44%) in the conventional therapy group, compared with 33 events among 19 patients (24%) in the intensive therapy group, representing a significant 53% RRR (p=0.008) with intensive therapy (Figure 7).

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Figure 7. Steno-2, an open-label, parallel-group, long-term study, randomized 160 patients with type 2 diabetes mellitus and microalbuminuria to receive conventional therapy (n=80) or an intensive regimen of stepwise lifestyle modification and pharmacologic treatment (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, daily vitamin and mineral supplements, aspirin ISO mg daily) (n=80). After a mean follow-up of 7.8 years, the primary composite end point (death from cardiovascular disease, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation) occurred in 35 patients (44%) in the conventional therapy group, compared with 19 patients (24%) in the intensive therapy group, representing a 53% relative risk reduction with the intensive regimen. BP=blood pressure; HR=hazard ratio; CI=confidence interval. Reproduced with permission from N Engl J Med. 2003;348:383–393.44

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While the Steno-2 findings help confirm the benefits of intensive treatment to control multiple CV risk factors in high-risk patients, the optimal strategies for risk assessment to identify such patients are still unclear.45,46 The Framingham Heart Study risk assessment tool, derived from 5300 study participants and their offspring aged 30–74 years—which incorporates risk factors such as age, gender, SBP and DBP, total cholesterol, low-and high-density cholesterol, smoking, and diabetes mellitus—is currently the most frequently used formula.45 Other CV risk assessment tools include the CV disease life expectancy model, developed using data from the Lipid Research Clinics Follow-up Cohort, the Canadian Heart Health survey and Canadian life tables; the Dundee Coronary Risk Disk, which provides an estimate of a patient's relative risk for CV mortality, matched for age and gender but derived solely in men (not validated in women); the PROCAM Risk Function, developed in Germany, with risk estimates that correlate well with Framingham assessments but cannot be used to predict CV risk in women and has unknown applicability to other populations; and the British regional heart study risk function, which has not been validated and cannot be used to predict CV risk in women.

These risk assessment tools generally include, in varying combinations, established risk factors such as age, gender, BP, various measures of cholesterol, diabetes status, smoking, family history, and anginal symptoms.45 Other, less well established CV risk factors excluded from these formulae include homocysteine, triglycerides, plasma renin, fibrinogen, and microalbuminuria.45 In an effort to improve risk detection and reduce the particularly high CV mortality rate and prevalence of metabolic syndrome in the southeastern United States, the Consortium for Southeastern Hypertension Control (COSEHC)47,48 has developed the first risk assessment tool that uses both nondiabetic glycemic and homocysteine levels as variables. Since the Framingham Heart Study is based on a population of predominantly white, healthy individuals living in Framingham, MA, its general applicability to other regions such as the southeastern United States has been questioned.47 The COSEHC approach, which advocates risk assessment starting in children at the age of 3 years, thus addresses inherent regional disparities in previous risk assessment standards and moves toward greater inclusion of risk factors associated with the metabolic syndrome. As research increasingly probes the significance of the more occult signs of CVD, identification of patients at risk for CVD utilizing these new risk stratification tools may become more accurate and clinically useful.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References

Assessment and treatment of CV risk factors is essential to prevent CVD and to slow its progression. Once high-risk patients are identified, therapeutic strategies that target multiple risk factors, including hypertension, should provide optimal reductions in CV risk. Lowering BP with antihypertensive therapy has been proven to significantly lower CV morbidity and mortality, and several classes of antihypertensive agents have demonstrated generally similar clinical benefits in reducing both BP and CV outcomes. Recent reviews of large-scale hypertension studies indicate that the β blocker atenolol failed to improve patient outcomes in numerous clinical trials, especially among older hypertensive patients. However, the β-blocker class is highly heterogeneous, and newer cardioselective, vasodilating β blockers such as nebivolol, with an improved hemodynamic profile compared with atenolol, may exhibit a different clinical profile. A variety of effective antihypertensive therapies is therefore available to physicians to reduce CV risk. The challenge remains to develop better CV risk calculation tools and guidelines to help identify high-risk patients earlier in the continuum of CVD to maximally reduce global risk.

References

  1. Top of page
  2. Abstract
  3. OVERVIEW OF HYPERTENSION TREATMENT
  4. THE ROLE OF β BLOCKERS IN HYPERTENSIVE HEART DISEASE
  5. NEBIVOLOL: A VASODILATING β BLOCKER
  6. FOCUS ON CV RISK FACTORS
  7. CONCLUSIONS
  8. References
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Figure 4. In a randomized, double-blind, placebo-controlled, dose-ranging study in 509 patients with essential hypertension (diastolic blood pressure [DBP] >95 mm Hg), 4 weeks of therapy with nebivolol at the three highest doses of 2.5, 5, and 10 mg, significantly reduced supine DBP, generally in a dose-dependent manner, compared with placebo. SBp=systolic blood pressure; *BP measured at peak drug levels (2 hours after administration).

Figure 5. In a double-blind, randomized, prospective, 2-week study, nebivolol had favorable effects compared with atenolol on systolic and diastolic left ventricular function in 25 patients with essential hypertension. Nebivolol and atenolol produced similar reductions in blood pressure, and heart rate was reduced with both agents, although to a greater degree with atenolol. Nebivolol significantly increased mean stroke volume, compared with a small increase with atenolol, and also caused a small increase in cardiac output and decreases in peripheral resistance and left ventricular end-systolic volume. In contrast, atenolol was associated with a decrease in cardiac output and increases in peripheral vascular resistance and left ventricular end-systolic volume. bpm=beats per minute. Reproduced with permission from Am J Cardiol. 2003;92:344-348.33

Figure 6. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial, patients aged 70 years and older (n=2128) who had been hospitalized with a diagnosis of heart failure within the past 12 months, irrespective of left ventricular ejection fraction (LVEF), or an LVEF of <35% within the past 6 months, were randomized in double-blind fashion to nebivolol, titrated from 1.25 mg daily to 10 mg once daily (n=1067), or placebo (n=1061). After a mean follow-up of 21 months, the primary composite outcome (all-cause mortality or cardiovascular hospital admission) occurred in 332 patients (31.1%) in the nebivolol group, compared with 375 patients (35.3%) given placebo (p=0.039). Adapted from Eur Heart J. 2005 ;26:215-225.40

Figure 7. Steno-2, an open-label, parallel-group, long-term study, randomized 160 patients with type 2 diabetes mellitus and microalbuminuria to receive conventional therapy (n=80) or an intensive regimen of stepwise lifestyle modification and pharmacologic treatment (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, daily vitamin and mineral supplements, aspirin ISO mg daily) (n=80). After a mean follow-up of 7.8 years, the primary composite end point (death from cardiovascular disease, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation) occurred in 35 patients (44%) in the conventional therapy group, compared with 19 patients (24%) in the intensive therapy group, representing a 53 % relative risk reduction with the intensive regimen. Bp=blood pressure; HR=hazard ratio; CI=confidence interval. Reproduced with permission from N Engl J Med. 2003;348:383-393.44