Cardiac Electrophysiology Review 2000;4:300–307  C 2000 Kluwer Academic Publishers. Manufactured in The Netherlands.

Beta-Blockers Jeffrey L. Anderson University of Utah School of Medicine, Salt Lake City, UT

Pharmacologic Effects of β -Adrenoceptor Blockade

β -Blockade During and After Myocardial Infarction

β-adrenoceptor blockade is associated with a number of beneficial pharmacologic effects in patients at risk for or with manifest coronary heart disease: antiischemic, antihypertensive, antiadrenergic; heart rate slowing, antiarrhythmic and, more specifically, antifibrillatory [1–6]. Given these and other pharmacologic and metabolic effects, it is not surprising that β-blockers have found such wide and increasing utility in cardiovascular medicine. A summary of properties of several of the many β-blockers available clinically is given in Table 1. The importance of differences in the ancillary properties of β-blockers is controversial [5]. Drugs with intrinsic sympathomimetic activity (ISA), or partial agonist activity, may cause a lesser reduction in heart rate at rest and may be better tolerated in patients with symptoms related to bradycardia. Mild ISA activity does not appear to interfere significantly with antiarrhythmic activity, but strong ISA activity may detract from antiarrhythmic and cardioprotective potential. The clinical importance of lipid solubility also is controversial. High lipid solubility may allow greater entry of drugs into the brain and has been postulated to cause non-β-blocker-related adverse effects such as lethargy or depression. To what extent lipid soluble β-blockers cause these symptoms (compared with placebo) and less lipid soluble drugs avoid these reactions is unclear. Nonselective β-blockers, which also block β-2 receptors, cause greater (side) effects on bronchial and vascular adrenoceptors, but selective and nonselective β-blockers are believed to have similar antiarrhythmic activity in similar β-1 blocking doses. Differences in pharmacokinetic properties of various β-blockers must be accounted for in clinical practice, however. Two broad categories exist: β-blockers that are lipid soluble, absorbed in the small intestine, and metabolized largely by the liver, and β-blockers that are water soluble, more gradually and incompletely absorbed, and eliminated unchanged by the kidney. Drugs in the first class (e.g., propranolol, metoprolol) typically have variable biovailability and short plasma half-lives and those in the second class (e.g., atenolol, sotalol) have less variance in bioavailability and longer plasma half-lives [5].

Several well-controlled studies have documented the beneficial effect of acute (early, intravenous, and oral) and chronic (oral) β-blocker therapy after myocardial infarction [2,6]. In older trials involving a total of over 50,000 patients, modest early (14%) and substantial (23%) late mortality reductions were demonstrated [2]. Less extensive randomized trial experience in the post-reperfusion era also is consistent with benefit of adjunctive βblockade on ischemic events [7,8]. Despite an extensive evidence base and supportive guidelines, β-blockers continue to be underutilized after MI [8,9].

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Current Guidelines for Use in CHD Acute, chronic post-MI/acute coronary syndrome The updated (1999) ACC/AHA guidelines for the management of patients with acute myocardial infarction (MI) have broadened the indications for β-blockade [8]. For the early (within 12 hours, including IV initiation) and in-hospital phases of MI, the following Class I (strongly recommended) indications are given: 1) for all MI patients without contraindications (e.g., severe left ventricular [LV] failure) within 12 hours of MI onset, regardless of reperfusion strategy; 2) for those with continuing or recurrent ischemic pain; 3) for patients with tachyarrhythmias, such as atrial fibrillation (AF) with a rapid ventricular response; and 4) non-STelevation MI (or unstable angina). The guidelines further state that moderate or severe LV failure early in the course of MI indicates rather than precludes use of an oral β-blockers before discharge. A Class I recommendation for long-term (oral) therapy in MI survivors is made for all but low-risk patients without a clear indication. Treatment should begin without a few days (if not begun acutely) and continue indefinitely. A Class IIa indication (generally recommended, evidence less

Address correspondence to: Jeffrey L. Anderson, M.D., Chief, Cardiology Division 4A-100, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132. E-mail: [email protected]

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Table 1. Selected properties of some commonly used beta-blockers Drug

β1-potency

β1-select.

Lipid sol.

Ancillary prop.

Half life (h)

Elimination

Acebutolol Atenolol Bisoprolol Bucindolol Carvedilol Esmolol Labetalol Metoprolol Nadolol Pindolol Propranolol Sotalol Timolol

0.3 1.0 10.3 1.0 10.0 0.02 0.3 1.0 1.0 6.0 1.0 0.3 6.0

+ ++ ++ 0 ± ++ 0 ++ 0 0 0 0 0

mod. weak weak

ISA, MSA

3–4 (AM 8–13) 6–9 9–12

R, H R R, H

7–10 9 min 3–4 3–4 14–24 3–4 3–4 9–10 4–5

H B H H R R H R R

high weak weak mod. weak mod. high weak weak

direct vasodil alpha-block, antiox alpha-block ISA MSA Class III

Source: Data primarily from Frishman WH: Comparative pharmacology of beta-adrenergic blockers. In: Deedwania PC (ed): Betablockers and cardiac arrhythmias. Marcel Dekker, NY, 1992; pp. 96–98. Updated for newer compounds from Physician’s Desk Reference 2000. Alpha-block = alpha1-adrenergic blocking activity; antiox = antioxidant activity; β1-(blocking) potency relative to propranolol; H = hepatic metabolism; ISA = intrinsic sympathomimetic activity; mod. = moderatge; MSA = membrane stabilizing activity; prop. = properties; R = renal elimination; Sol. = solubility; vasodil. = vasodilating activity; AM = half life of acebutolol metabolite

compelling) is given for low-risk patients and survivors of non-ST-elevation MI. Even patients with moderate to severe LV failure should be considered for long-term therapy (Class IIb indication) if therapy is titrated and closely monitored. Further, evidence now suggests that the benefits of β-blockers outweigh risks in many patients with “relative contraindications”, including asthma, insulin-dependent (and non-dependent) diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, first degree AV block, and moderate LV failure. Closely monitored, slowly titrated therapy rather than avoidance of β-blockers should be considered in these patient groups. Chronic CAD, chronic stable angina ACC/AHA/ACP-ASIM also have recently (1999) updated Guidelines for the Management of Patients With Chronic Stable Angina [10]. β-blockers are given a Class I pharmacotherapy recommendation as initial therapy (in the absence of contraindications) to prevent MI and death and to reduce symptoms (Level of evidence: A in patients with prior MI; Level of evidence: B, without prior MI).

Hypertension Current guidelines β-blockers continue to have a prominent place in current guidelines for antihypertensive therapy although the role for alternative therapies has grown. The U.S. Joint National Committee (JNC) VI guidelines (1997) state that when a decision has

been made to begin antihypertensive therapy, and there are no indications for another type of drug, a diuretic or β-blocker should be chosen because numerous randomized clinical trials have shown a reduction in morbidity and mortality with these agents [11]. β-blockers also are recommended agents in combination regimens. The recent (1999) Canadian recommendations for management of hypertension list β-blockers as one of three preferred agents (together with thiazide diuretics and angiotensin-convertingenzyme inhibitors) for initial management in patients <60 years of age [12]. However, in patients >60 years old, β-blockers assume an adjunctive role, with thiazides and long-acting dihydropyridine calcium channel blockers being recommended as the preferred initial regimen. In the large, ongoing comparative endpoint trial, ALLHAT, now well along into follow-up, representative β-blocker, angiotensin-convertingenzyme inhibitor, and calcium channel antagonist agents continue to pass data and safety monitoring review and remain under study. Antihypertensive β -blocker therapy and risk for type 2 diabetes Recently, the prospective ARIC study in 12,550 adults evaluated the development of diabetes in hypertensive subjects treated with various antihypertensive therapies [13]. Those receiving β-blocker but not thiazide, calcium-channelantagonist, or angiotensin-converting-enzyme (ACE) inhibitor therapy were found to be at greater risk of developing diabetes (relative hazard, 1.28

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[1.04–1.57]). The authors caution that the 28% increased risk of diabetes must be weighed against the proven benefits of β-blockade to reduce the risk of cardiovascular events. The therapeutic consequences of this study are unclear, but the findings may be a factor in selecting therapy for patients at low risk of CV events. In contrast, results of the recent HOPE study argue in favor of ACE-inhibitor therapy in patients at risk of developing diabetes [14]. Ramipril, assigned to patients at high-risk of cardiovascular events, reduced the relative risk of developing diabetes by 34% (from 5.4% to 3.6%, p < .001) over the 5 years of follow-up.

Perioperative β -Blockade In an important recent study, Poldermans et al. studied the effect of β-blockade (bisoprolol) on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery [15]. High-risk patients who had both clinical risk factors and a positive dobutamine echocardiogram were enrolled and randomized to standard care alone (N = 53) or with perioperative bisoprolol (N = 59). Within 30 days, 2 patients died in the bisoprolol group and none had MI, whereas 9 patients died and 9 had nonfatal MI in the control group (total event rates, 3.4% vs. 34%, p < 0.001). This study strongly reinforces the concept that βblockade represents effective preventive therapy for perioperative ischemic events in high risk patients undergoing vascular surgery. Consideration of β-blocker therapy for patients undergoing other major types of surgery also seems reasonable.

β -Blockers in Heart Failure Rationale Increased sympathoadrenal stimulation, although often appropriate (adaptive) as an acute response to circulatory failure, is now believed to be generally maladaptive in chronic heart failure (HF). Both direct (myocardial toxic) and indirect (increased preload, afterload) factors are triggered in HF that lead to progressive deterioration of myocardial function and electrical instability. β-blockers, by interrupting this viscious neurohumoral cycle, may prevent or (partially) reverse cardiac dysfunction and dysrhythmia. Earlier work The role of β-blockade for patients with left ventricular dysfunction has long been debated. Its adverse potential in those with decompensated heart failure is well known. As a result, it had long been contraindicated in heart failure patients. Studies dating to the late 1970’s have questioned this conventional wisdom, however [16–20]. When initi-

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ated in small, gradually increasing doses to patients whose left ventricular dysfunction has been stabilized with conventional therapy, β-blockers have been shown to be surprisingly well tolerated, to improve functional class, reduce heart failure symptoms (dyspnea, fatigue) with long-term use (over months), and to increase ejection fraction [17–20]. Guidelines on appropriate patient selection and effects of β-blockers on mortality, however, are just now emerging (see below). Carvedilol HF program The U.S. Carvedilol Heart Failure study program raised the strong likelihood of survival benefit of at least certain β-blockers in HF [21]. Among 4 differing but parallel study protocols in mild to moderately severe HF and ejection fraction ≤35%, 398 patients were randomized to placebo and 696 to carvedilol on a background of digoxin, diuretics, and angiotensin-converting-enzyme inhibitor therapy and followed for 6–12 months. The study was stopped early on recommendation of the data and safety monitoring board when the observed mortality rates for the program overall were found to be reduced to 3.2% in the carvedilol groups compared to 7.8% in the placebo groups (p < .001). In addition, cardiovascular hospitalizations were reduced from 20% to 14% (p = 0.03). Carvedilol was well tolerated; worsening HF occurred less frequently with carvedilol than placebo. Because mortality was not a prespecified endpoint, these results (especially, magnitude of effect) must be viewed as provisional. Carvedilol has been approved for the general indication of “reduction of HF progression”. CIBIS-II The Cardiac Insufficiency Bisoprolol Study II, reported in 1999, enrolled 2647 symptomatic, stable HF patients (EF ≤ 35%, primarily class III) receiving standard therapy with diuretics and angiotensin-converting-enzyme inhibitors [22]. Patients were randomized to the β-1 selective blocker bisoprolol (1.25 mg titrated to 10 mg/d) or placebo and followed for a mean of 1.3 years. CIBIS-II was stopped early, after the second interim analysis, because of a significant mortality reduction associated with bisoprolol (11.8% vs. 17.3%, hazard ratio 0.66 [CI 0.54–0.81], p < 0.0001). Sudden death was substantially reduced on bisoprolol, relative hazard = 0.56 (0.39–0.80, p = 0.001). Thus, bisoprolol substantially benefited stable HF patients, but results should not be extrapolated to class IV or unstable patients. MERIT-HF The Metoprolol CR XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF),

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published in 1999, randomized 3991 patients with chronic HF and ejection fraction (EF) ≤0.40 to a sustained-release formulation of the β1-selective agent metoprolol (CR /XL) or placebo [23]. Metoprolol was initiated with a dose of 12.5–25 mg/day and gradually uptitrated over 8 weeks to a target dose of 200 mg/day. The primary endpoint was all-cause mortality using the intention-to-treat principle. The study was stopped early on recommendation of the safety committee because of overwhelming efficacy after a mean follow-up time of 1 year. Assignment to metoprolol was associated with a reduction in mortality from 11.0% to 7.2% per patient-year of follow-up, giving a relative mortality risk of 0.66 (CI = 0.51–0.81, adjusted p = 0.0062). Immediate and progressive separation of the survival curves after initiation suggested that survival benefits began immediately and continued throughout the period of therapy. Both sudden deaths (representing 58% of total deaths) and progressive HF deaths (24% of the total) were reduced by beta-blockade (relative risks, 0.59 [0.45−0.78], p = 0.0002, and 0.5 l [0.33−0.79], p = 0.002, respectively). Metoprolol was well tolerated. The earlier, smaller (N = 383) endpoint trial, MDC (Metoprolol Dilated Cardiomyopathy Study) [24], which used short-acting metoprolol, had shown a statistically borderline primary endpoint effect (34%, p = 0.058), with essentially all of the benefit due to reduction in need for cardiac transplantation rather than death. Thus, MERIT-HF represents a major advance in defining the specific mortality benefit of metoprolol in HF, at least when given in a long-acting formulation. BEST Bucindolol is a non-specific β-adrenoceptor blocker with mild vasodilator activity that is welltolerated in stable HF, decreases HF symptoms, improves functional class, and increases EF [20]. Its mortality effect in a racially (23% black) and functionally (226 class IV pts) mixed population was studied in the NIH-supported Beta-blocker Evaluation of Survival Trial (BEST)[25]. Preliminary results were presented at the annual American Heart Association Scientific Sessions in November 1999 [26]. BEST randomized 2708 patients, following them for a mean of 2 years before it was stopped by its data and safety monitoring committee because of futility (i.e., no chance of showing benefit even if study allowed to go to completion) and “consistency with other β-blocker trials”. Overall, mortality insignificantly trended lower (relative hazard, 0.90 [0.78–1.02], p = 0.10). However, significant benefit was seen in white patients, whereas an adverse mortality trend was observed in blacks. Similarly, class III patients benefited, whereas an adverse trend occurred in

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class IV patients. Thus, BEST supports the beneficial results of other trials, which have studied predominantly white, class II–III populations, but it raises questions about the role of β-blockade in black and functional Class IV populations. Whether differences in benefit also may depend on drugspecific ancillary properties of β-blockers, as well as patient selection, remains to be determined. COPERNICUS Not yet published, COPERNICUS, a study of carvedilol versus placebo for patients with advanced HF, was recently stopped early because of a major benefit on survival. While details of the study are awaited, COPERNICUS may add further strength to the therapeutic argument for use of β-blockade in HF in general, and carvedilol for advanced HF in particular. Withdrawal risks The major mortality trials have treated patients through study end (indefinitely) and did not address the issue of whether therapy could or should be later discontinued. A small amount of observational experience suggests that discontinuation may be fraught with hazard [27]. Morimoto et al. tapered and stopped metoprolol in 13 patients with dilated cardiomyopathy (DCM) who had received therapy for ≥30 months [28]. Seven deteriorated, 4 dying suddenly or of HF progression within 4 months. This experience, although small, is in keeping with earlier reports of deterioration with β-blocker discontinuation [27]. Current guidelines β-blocker therapy represents the most important recent addition to the pharmacological management guidelines for HF. In the recent (1999) Heart Failure Society of America (HFSA) Practice Guidelines [29], the following 7 recommendations are made: 1) β-blocker therapy should be routinely given to clinically stable patients with LV systolic dysfunction (EF ≤ 40%) and mild to moderate (Class II–III) HF symptoms who are on standard therapy and, 2) should be considered for those without symptoms (Class I). 3) β-blocker therapy should begin after a period of clinical stability on standard therapy, to maximize safety. 4) There is insufficient evidence currently to recommend use of β-blockers for patients with symptoms at rest (Class IV). 5) β-blocker therapy should begin with low doses, with slow up-titration (at ≥2 week intervals) during clinical reevaluation. 6) Patients who experience deterioration in HF status or symptoms should generally be continued on β-blocker therapy. 7) Patient education is important regarding expected side effects and symptoms of HF exacerbation.

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β -Blockers as Antiarrhythmic/ Antifibrillatory Agents Role in VT/VF prevention β -blockers as sole antifibrillatory therapy. Sudden (arrhythmic) death has consistently been reduced by β-blockers in high-risk patients after MI and with clinical HF, when compared to placebo plus standard therapy (see above; 2,4,6,21–26). Nevertheless, arrhythmic mortality remains high in certain subgroups, prompting the testing of additional measures (see below). Adjunct to amiodarone. An unexpected but provocative observation in the amiodarone studies in high-risk post-MI patients (EMIAT, CAMIAT) was a striking, favorable interaction with βblockers [30]. Using the pooled database of these 2 studies, lower relative risks were found for allcause mortality, cardiac death, and arrhythmic death or resuscitated cardiac arrest. The treatment interactions were significant for both cardiac (p = 0.05) and arrhythmic death (p = 0.03) and were consistent across subgroups. The findings, although post-hoc, are robust, and suggest that in practice, not only is the concurrent use of β-blockers with amiodarone not hazardous, but is beneficial. In another study, the beneficial effects of carvedilol in HF patients was not affected by concurrent treatment with amiodarone [31]. These and other clinical and basic studies are consistent with a beneficial interaction of β-blockers and amiodarone in antiadrenergic modulation [32]. Adjunct to ICD Rx. 1. Sotalol/ICD. Reducing the frequency of shocks for patients with implantable cardioverter-defibrillators is a worthwhile therapeutic goal. To test the efficacy and safety of sotalol for this purpose, 302 ICD patients, stratified by ejection fraction (≤ or >30%) were assigned to sotalol (160–320 mg/d) or placebo and followed for 12 months [33]. Endpoints were first shock, first appropriate shock, and first inappropriate shock (for supraventricular arrhythmia) and death. Sotalol substantially reduced the risk of shock or death (by 48%, p < .001), appropriate shock or death (by 44%, p = 0.007), and inappropriate shock or death (by 64%, p = 0.004). The mean frequency of shocks also was lower with sotalol (1.4 vs. 3.9/year, p = 0.008). The benefit of sotalol was seen in both the lower and higher ejection fraction strata. Thus, oral sotalol, which combines β-blockade with class III antiarrhythmic activity, is a safe, efficacious therapy for reducing ICD shocks for patients with a broad range of ejection fractions.

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2. BEST-ICD: BEST-ICD is a multicenter, randomized study, underway in Europe [34]. BEST-ICD is testing whether electrophysiologic-guided therapy, including defibrillator implantation if indicated, will provide additional survival benefit in 1200 patients surviving MI with depressed ejection fraction (≤35%) and an arrhythmic risk factor (complex ventricular ectopy, decreased heart rate variability, or ventricular late potentials) who are already being treated with β-blockers [34]. Adjunct in AF therapy Rate control. Digoxin, calcium-channel blockers (verapamil, diltiazem), and β-blockers, alone or in combination, are the major drugs for rate control in atrial fibrillation with rapid ventricular response. Of these, β-blockers are most effective as single agents and combinations with β-blockers as combined regimens. In one recent trial, Farshi et al. evaluated the effects of 5 regimens on 24 hour ventricular rate in 12 patients with chronic atrial fibrillation [35]. Regimens included: 1) digoxin (0.25 mg/d), 2) diltiazem-CD (240 mg/d), 3) atenolol (50 mg/d), 4) digoxin and diltiazem, and 5) digoxin and atenolol. Atenolol provided the best rate control during daily activity of the single-drug regimens, and atenolol plus digoxin resulted in the most effective overall control of ventricular rate. Rhythm control β-blockade alone has modest efficacy in terminating acute AF and preventing recurrence, and, in combination with Class III (repolarizationprolonging) activity (e.g., sotalol), allows for generally greater effectiveness. 1. Sotalol vs. placebo for ambulatory AF. The d,l-Sotalol Atrial Fibrillation/Flutter Study Group recently reported results of their randomized trial of 3 fixed doses (80, 120, 160 mg twice daily) for maintenance of sinus rhythm in 253 patients with recurrent atrial fibrillation or flutter [36]. Using transtelephonic monitoring, median times to symptomatic recurrence were found to be 27, 106, 229, and 175 days for placebo, 80, 120, and 160 mg BID groups, respectively. Times to recurrence were significantly longer compared to placebo in the 2 higher sotalol dose groups. No proarrhythmia was noted. The 120-mg twice daily dose appeared to provide the most favorable risk/ benefit ratio. 2. Sotalol vs. placebo for post-operative AF. In a placebo-controlled study [37], Gomes et al. randomized 85 patients undergoing coronary artery bypass surgery to receive either sotalol

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Table 2. Results of some end-point trials of beta-blockers Trial/Drug (ref)

N

Population

Endpoint

Risk reduction

P

Overview (2) Carvedilol (20) CIBIS-II/bisoprolol (21) MERIT-HF/metopr (22) BEST/bucindolol (25) Post-Op/bisoprolol (14) Sotalol-ICD (32) Sotalol/AF (35)

50,000 1094 2647 3991 2708 112 302 85

Post-MI Mild-mod HF Mod HF Mod HF Mod/Sev HF Hi-R Vasc Sg ICD patients Post-CABG

Mortality Mortality* Mortality Mortality Mortality Death/MI Shock/Death AF

23% 65% 34% 34% 10%** 90% 48% 67%

<.001 <.001 <.001 0.006 0.10 <.001 <.001 0.008

CABG = coronary artery bypass graft surgery; Hi-R Vasc Sg = high risk vascular surgery; ICD = implantable cardioverter defibrillator; MI = myocardial infarction; mod = moderate; Sev = severe

(mean dose 190 mg/d), beginning 24–48 hours before surgery, or placebo. Sotalol was associated with a markedly lower incidence of postoperative AF (12.5% vs. 38%, p = 0.008) and a non-significantly shorter hospital stay (mean, 7 vs. 8 days) than placebo and was well tolerated. 3. Pure β-blockers vs. sotalol for post-operative AF. In a comparative study, sotalol (120 mg/d) was randomly compared with metoprolol (75 mg/d) in 191 patients undergoing coronary artery bypass grafting [38]. Sotalol modestly increased QT interval compared with metoprolol (by 31 msec) but caused no proarrhythmia. AF occurred in 16% of sotalol and 32% of metoprolol patients (p < .01), and sinus rate was better controlled with sotalol. 4. Sotalol vs. amiodarone. Amiodarone appears to be somewhat more effective than the βblocker Class III agent sotalol in preventing AF recurrences. In the Canadian Trial of Atrial Fibrillation, 403 patients were converted from AF and randomized to amiodarone or either sotalol or propafenone [39]. After 16 months, fewer patients who were assigned to amiodarone (35%) than to sotalol or propafenone (63%) had recurrence of AF (p < .001); however, more discontinued amiodarone because of adverse effects (18%) than sotalol or propafenone (11%). A smaller Greek study (70 patients) also found amiodarone to be more effective [40]: 29% on amiodarone, compared with 60% taking sotalol, developed AF recurrence during 12 months of observation.

Neurocardiogenic Syncope β-blockers continue to be useful for patients with neurocardiogenic (malignant vasovagal) syncopal syndromes, based on a relatively limited but generally supportive database. In small trials, metoprolol has been reported to be more effective than clonidine [41], and pindolol (which has intrin-

sic sympathomimetic activity and is better tolerated by some) also has been shown to be of clinical benefit [42]. In another experience, low blood pressure at rest before the initial tilt-table test predicted failure of β-blocker therapy [43]. Variability in tilt-table positivity over time, with substantial “placebo” or “training” effects in tilt-positive patients, continues to be reported, as well.

Conclusion The β-adrenoreceptor blockers continue to find both expanded and more focused uses in cardiovascular medicine. In general, their beneficial potential exceeds current usage. Recent clinical trials have added to the previous solid outcomes’ database (Table 2). New indications include utility in compensated HF and perioperative reduction in ischemic complications, dysrhythmia (i.e., AF, VF), and mortality. They continue to form firstline therapy for most patients with hypertension. Their preventive utility continues to be recognized after MI, and they continue to have first-line status for chronic angina and rate control for AF. The database supporting their ability to prevent ventricular fibrillation and sudden death in many high-risk patients (i.e., with CAD, LV dysfunction) continues to grow. At the same time, understanding of disadvantages (e.g., increasing risk for type 2 diabetes in hypertensive patients) or clinical advantages of specific agents (e.g., carvedilol vs. propranolol for HF) of the β-blocker class is growing. These advances should lead to generally more appropriate usage and greater clinical benefit.

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