Beta-blockers in the management of cardiovascular diseases

Prabhat Pokhrel, MD, MS, PhD, 1460 N Center Rd, Burton, MI 48509.

E-mail address: ppokhrel@genesys.org.

This article was designed to be viewed and distributed as a PDF. Please download the PDF for easiest reading.

The use of beta-blockers (�-blockers) in clinical practice has been evolving for more than half a century. Currently, these medications are used for a number of medical condi- tions such as unstable angina (USA), acute myocardial in- farction (AMI), heart failure (HF), hypertension (HTN), atrial fibrillation (AF), ventricular arrhythmias, migraine headache, hyperthyroidism, essential tremor, aortic dissec- tion, social phobia, glaucoma, esophageal varices, and so on.1-3 Despite the clear beneficial effects of �-blockers on morbidity and mortality in medical conditions, such as HF and stable post- AMI, they are often under-prescribed or under-dosed.4,5 In patients with HTN, whether �-blockers should be among the first line of medications in the absence of compelling evidence is being questioned. Not all�-blockers are cardioprotective in stable HF patients with left venticular dysfunction. For other conditions such as peripheral vascular disease (PVD) and chronic obstructive pulmonary disease (COPD), there is not enough evidence to contradict the use of �-blockers (Table 1).6,7

Although some therapeutic effects of �-blockers can be attributed to its class, others are specific to an individual�-blocker not only because of the differences in their phar- macokinetic, pharmacodynamic, and intrinsic properties, but also owing to the difference in the genetic polymor- phism of the patients.8,9 In a recent meta-analysis, long- acting metoprolol, carvedilol, atenolol, and propranolol were compared with their respective brand-name counter- parts for their pharmacological effectiveness. The study demonstrated that generic �-blockers and their brand-name counterparts did not differ significantly in the clinical out- comes tested. However, the clinical trials reviewed were done in healthy, small populations and for a short period of time, which suggests long-term outcomes would be similar but have yet to be demonstrated.10

SORT Levels of Recommendation:

A = Recommendation based on consistent and good quality patient-oriented evidence.

B = Recommendation based on inconsistent or limited quality patient-oriented evidence.

C = Recommendation based on consensus, usual practice, opinion, disease-oriented evidence, and case series for studies of diagnosis, treatment, prevention, or screening.

For more information about the SORT evidence rating system visit: http://www.aafp.org/online/en/home/publications/journals/afp/ afpsort.html.

‌132 Osteopathic Family Physician, Vol 2, No 5, September/October 2010

Table 2 lists �-blockers based on their receptor selectivity as cardioselective (atenolol, bisoprolol, metoprolol, nebivolol) and noncardioselective. Noncardioselective �-blockers are fur- ther subdivided into those with intrinsic sympathomimetic ac- tivity (ISA) (acebutolol, pindolol), those without ISA (nadolol, propranolol, sotalol), and those with alpha-adrenergic– block- ing activities (carvedilol, labetalol). Cardioselective �-blockers bind mainly to �1-receptors, whereas nonselective �-blockers bind to both �1 and �2 receptors. At higher doses, cardiose- lective �-blockers bind to �2 receptors as well.

�-blockers and lipids

‌Effects of different �-blockers on the lipid profile are variable. In general, noncardioselective �-blockers without ISA increase se- rum triglyceride, low-density lipoprotein cholesterol, very-low- density lipoprotein cholesterol, and total cholesterol, and they decrease high-density lipoprotein. Cardioselective �-blockers and those with ISA have lesser effects on lipid profile. Acebutolol was found to be lipid-neutral. Pindolol, on the other hand, gave mixed results on lipid profile from being lipid-neutral to lipid-lowering. Carvedilol has been reported to increase insulin sensitivity and decrease triglycerides and increase high-density lipoprotein. La- betalol, which belongs to the same subgroup as carvedilol, was found to be neutral. When metoprolol was administered to non- diabetic hypertensive patients, insulin sensitivity was unchanged, high-density lipoprotein was decreased, and total cholesterol, tri- glyceride, and low-density lipoprotein were increased.11,12

�-blockers and HTN

Whether �-blockers should be used as a first-line agent in the absence of compelling indications in hypertensive pa-

tients is recently being questioned. Several clinical trials have tried to quantify the effects �-blocker on morbidity and mortality when used as the first-line antihypertensive therapy. A review of 13 clinical trials, with more than 91,000 subjects in which �-blockers were compared with placebo, diuretics, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB) concluded that �-blockers, when used as a first line therapy for HTN, were inferior to ACEI, ARB, and CCB in reducing some of the important outcomes measured. Although �-blockers were superior to placebo in reducing the risk of stroke, it did not change the all-cause mortality, incidence of coronary heart disease, or death from cardiovascular events. When compared with CCB, ACEI, and ARB, the effect of �-blockers on stroke was inferior.

�-blockers were also inferior to CCBs in reducing cardio- vascular events.13

A review of nine clinical trials in which atenolol was either compared with placebo (4 studies with 6825 patients) or with another antihypertensive agent (5 studies with 17,671 patients) concluded that, compared with placebo, atenolol was no better in reducing total mortality, cardio- vascular mortality, myocardial infarction, and stroke. Com- pared with other antihypertensive therapy, patients in the atenolol group had higher mortality as well as cardiovascu- lar mortality and stroke.14

A review of 18 randomized, clinical trials in which

�-blockers were used as first-line treatment for HTN ad- vised against the use of �-blockers as the first-line antihy- pertensive agent.15 This was supported by another meta- analysis that reviewed 21 HTN trials involving 145,811 patients.16 Outcomes of �-blockers also seemed to depend on the age of hypertensive patients. �-blockers, compared with placebo or other antihypertensive therapy, significantly reduced the composite outcome (death, stroke, or MI) inphylaxis. It may be taken with or without food.

Results from the Losartan Intervention for Endpoint Re- duction in Hypertension (LIFE) trial have shown that losar- tan was significantly better in reducing incidence of fatal or nonfatal stroke compared with atenolol in high-risk patients (HTN comorbid with diabetes, cardiovascular disease, left ventricular hypertrophy, and/or isolated systolic HTN) with HTN. A significant number of patients (77%) in the losartan group had a regression of left ventricular hypertrophy com- pared with the atenolol group. The fall in blood pressure in those two groups was similar (30.2/16.6 losartan vs. 29.1/ 16.1 atenolol). The LIFE trial also cautioned about an ap- parent increase in incidence of new-onset diabetes that was associated with atenolol vs. losartan (8.0% vs. 6.0%, P < 0.001).18

‌Data from the Medical Research Council (MRC) trial in which hydrochlorothiazide [HCTZ] plus amiloride was compared with atenolol in elderly hypertensive patients suggested that HCTZ and amiloride were superior to ateno- lol in improving coronary events and cardiovascular or all-cause mortality events. Reduction in the cerebrovascular incidence was noticeable in the diuretics group (31%, P = 0.04) as well as the diuretics plus atenolol group (25%, P = 0.04). Atenolol alone showed an insignificant decrease in the rate of cerebrovascular events when compared with placebo (9% vs. 10.8%).19

Table 3 Hypertension and �-blocker clinical trials Trials Drugs tested

CAPPP Captopril �-blocker and/or diuretic

INVEST

Verapamil Atenolol

Conclusions

No difference in cardiovascular events except in diabetic patients; captopril was superior in patients with HTN

No difference in primary or secondary outcomes in patients with HTN

Losartan better than atenolol in reducing fatal or nonfatal stroke, regression of LVH in patients with HTN

Amlodipine superior to atenolol in lowering nonfatal MI, fatal coronary events, strokes, all-cause mortality, lower incidence of diabetes

�-blockers did not reduce coronary events or cardiovascular or all-cause mortality, where as diuretic did

Same as STOP-Hypertension-2 trial

Similar benefit between all drugs on fatal or nonfatal-stroke, MI, and other cardiovascular mortality

Ref

24

62

LIFE

Losartan Atenolol

18

Atenolol Amlodipine

20

MRC

Propranolol Atenolol HCTZ Amiloride

18

NORDIL

STOP-Hypertension-2

�-blocker, diuretics, or both Diltiazem Lisinopril, enalapril, felodipine, isradipine, diuretic �-blockers

23

22

MRC, Medical Research Council; STOP, Swedish Trial in Old Patients with Hypertension; NORDIL, Nordic Diltiazem Study; LIFE, Losartan Intervention Endpoint Reduction in Hypertension; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcome Trial–Blood Pressure Lowering Arm; INVEST, International Verapamil-Trandolapril Study; CAPPP, Captopril Prevention Project; HCTZ, Hydrochlorothiazide.

The Anglo-Scandinavian Cardiac Outcome Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) included 19,257 high-risk patients with HTN and randomized them to either the amlodipine or atenolol groups. After five and half years

of follow-up, the trial was stopped early when the atenolol group showed less cardiovascular benefit, higher stroke, and more mortality compared with the amlodipine group (HR 0.77 vs. 0.86).20 Whether metoprolol, bisoprolol, or carve- dilol are superior to atenolol in preventing adverse cardio- vascular events in high-risk hypertensive patients remains to be elucidated. In the International Verapamil-Trandolapril Study (INVEST) there was no difference between the ateno- lol and verapamil groups in the incidence of primary (death, nonfatal myocardial infarction, nonfatal stroke) or second- ary outcomes.21

Table 3 summarizes results from some the clinical trials where �-blockers were compared with other antihyperten- sive agents. Current evidence based on several clinical trials (CAPPP, STOP-Hypertension-2, NORDIL, LIFE, ASCOT-

BPLA)22-24 and meta-analysis does not support the use of

�-blocker as first-line therapy in the treatment of HTN in patients older than 60 years of age in the absence of com- pelling indications (previous MI, HF, AF, frequent migraine headache).25-27 To date, there is no recommendation for whether atenolol should be replaced by another �-blocker or even if �-blockers in general should be used as a first- or second-line antihypertensive therapy in the absence of com- pelling indication. More clinical trials are needed to deter- mine whether newer �-blockers nebivolol or carvedilol re- duce the composite outcome (stroke, MI, or death) in hypertensive patients.

�-blockers and HF

ACEIs and �-blockers are first-line therapy for HF patients with left ventricular dysfunction. �-blockers, at least in part by decreasing the activation of the sympathetic nervous

Table 4 Heart failure and �-blocker clinical trials Clinical trials Drugs tested (target dose)

BEST trial Bucindolol

CBIS and CBIS II trials Bisoprolol (10 mg/day)

Trial outcomes

Reduced only cardiovascular mortality. No reduction in other causes of mortality evaluated (MI, sudden death, HF death)

Significant reduction in hospitalization, all-cause mortality by 34%

Improved quality of life, LVEF, no significant change in mortality

Significant reduction in hospitalization, all-cause mortality by 34%

Significant reduction in hospitalization, all-cause mortality by 35%

Significant reduction in mortality by 35% Significant reduction in mortality by 23%

Ref

40

35

MDC

Metoprolol

32

MERIT-HF

Metoprolol (200 mg/day)

33

US Carvedilol

Carvedilol (6.25-25 mg every 12 hours)

34

COPERNICUS CAPRICORN

Carvedilol (25 mg every 12 hours)

Carvedilol (25 mg every 12 hours)

36

37

MDC, Metoprolol in Dilated Cardiomyopathy; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure; CBIS, Cardiac Insufficiency Bisoprolol Study; CBIS II, Cardiac Insufficiency Bisoprolol Study II; BEST, Beta-blocker Evaluation of Survival.

‌McHugh et al Beta-Blockers in the Management of Cardiovascular Diseases 135

system, improve the morbidity and mortality of patients with HF.28,29 Data from more than 20 placebo-controlled clinical trials (Table 4) involving about 20,000 patients with HF (MDC, MERIT-HF, RESOLVED, COPERNICUS,

MOCHA, PRECISE, CIBIS, and CIBIS II) and meta-anal- ysis have shown that use of �-blockers in patients with stable NYHA class II to IV HF significantly reduces mor- bidity (4 fewer hospitalization per 100 patients treated) and in some trials even mortality (3.8 lives saved per 100 pa- tients who received �-blocker). There is no convincing evidence that use of �-blockers has any beneficial effect on patients with class I NYHA HF, but it should be used in patients with class I NYHA HF with comorbid conditions such as patients with myocardial infarction and/or chronic USA. Both selective (bisoprolol, sustained-release metopro- lol succinate) and nonselective (carvedilol) �-blockers were effective in reducing morbidity and mortality in HF pa- tients, at least in part by improving left ventricular ejection fraction up to 10%, exercise capacity, and cardiac remod- eling, and by reducing the incidence of AF.30-34

‌The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) trial evaluated the effectiveness of bisoprolol in 2647 pa- tients with symptomatic NYHA class III or IV HF with ejection fraction (EF) <35%. The trial was terminated early because of significant reduction in mortality rate (32% less) in bisoprolol group. There was also 25% fewer deaths from cardiovascular cause and a 39% reduction in sudden death in bisoprolol group.35 Similar results were obtained in The United States Carvedilol Heart Failure Study Group, The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, The Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN), and The Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) trials.36,37

The beneficial effect of �-blockers in HF patients may not be a result of its class. �-blockers with sympathomi- metic activity (acebutolol, pindolol) or with class III anti-

arrhythmic activity (sotalol) should not be used in HF pa- tients because of an increase in morbidity and mortality.38-40 In a randomized, double-blind, placebo-controlled trial in- volving 2708 patients with NYHA class III (92% of pa- tients) and class IV (8% of patients) with EF 35% or less, bucindolol did not show any survival benefit.41 Currently the American College of Cardiology/American Heart Asso- ciation guidelines recommend only one of the three �-blockers (bisoprolol, carvedilol, and metoprolol succinate) for pa- tients with stable chronic systolic HF. Fluid retention may need to be minimized before starting �-blockers by increas- ing diuretic dose. These recommendations also apply to all patient populations, even those who were under-represented in those clinical trials.42

The difference in the beneficial effects of �-blockers in HF with left ventricular dysfunction patients should be interpreted with caution and should be based on the large clinical trials. In small clinical trials performed so far, some �-blockers have shown promising results in the treatment of HF patients; there- fore, in the absence of larger clinical trials, only those �-block- ers with evidence-based data (e.g., carvedilol, metoprolol, and bisoporolol) should be considered for use in patients with HF.43,44 During HF exacerbation and decompensation, �-blockers should not be discontinued unless the patient manifests signs and symptoms of severe systemic hypoperfusion. In such patients, the �-blocker should be discontinued but restarted once the patient is hemodynamically stable. De- compensated HF patients who are not on a �-blocker should be stabilized first and the �-blocker started when patients are discharged (Table 5).

�-blockers in stable angina and acute coronary syndrome

The 2002 American College of Cardiology (ACC)/Ameri- can Heart Association (AHA) guidelines updated in 2007

Table 5 Recommended �-blocker doses for HF patients with systolic dysfunction

Initial starting Dosing frequency

�-blocker dose per day

Bisoprolol 1.25 mg 1

Carvedilol 3.125 mg 2

Metoprolol succinate CR/XL 12.5 or 25 mg 1

Target daily dose

10 mg/day

50-100 mg/day

200 mg/day

Ref

35

34,36,37

32,33

‌136 Osteopathic Family Physician, Vol 2, No 5, September/October 2010

‌Although beneficial outcomes of �-blockers in angina are thought to be a class effect, the ACC/AHA guidelines state that �-blockers without ISA are preferred in patients with USA or non–ST-segment elevation/non–Q wave myo- cardial infarction. The therapeutic goal of �-blocker use is to reduce anginal symptoms and improve exercise toler- ance, minimizing adverse effects with a target resting heart rate in the range of 55– 60 beats/min as recommended by 2002 ACC/AHA guidelines and guidelines focused update in 2007.43

�-blocker use in patients with a history of AMI or HF improves mortality. There are no convincing data that sup- port a decrease in mortality from �-blocker use in patients with stable angina without MI or HF. �-blockers have not been shown in any clinical trial to decrease the incidence of MI. However, it has been demonstrated to reduce the mor- bidity and mortality if given after AMI.48 Multiple trials and meta-analysis have supported the beneficial effects of

�-blockers on morbidity and mortality after an ST eleva- tion– or non-ST– elevation AMI. Moreover, timely use of

�-blocker has also shown to reduce the size of infarct.49 Results from a randomized, placebo-controlled trial

(COMMIT/CCS2 trial) of about 45,000 subjects indicated that early use of �-blockers in patients with an AMI reduces the risk of re-infarction and ventricular fibrillation, but may increase the risk of cardiogenic shock. Therefore, authors of the article recommend using �-blockers in AMI only after patients are hemodynamically stable.50,51

Results from the TIMI-IIB trial supports that early meto- prolol administration significantly reduces recurrent chest pain, re-infarction, or death within the first 21 days after an AMI. ACC/AHA recommends starting a �-blocker in all patients within 24 hours of AMI, unless contraindicated.52-54

�-blockers and AF

Atrial fibrillation (AF) is a common cardiac arrhythmia and is a frequent complication in HF patients. Results from the COMET trial suggested that AF in HF patients increases the risk of death and number of hospitalizations.55 New-onset AF in HF patients who were already on a �-blocker was also associated with increased mortality.55 Several clinical trials have shown that �-blockers like metoprolol or carve- dilol alone or in combination with other medications such as digoxin or CCB have favorable outcome on morbidity and mortality from AF.56-58 Therapeutic effect of �-blockers in AF is mainly a result of ventricular rate control and may be a class effect.59 In the AFFIRM trial, �-blocker alone was as effective as digoxin or CCB plus digoxin, but was superior to CCB alone in its efficacy to control heart rate at rest and during exertion.59

Perioperative use of �-blockers

Because AF is one of the common complications in post- operative surgery, especially after heart surgery such as coronary artery bypass grafting (CABG), a �-blocker is frequently used preoperatively to prevent the incidence of AF. Although all �-blockers are effective, results from the COMPACT study showed that carvedilol was better than metoprolol in the prevention of postoperative AF in patients after CABG.60

In general, clinical trials investigating the use of �-block- ers (metoprolol, atenolol, bisoprolol) in the noncardiac peri- operative period have yielded conflicting results. In a ran- domized, controlled trial conducted in 190 hospitals and 23 countries (POISE trial), metoprolol (100 mg) given 2 to 4 hours before noncardiac surgery, and 200 mg a day there- after for 30 days, produced mixed results. At 30 days, death from cardiovascular events, nonfatal myocardial infarction, or nonfatal cardiac arrest (primary endpoint) decreased from 6.9% in the placebo group to 5.8% in the metoprolol group (95% CI 0.70-0.99, P < 0.0399). Incident of myocardial infarction was decreased from 5.7% (placebo) to 4.2% (metoprolol) (95% CI 0.60-0.89, P < 0.0017). Total mor- tality and incident of stroke, however, were increased sig- nificantly in metoprolol groups.61 Similar results were ob- tained from other systematic reviews and meta-analysis of 22 trials.

‌McHugh et al Beta-Blockers in the Management of Cardiovascular Diseases 137

‌Careful patient selection and close monitoring (blood pressure and heart rate) are important factors that could determine the effectiveness of �-blockers when used perio- peratively.62 In November 2009, the American College of Cardiology Foundation (ACCF) and AHA released a report entitled “Focused Update to the Practice Guideline from 2007.”63 Some of the recommendations from this updates are (1) patients who are already on a �-blocker for ACCF/ AHA Class I indications should continue taking it (Level of Evidence [LOE]: C); (2) �-blockers are recommended for patients undergoing vascular surgery but are at high cardiac risk because of CAD from their history or based on stress testing (LOE: B); (3) A �-blocker is reasonable in patients who undergo vascular surgery and are identified to have high cardiac risk such as history of ischemic heart disease; history of compensated or previous HF; history of cerebro- vascular disease, diabetes mellitus, and renal insufficiency (serum creatinine >2 mg/dL) (LOE: C); (4) it is reasonable to use �-blockers in patients who are undergoing interme- diate-risk surgery and are at high cardiac risk (presence of more than one clinical risk factors) or have CAD (LOE: B). In patients who are undergoing intermediate-risk surgery or vascular surgery, do not have CAD but have one clinical risk factor, usefulness of the �-blocker is uncertain (LOE: C). The value of �-blockers is uncertain in patients under- going vascular surgery and who have no clinical risk factor for cardiac complications and are not already on a �-blocker (LOE: B). High-dose blocker without titration may be harmful to patients who were not taking a �-blocker previ- ously and are undergoing noncardiac surgery (LOE: B).63

References

1. Schellenberg R, Lichtenthal A, Wohling H, et al: Nebivolol and metoprolol for treating migraine: an advance on �-blocker treatment? Headache. 48:118-125, 2008

2. Sarafidis PA, Bakris GL: Antihypertensive treatment with beta-block- ers and the spectrum of glycemic control. QJM 99:431-436, 2006

3. Bangalore S, Messerli FH, Kostis JB, et al: Cardiovascular protection using beta-blockers. A critical review of the evidence. J Am Coll Cardiol 50:563-572, 2007

4. Wald D, Milne S, Chinn R, et al: Beta blocker therapy for patients with heart failure in primary care. Br J Cardiol 11:408-412, 2004

5. Franciosa JA, Massie BM, Lukas MA, et al: Beta-blocker therapy for heart failure outside the clinical trial setting: findings of a community- based registry. Am Heart J 148:718-726, 2004

6. Lelias JM, Kaghad M, Rodriguez M, et al: Molecular cloning of a human beta-3-adrenergic receptor cDNA. FEBS Lett. 324:127-130, 1993

7. Shin J, Johnson JA: Pharmacogentics of beta-blockers. Pharmacother- apy 27:874-887, 2007

8. Paravastu SCV, Mendonca D, Da Silva A: Beta blockers for peripheral arterial disease. Cochrane Database of Systematic Reviews 2008, Issue

   4. Art. No.: CD005508. DOI: 10.1002/14651858.CD005508.pub2.

9. Nuttall SL, Routledge HC, Kendall MJ: A comparison of the �1- selectivity of three �1-selective �-blockers. J Clin Pharm Ther 28: 179-186, 2003

10. Kesselheim AS, Misono AS, Lee JL, et al: Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a sys- tematic review and meta-analysis. JAMA 300:2514-2526, 2008

    
    

11. Flakner B, Francos G, Kushner H: Metoprolol succinate, a selective beta-adrenergic blocker, has no effect on insulin sensitivity. J Clin Hypertens 8:336-343, 2006

12. Malmqvist K, Kahan T, Isaksson H, et al: Regression of left ventric- ular mass with captopril and metoprolol, and the effects on glucose and lipid metabolism. Blood Press 10:101-110, 2001

13. Bradley HA, Wiysonge CS, Volmink JA, et al: How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens 24:2131-2141, 2006

14. Carlberg B, Samuelsson O, Lindholm LH: Atenolol in hypertension: is it a wise choice? Lancet 364:1684-1689, 2004

15. Lindholm LH, Carlberg B, Samuelsson O: Should beta-blockers re- main first choice in the treatment of primary hypertension? A meta- analysis. Lancet 366:1545-1553, 2005

16. Khan N, McAlister FA: Beta-blockers for the treatment of primary hypertension [letter]. Lancet 367:208, 2006

17. Khan N, McAlister A: Re-examining the efficacy of �-blockers for the treatment of hypertension: a meta-analysis. CMAJ 174:1737-1742, 2006

18. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 359:995-1003, 2002

19. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 304:405-412, 1992

20. Poulter NR, Wedel H, Dahlof B, et al: Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lower- ing Arm (ASCOT-BPLA). Lancet 366:907-913, 2005

21. Pepine CJ, Handberg EM, Cooper-Dehoff RM, et al: A calcium an- tagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil- Trandolapril Study (Invest): a randomized controlled trial. JAMA 290:2805-2816, 2003

22. Hansson L, Lindholm LH, Ekbom T, et al: Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortal- ity and morbidity the Swedish Trial in Old Patients with Hyperten- sion-2 study. Lancet 354:1751-1756, 1999

23. Hansson L, Hedner T, Lung-Johansen P, et al for the NORDIL Study Group. Randomised trial of effects of calcium antagonist compared with diuretics and beta-blockers on cardiovascular morbidity and mor- tality in hypertension: the NORDIC Diltiazem (NORDIL) study. Lan- cet 356:359-365, 2000

24. Hansson L, Lindholm LH, Niskanen L, et al: for the Captopril Pre- vention Project (CAPPP) study group. Effect of angiotensin-convert- ing-enzyme inhibition compared with conventional therapy on cardio- vascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet 353:611-616, 1999

25. Bradley HA, Wiysonge CS, Volmink JA, et al: How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens 24:2131-2141, 2006

26. Wiysonge CSU, Bradley HA, Mayosi BM, et al: Beta-blockers for hypertension. Cochrane Database of Systematic Reviews 2007, Issue

    1. Art. No.: CD002003. DOI: 10.1002/14651858.CD002003.pub2.

27. Lindholm LH, Carlberg B, Samuelson O: Beta blockers in primary hypertension: do age and type of beta-blocker matter? J Hypertens 24:2143-2145, 2006

28. Cohn JN, Levine B, Olivari MT, et al: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311:819-823, 1984

29. Neubauer GE, Gaudron P, Horn M, et al: Beta-blockers in cardiac failure. Eur Heart J 15:16-24, 1994

30. Brophy JM, Joseph L, Rouleau JL: �-blockers in congestive heart failure: a Bayesian meta-analysis. Ann Int Med 134:550-560, 2001

31. Waagstein F, Hjalmarson A, Varnauskas E, et al: Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 37:1022-1036, 1975

    ‌138 Osteopathic Family Physician, Vol 2, No 5, September/October 2010

     

    
    

32. Waagstein F, Bristow MR, Swedberg K, et al: Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in dilated cardiomyopathy (MDC) trial study group. Lancet 342:1441-1446, 1993

33. Hjalmarson A, Goldstein S, Fagerberg B, et al: Effects of controlled- release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT- HF Study Group. JAMA 283:1295-1302, 2000

34. Colucci WS, Packer M, Bristow MR, et al: Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carve- dilol Heart Failure Study Group. Circulation 94:2800-2806, 1996

35. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 353:9-13, 1999

36. Packer M, Coats AJ, Fowler MB, et al: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651-1658, 2001

37. Dargie HJ: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN ran- domized trial. Lancet 357:1385-1390, 2001

38. Waldo AL, Camm AJ, deRuyter H, et al: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD investigators. Survival with oral d-sotalol. Lancet 348:7-12, 1996

39. Ikram H, Fitzpatrick D: Double-blind trial of chronic beta blockade in congestive cardiomyopathy. Lancet 2:490-493, 1981

40. Domanski M, Coady S, Fleg J, et al: Effect of statin therapy on survival in patients with nonischemic cardiomyopathy (from the beta- blocker evaluation of survival trial (BEST). Am J Cardiol 99:1448- 1450, 2007

41. Beta-blocker evaluation of survival trial investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart fail- ure. N Eng J Med 344:1659-1667, 2001

42. Fonarow GC: A review of evidence-based �-blockers in special pop- ulations with heart failure. Rev Cardiovasc Med 9:84-95, 2008

43. Go AS, Yang J, Gurwitz JH, et al: Comparative effectiveness of different beta-adrenergic antagonists on mortality among adults with heart failure in clinical practice. Arch Intern Med 168:2415-2421, 2008

44. Kramer JM, Curtis LH, Dupree CS, et al: Comparative effectiveness of beta-blockers in elderly patients with heart failure. Arch Intern Med 168:2422-2428, 2008

45. Anderson JL, Adams CD, Antman EM, et al: ACC/AHA 2007 guide- lines for the management of patients with unstable angina/non-ST- elevation myocardial infarction: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable angina/non- ST-elevation myocardial infarction). Circulation 116:803-877, 2007

46. Warren SG, Brewer DL, Orgain ES: Long-term propranolol therapy for angina pectoris. Am J Cardiol 37:420-426, 1976

47. Jackson G, Schwartz J, Kates RE, et al: Atenolol: once-daily cardio- selective beta blockade for angina pectoris. Circulation 61:555-560, 1980

48. Shu D, Dong B, Wu T, et al: Beta blockers for stable angina (protocol). Cochrane Database of Systemic Reviews. 2005, Issue 1. Art. No.: CD005152. DOI: 10.1002/14651858.CD005152.

49. Yusuf S, Peto R, Lewis J, et al: Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27:335-371, 1985

50. Chen ZM, Pan HC, Chen YP, et al; COMMIT (Clopidogrel and metoprolol in myocardial infarction trial) collaborative group: Early intravenous then oral metoprolol in 45,852 patients with acute myo- cardial infarction: randomized placebo-controlled trial. Lancet 366: 1622-1632, 2005

51. Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA 270:1589-1595, 1993

52. Roberts R, Rogers WJ, Mueller HS, et al: Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B study. Circulation 83:422-437, 1991

53. Gislason GH, Rasmussen JN, Abildstrom SZ, et al: Long-term com- pliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction. Eur Heart J 27:1153- 1158, 2006

54. Viskin S, Kitzis I, Lev E, et al: Treatment with beta-adrenergic block- ing agents after myocardial infarction: from randomized trials to clin- ical practice. J Am Coll Cardiol 25:1327-1332, 1995

55. Swedberg K, Olsson, LG, Charlesworth A, Cleland J, Hanrath P, Komajda M, Metra M, Torp-Pedersen C, Poole-Wilson P. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. Eur Heart J 26:1303-1308, 2005

56. Ramaswamy K: Beta-blockers improve outcome in patients with heart failure and atrial fibrillation. U.S. Carvedilol study. Card Electro- physiol Rev 7:229-232, 2003

57. Kuhlkamp V, Bosch R, Mewis C, et al: Use of beta-bockers in atrial fibrillation. Am J Cardiovasc Drugs 2:37-42, 2002

58. Rawles JM, Metcalfe MJ, Jennings K: Time of occurrence, duration and ventricular rate of paroxysmal atrial fibrillation: the effect of digoxin. Br Heart J 63:225-227, 1990

59. Olshansky B, Rosenfeld LE, Warner AL, et al: The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study: ap- proach to control rate in atrial fibrillation. J Am Coll Cardiol 43:1201- 1208, 2004

60. Kamei M, Morita S, Hayashi Y, et al: Carvedilol versus metoprolol for the prevention of atrial fibrillation after off-pump coronary bypass surgery: rationale and design of the carvedilol or metoprolol post- revascularization atrial fibrillation controlled trial (COMPACT). Car- diovasc Drugs Ther 20:219-227, 2006

61. POISE Study Group; Devereaux PJ, Yang H, Yusuf S, et al: Effects of extended-release metoprolol succinate in patients undergoing non- cardiac surgery (POISE trial): a randomized controlled trial. Lancet 371:1839-1847, 2008

62. Black CD, Mann HJ: Intrinsic sympathomimetic activity: physiologi- cal reality or marketing phenomenon. Drug Intell Clin Pharm 18:554- 559, 1984

63. Fleischmann KE, Beckman JA, Buller CE, et al: 2009 ACCF/AHA focused update on perioperative beta blockade: a report from the American College of Cardiology Foundation/American Heart Associ- ation Task Force on Practice Guidelines. Circulation 120:2123-2151, 2009