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General

Beta-blockers: efficacy in cardiovascular diseases

Drugs blocking beta adrenergic receptors (beta-blockers) have become central to the management of cardiovascular diseases. Specifically, they have proven efficacy in:

1. Treatment of angina

2. Prevention of recurrent myocardial infarction

3. Treatment of hypertension

4. Treatment of symptoms of heart failure due to systolic dysfunction

5. increasing survival in patients with heart failure due to systolic dysfunction

6. Improvement of ventricular function in patients with heart failure due to systolic dysfunction

This chapter focuses on the use of beta-blockers in patients with left ventricular systolic dysfunction.

Selected beta-blockers are indicated for the chronic management of patients with congestive heart failure symptoms and reduced ventricular systolic function due to ischemic heart disease, nonischemic cardiomyopathy, and regurgitant valvular lesions. Large clinical trials have shown that three-beta blockers benefit symptoms and survival time in patients with heart failure and reduced ventricular systolic function:

1. Metoprolol CX/XL, which was studied in the Metoprolol CR/XL (Controlled Release/Extended Release) Randomized Intervention Trial in Chronic Heart Failure.

(MERIT-HF).

2. Carvedilol, which was shown to have benefit in a parallel series U.S.-based dose ranging, efficacy, and mortality studies.

3. Bisoprolol, which was shown in the cardiac insufficiency bisoprolol study II (CIBIS II) trial to reduce mortality in patients having in NYHA Class III and IV symptoms.

Although not discussed in detail in this chapter, beta-blockers may have efficacy not proven in large clinical trials for patients with heart failure symptoms due to:

1. Hypertrophic obstructive cardiomyopathy (HOCM). The negative effect of beta-blockers on ventricular contractility may alleviate outflow obstruction and may improve diastolic performance (see below).

2. Concentric cardiomyopathy. Similar to HOCM and isolated diastolic dysfunction, there may be benefits to diastolic function in this patient group.

3. Heart failure symptoms with preserved left ventricular systolic function (primary diastolic dysfunction). Reduced heart rate resulting from beta blockade may increase diastolic filling times, which can lower diastolic filling pressure and alleviate pulmonary congestion.

Differences between drugs within the class

Beta-blockers can be broadly classified in the following categories:

Nonselective beta-blockers that block both beta-1 and beta-2 adrenergic receptors. Prototypes include propranolol and nadolol.
Beta-blockers that are selective for the Beta-1 receptors. Prototypes include metoprolol, atenolol)
Agents that block both beta adrenergic receptors and alpha adrenergic receptors (prototypes include labetalol, carvedilol).
Beta-blockers that also have “intrinsic sympathomimetic” action, meaning that they have weak beta agonist action as well as beta blocking effects. They are in effect weak agonists that stimulate the beta receptors to a lesser degree than endogenous catecholamines. They therefore provide some beta adrenergic stimulation but prevent the full stimulation provided by the sympathetic nervous system and endogenous catecholamines. Pindolol is representative of this class of beta-blockers.

The three beta-blockers shown to benefit survival in heart failure are either beta-1 selective (metoprolol, bisoprolol) or block both beta and alpha receptors (carvedilol).

Not only the class but the formulation of the beta-blocker is of clinical significance. The MERIT-HF trial showed benefit for extended release metoprolol (metoprolol succinate). Prior studies did not show convincing evidence for improved survival with short acting metoprolol (metoprolol tartrate) and a trial comparing carvedilol and immediate release metoprolol (Carvedilol or Metoprolol European Trial [COMET]) showed superior benefit to all-cause mortality with carvedilol. The sustained delivery of beta blockade may account for the superior benefit of extended release metoprolol.

Although many beta-blockers are available and supported by different drug formularies, it is not certain that the benefit of beta-blockers in heart failure is a “class effect” that extends to all agents. This is exemplified by the above noted benefit of extended but not immediate release metoprolol in heart failure.

Even if the benefits of beta-blockers are a class effect, the appropriate dosing of a given beta-blocker to ensure improved symptoms and survival must be demonstrated in large clinical trials. Only extended release metoprolol, carvedilol, and bisoprolol have clear evidence of benefit to symptoms and survival with established dosing targets. Accordingly, the principles of evidence-based medicine indicate that only these three agents should be used for the management of patients with heart failure.

Administration

Effective administration of beta-blockers first requires that the patient be at or close to normal fluid balance. Experience has shown that administration of beta-blockers to patients who are in a state of volume overload can lead to hemodynamic decompensation or exacerbation of pulmonary congestion.

Beta blockade under these conditions acutely interrupts the enhanced activation of the sympathetic nervous system that is required to maintain hemodynamic stability in volume overload states. It is important to note that beta blockade is not initial treatment for acute decompensated heart failure.

The clinical trials that showed efficacy of beta blockade in patients with heart failure introduced therapy at low doses and with gradual dose increases to minimize adverse effects. This strategy to “start low and go slow” has become the standard in initiating and titrating beta-blocker therapy to target doses (Figure 1).

Figure 1.n

Dosing titration for beta-blockers.

Administration of the three beta-blockers having proven benefit in heart failure is guided by the clinical trials that established their efficacy. In general, other medications for the treatment of heart failure, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics should be stabilized prior to initiating beta-blocker therapy.

The following are standard dosing regimens for the three beta-blockers with proven efficacy in patients with heart failure:

Carvedilol: There is both an immediate release and extended release form of carvedilol. Therapy with the immediate release form can be initiated at 3.125 mg twice a day.

This low dose provides a minimal detectable drug level but was used in early clinical trials to minimize adverse responses to beta blockade. The dose is doubled every 2 weeks to a target dose of 25 mg twice a day. In original dose ranging studies, doses of 50 mg twice a day were administered to patients who weighed greater than 80 kg.

Although this dose strategy may still be followed, many patients, even with increased weight, note side effects of fatigue or hypotension that preclude dosing at this level. A notable exception are patients who have hypertensive cardiomyopathy with persistent elevation of blood pressure.

In these patients, the higher doses of carvedilol are often well tolerated and LV function may significantly improve with the blood pressure reduction mediated by these doses. Some patients may require a tailored approach to dose titration.

One strategy is to increase only the evening dose of carvedilol for 1 to 2 weeks before advancing the morning dose. This avoids day time symptoms of fatigue or light-headedness and appears to provide a period in which the patient can adapt to an increased dose before proceeding to increases in both the morning and evening doses.

Extended release carvedilol may be initiated at a dose of 10 mg a day. The dose is then doubled every 2 weeks as tolerated to a maximum dose of 80 mg a day. If the patient does not tolerate a given dose, the previous tolerated dose can be maintained for long-term dosing. If left ventricular function or symptoms do not improve in the following months, future efforts may be made to increase dosing to 80 mg a day.

Extended Release Metoprolol: Extended release metoprolol dosing was initiated at 12.5 mg a day in the MERIT-HF trial. In many cases, dosing may begin at 25 mg a day. The dose may be reduced to 12.5 mg a day if an initial 25 mg dose is not tolerated and a starting dose of 12.5 may be considered if the patient has greater than NYHA functional class II symptoms.

The dose is doubled every 2 weeks to attain a target dose of 200 mg a day or the maximum dose tolerated. The MERIT-HF trial demonstrated that a majority of patients can tolerate higher doses of extended release metoprolol. The average final dose in that trial was 159 mg a day and 64% of patients tolerated the target dose of 200 mg a day.

Bisoprolol: Dosing of bisoprolol for patients with congestive heart failure is best guided by the CIBIS II dosing protocol. Initial dosing is at 1.25 mg a day and is maintained for 1 week. Dosing is increased to 2.5 mg in the second week and to 3.75 mg in the third week. Subsequently, dosing can be increased every 4 weeks to 5 mg, then to 5.75 mg to a maximum of 10 mg. If a patient is not able to tolerate a given dose, the previously tolerated dose can be used as maintenance therapy with future efforts to increase the dose based on the need to further improve symptoms or ventricular function.

Administration during and following hospital admission for acute decompensated heart failure: Continuing beta-blocking medications during admission for acute decompensated heart failure depends on the severity of hemodynamic compromise. Discontinuation of beta-blocker therapy is required in patients with cardiogenic shock to stabilize blood pressure and ensure adequate organ perfusion.

However, data from the large Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry indicate that continuation of beta blockade in patients who are admitted to the hospital due to worsening heart failure symptoms but without cardiogenic shock is often possible and is in fact associated with a significant reduction in the risk of adverse postdischarge clinical outcomes. including death.

Furthermore, patients who initiated beta-blocker therapy prior to discharge from a hospitalization for acute decompensated heart failure tolerated beta-blocker therapy well and were found to have improved postdischarge outcomes. Therefore, efforts should be made to continue beta-blocker therapy if at all possible for patients who have been admitted for worsening heart failure, and beta-blocker therapy should be initiated prior to discharge in patients admitted for acute decompensated heart failure if it was not previously prescribed.

There is no firm evidence-based medicine guiding reinitiation of beta-blocker therapy when it has become necessary to interrupt this treatment during a hospital admission. However, approaches to reinitiation of beta-blocker therapy have been proposed.

One approach is the following: If beta-blocker therapy has been discontinued for cardiogenic shock, or if therapy has been interrupted for a week or more, therapy should be reinstituted as if the patient had never received beta-blocker therapy (see above). If the patient has not had cardiogenic shock and therapy has been interrupted for less than 1 week, beta-blocker therapy can be reinitiated at half the previously prescribed dose and uptitrated according to initial treatment guidelines.

Pharmacologic action

Endogenous sympathetic nervous system activity and circulating catecholamines increase contractility of the left ventricle. Both sympathetic nervous system stimulation and circulating catecholamines act through the beta adrenergic receptors.

The predominant receptor in the ventricle is the beta-1 adrenergic receptor, with approximately 20% of the total receptor numbers in the normal ventricle being beta-2. Stimulation of beta-1 adrenergic receptors results in a cascade of events including association with guanosine triphosphate (GTP)-binding proteins (G proteins) that mediate the production of the second messenger cyclic adenosine monophosphate (AMP) and the activation of protein kinase A.

This cascade results in the activation of proteins that enhance cytosolic calcium transients with resultant binding and dissociation of ventricular contractile proteins. As a consequence, there are increases in both ventricular contractility and relaxation. Beta-2 receptors also act through this pathway and may alternately stimulate inhibitory G proteins. In the peripheral vasculature, the latter pathway mediates vasodilation following beta-2 receptor stimulation.

Early studies showed marked increase in activity of the sympathetic nervous system and increased adrenal production of catecholamines in both animal models of heart failure and human subjects. This increased activity was thought to be a mechanism to compensate for decreased ventricular function in patients with heart failure. For this reason, prior to definitive clinical trials, beta-blockers were considered to be contraindicated in patients with heart failure.

However, further evidence suggested that chronic detrimental effects to cardiovascular function ultimately superseded the acute benefits to ventricular contractile function and hemodynamic support. These adverse actions include:

Direct damage to the myocytes mediated by excessive sympathetic and catecholamine stimulation. This damage is thought to resemble the myocardial necrosis that accompanies states of catecholamine excess, such as seen in patients with pheochromocytoma.
Chronic stimulation of the beta receptor leads to diminished response to catecholamine stimulation. With continued sympathetic and catecholamine stimulation there is downregulation of beta-1 receptor responsiveness.

Therefore, continued sympathetic and circulating catecholamine stimulation no longer augment myocardial contractility, leading to further decreases in ventricular function. Diminished beta receptor stimulation results from several mechanisms, including decreasing numbers of beta receptors on the cell surface. In addition, there is a process of beta receptor “uncoupling,” with a decrease in the association of the beta receptors with the G proteins necessary to generate the downstream signaling that promotes increased ventricular function.
Stimulation of beta receptors resident on the surface of circulating monocytes, as well as other cells, can lead to the production of proinflammatory cytokines. Further myocardial damage can be mediated by this proinflammatory action.
Activation of gene programs that decrease myocardial contractility. Evidence suggests that persistent stimulation of beta receptors may activate gene programs that do not favor production of contractile proteins that most efficiently mediate myocardial contractility. Other gene programs that alter myocardial energy stores and that inhibit the efficient use of metabolic substrates may also be activated.

Beta-blockers act by competitive binding to the beta receptors, thus preventing sympathetic and circulating catecholamine stimulation of the receptor and the downstream signaling pathways they initiate. As noted in the discussion of intraclass drug variation, some beta-blockers are selective for the beta-1 receptors (e.g., metoprolol) and some nonspecifically block both the beta-1 and beta-2 receptors (e.g., carvedilol, bisoprolol).

However, any beta blocking agent given in a high enough dose will ultimately block both beta-1 and beta-2 receptors and function as a nonspecific blocker.

Beta-blockers interrupt chronic adrenergic receptor stimulation and therefore reverse the attendant adverse effects on myocardial structure and function discussed above. However, beta blockade must be delivered in a manner that both prevents the long-term detrimental effects of chronic sympathetic nervous system and catecholamine stimulation without eliminating the short-term benefits of adrenergic stimulation of myocardial contractility and hemodynamic support.

Initial low doses of beta-blockers with gradual progressive dose increases achieve the balance between preserving the short-term benefit of adrenergic stimulation and reversing its long-term adverse effects.

In addition to interrupting beta adrenergic stimulation, the alpha blocking effects of carvedilol may further contribute to the benefit of long-term drug administration. Alpha blockade promotes arterial vasodilation and thus reduces resistance to ejection of blood by the ventricle thus increasing cardiac output and improving ventricular ejection fraction.

Indications and contraindications

Indications: The three beta-blockers listed above are indicated for the treatment of mild to moderate heart failure symptoms, resulting in reduced ventricular function (ejection fraction <40%) in patients with ischemic or nonischemic cardiomyopathy who are treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. They are also indicated for the reduction of hospitalizations for decompensated heart failure and improved survival time in patients with reduced ventricular function.

A specific subset of patients benefiting from beta-blocker therapy are those who have suffered a myocardial infarction with subsequent reduction of ventricular function. Evidence is particularly strong for the benefit of carvedilol in this patient population. Although there is not a strong basis in clinical trials, expert opinion also supports the use of beta-blockers in patients with asymptomatic reduction in ventricular function with the goal of improving ventricular function and prevention of the onset of heart failure symptoms.

Contraindications:

Bronchospastic lung disease. Beta blockade can induce bronchospasm in patients with bronchospastic lung disease. For this reason, these agents should be avoided in patients with severe lung disease.
Second-degree and complete heart block, sick sinus syndrome, or symptomatic bradycardia from any cause. Patients with high grade heart block or symptomatic bradycardia can develop severe bradycardia and hypotension with administration of beta-blocking agents. In some cases, pacemaker therapy may be considered to allow such patients to derive the benefits of beta-blocker therapy.
Cardiogenic shock or severe decompensated heart failure. Although long-term benefit can be derived from blockade of sympathetic and catecholamine beta adrenergic stimulation, these mechanisms provide important short-term circulatory and ventricular contractile support in acute exacerbations of heart failure. Therefore, beta-blockers should not be initiated in these settings.

As noted above, some data suggest that efforts may be made to continue beta-blocker therapy in the setting of acute decompensated heart failure in those who have been regularly taking these medications. However, initiation of beta-blocker therapy should not be attempted in this setting until volume overload states have been resolved.

Undesirable effects

Table I. Undesirable Effects and Approaches to Management

Table I.

Undesirable Effect	Approach
Fatigue	Reduce dose; uptitrate more slowly; try selective beta-blocker (extended release metoprolol); reduce diuretics if possible
Bradycardia	Reduce dose; try selective beta-blocker; consider pacemaker therapy
Hypotension not related to bradycardia	Consider reduction of diuretic if tolerated; try selective beta-blocker to avoid alpha blockade associated hypotension encountered with carvedilol
CNS: depression, hallucinations, sexual dysfunction	Consider change in beta-blocker, especially one that is less lipophilic; consider use of antidepressant; consider use of phosphodiesterase-5 inhibitor for sexual dysfunction
Diabetes: Masked or attenuated symptoms of hypoglycemia	Educate patient regarding risk of altered symptoms; more frequent glucose monitoring, especially with change in antidiabetic medication or beta-blocker dosing
Peripheral vascular disease: vasospasm or worsening ischemia	Consider dose reduction; consider use of carvedilol to minimize unopposed alpha adrenergic stimulation
Beta-blocker withdrawal	Less common with longer acting beta-blockers; if possible, withdraw beta-blockers with gradual dose reduction (e.g., absence of cardiogenic shock or hemodynamic compromise)

Undesirable Effects

1. Fatigue. Fatigue is perhaps one of the most common undesirable effects of beta blockade. Often this occurs with initial dosing of the beta-blocker and resolves after 1 to 2 weeks of treatment.

This appears to be a response to the interruption of the stimulatory effects of catecholamines on beta adrenergic receptors. It may be necessary to specifically encourage patients to continue treatment until fatigue resolves.

Patients should be monitored for significant hypotension or bradycardia, which may contribute to fatigue. In these cases, it may be necessary to reduce initial doses of the beta blocking agent or reduce twice a day dosing to once a day until the patient tolerates the beta blocker.

Adjustment of diuretic medications may also reduce symptoms of fatigue in patients whose diuretic requirements have diminished after episodes of volume overload. Some studies have suggested that metoprolol may be preferable to carvedilol in patients with severe beta-blocker associated fatigue. It is speculated that the beta-1 receptor specificity of metoprolol may minimize reductions in heart rate with activity and therefore reduce fatigue.

2. Bradycardia. All of the beta-blockers can reduce resting and exercise heart rate. In addition to symptoms of fatigue noted above, this may result in symptoms of presyncope and reduced exercise tolerance.

In some cases, metoprolol may be used over nonselective beta-blockers such as carvedilol to minimize these symptoms. Dose adjustment to prevent bradycardia may be required and in some cases pacemaker implantation may be considered to permit use of beta-blocking agents.

3. Hypotension. Reduction in systemic blood pressure is typically seen with beta-blockers. This can be due to reduction of heart rate, but also can result from beta-blocker changes in cardiac output. Symptomatic reduction in blood pressure may require dose reduction and in some cases prevents use of beta-blockers in selected patients.

4. Central nervous system effects. Beta-blockers can be associated with new onset or worsening of depression. In some patients, beta-blockers have been associated with vivid dreams or hallucinations. In addition, sexual dysfunction sometimes associated with beta-blockers may be considered in this category.

The incidence and severity of CNS effects appears to be related to the lipophilicity of the specific beta-blocker and the consequent capacity of the different beta-blockers to cross the blood brain barrier. Of the three beta-blockers with proven benefit in patients with heart failure, carvedilol is the most lipophilic.

Changing to a less lipophilic beta-blocker may reduce or eliminate these symptoms. In some cases, antidepressant therapy may be considered to permit beta-blocker administration. Use of phosphodiesterase-5 inhibitors such as sildenafil may be effective in addressing beta-blocker associated sexual dysfunction.

5. Diabetes. Beta-blockers may worsen or prolong hypoglycemia in patients with diabetes. This is due to the interruption to the sympathetic and catecholamine driven mechanisms that compensate for hypoglycemia. Beta-blockers ay also predispose to significant hypertension during hypoglycemia due to unopposed vascular alpha adrenergic stimulation.

Symptoms of hypoglycemia, such as increased heart rate, may be minimized and thus reduce or eliminate patient awareness of significant reductions in blood glucose. Patient and physician awareness of these potential complications is essential to safely administer beta-blockers in patients with diabetes. There is some evidence that carvedilol may contribute to worsening glucose tolerance. This may require adjustment of the antidiabetic medical regimen to maintain target levels of glucose.

6. Peripheral vascular disease. Symptoms of peripheral vascular disease may be exacerbated by beta blockade due to unopposed alpha agonist activity and consequent vasoconstriction. Patients with vasospastic diseases, such as Raynaud phenomenon, may have significant worsening of symptoms.

7. Beta-blocker withdrawal. Abrupt discontinuation of beta-blockers can lead to a “rebound” effect characterized by tachycardia and hypertension. Patients with ischemic heart disease may have exacerbation of angina or acute ischemic events.

In general, the risk of this rebound phenomenon decreases with increasing half-life of the beta-blocker. Carvedilol, sustained release metoprolol, and bisoprolol all have relatively long half-lives, minimizing the risk of beta-blocker withdrawal rebound. However, if beta-blocker discontinuation is necessary, it is preferable to do so in gradual fashion if possible.

Alternative approaches

In patients for whom beta-blockers are contraindicated or who are intolerant of beta blockade, the addition of an angiotensin receptor blocker to angiotensin-converting enzyme inhibitor therapy should be considered. It has been suggested that angiotensin receptor blockade counteracts the increase in angiotensin-converting enzyme activity that can follow chronic angiotensinic converting enzyme inhibitor therapy.

Some clinical trials have shown clinical benefit of this drug combination. Patients should be monitored for hyperkalemia and symptomatic hypotension. Alternatively, an aldosterone antagonist, such as spironolactone or eplerenone, may be added to angiotensin-converting enzyme inhibitor therapy. Again, serum potassium should be monitored closely with this combination.

A third alternative is the combination of hydralazine and isosorbide dinitrate. The utility of this combination was demonstrated in a Veterans Administration trial that showed hydralazine and isosorbide dinitrate significantly improved survival time in patients with heart failure.

In this trial, hydralazine was administered for the first 2 weeks at a dose of 37.5 mg four times a day and then increased to 75 mg four times a day. Isosorbide dinitrate was administered as 20 mg four times a day for 2 weeks and then increased to 40 mg four times a day.

This regimen was designed prior to the use of angiotensin-converting enzyme inhibitors for heart failure, and therefore in the current era, lower doses are often used to minimize hypotension that can result from concomitant administration of these three agents. This regimen may especially be considered in African American patients with heart failure based on a trial of the drug BiDil, which is a combination of hydralazine and isosorbide dinitrate and which showed significant benefit to survival in this patient population.

One BiDil tablet contains 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine. The initial dose is one tablet three times a day and this can be increased to two tablets three times a day. The same dosing can be administered as isosorbide dinitrate and hydralazine given as separate medications and provides further guidance for the dosing of these agents in the background of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy.

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