The current focus of the management of the acute coronary syndromes (ACS) is on antithrombotic and antiplatelet agents and the selection and timing of revascularization procedures. With a few notable exceptions, use of beta blockers and calcium channel blockers (CCBs) and other agents to alleviate ischemia through other mechanisms have received little in the way of new scrutiny since preparation of this chapter in the previous edition of this book. Many recommendations are based on small studies which were performed prior to the widespread use of early revascularization, either percutaneous or by means of thrombolysis, and prior also to the availability of newer anticoagulants and oral and intravenous antiplatelet agents that have revolutionized the management of these conditions. It is also important to recognize that at the time many of the earlier studies were performed, therapeutic strategies subsequently shown to be harmful and hence abandoned were in use and may have confounded the interpretation of the results. For example in ISIS-1 more patients in the control arm were prescribed CCBs, a practice now discouraged. The change that has occurred in the definition of the ACS also renders interpretation of the information difficult and extrapolation from older studies problematic.
Previously, the clinical syndromes of unstable angina and myocardial infarction were seen as distinct entities and often studied as such. It is now recognized that particularly in the early hours, when important therapeutic decisions have to be made, the distinctions may not be clear-cut. Rather they are part of a continuum and the diagnostic category of any single patient may change with time, the availability of repeated laboratory tests, or evolution of electrocardiographic changes. The integration of previous knowledge and experience with the beta blockers, CCBs, and other pharmacologic therapy into the modern management of the acute coronary syndromes is often not straightforward.
Pharmacologic Properties
Beta blockers act primarily by reducing myocardial oxygen demand, with negative chronotropic and inotropic effects that reduce heart rate, stroke volume, and blood pressure. A less well known metabolic effect of reducing blood free fatty acid levels improves metabolism of ischemic myocardium. Beta blockers also have antiarrhythmic effects as demonstrated by experimental studies showing an increase in ventricular fibrillation threshold and clinical trials showing a relative risk reduction in sudden cardiac death. Prolonged diastole consequent on the bradycardia increases coronary diastolic blood flow and hence myocardial perfusion. Adverse remodeling may be reversed and left ventricular hemodynamic function improved by beta blocker administration in combination with other agents after myocardial infarction. ,
Calcium channel blockers (CCBs) are all potent vasodilators. Reduced afterload reduces myocardial oxygen demand and coronary vasodilatation may increase supply. The non-dihydropyridines, verapamil and diltiazem, have negative inotropic effects and cause modest reductions in heart rate.
Nitrates act by forming nitric oxide within smooth muscle cells to stimulate the production of the vasodilator cyclic guanosine monophosphate (cGMP) via guanylate cyclase. They exert their anti-ischemic effect through several different mechanisms. They are potent venodilators and peripheral venous pooling, reduced venous return, and reduction in ventricular volume with consequent reduction in ventricular wall stress reduces myocardial oxygen demand. Reduced aortic systolic pressure provides a similar benefit. Reduction in left ventricular end-diastolic pressure improves the trans-myocardial perfusion gradient and subendocardial coronary perfusion improving myocardial oxygen supply. These peripheral effects may be more important than direct effects of dilating large coronary arteries and arterioles, relieving any epicardial coronary spasm or dynamic stenoses and dilatation of collaterals, which may have a direct effect on improving myocardial oxygen supply.
Ranolazine , unlike other agents discussed in this chapter, alleviates myocardial ischemia without clinically significant effects on heart rate or blood pressure. It is considered to have two modes of action. First, it has been emphasized that it acts as a partial fatty acid oxidation inhibitor, similar to trimetazidine. Secondly, as more recently emphasized, it inhibits the late phase of the cardiac inward sodium current (I Na ) during repolarization. This current is more active during periods of myocardial ischemia, increasing intracellular sodium and hence calcium concentrations. Increased intracellular calcium may impair diastolic function and precipitate ventricular arrhythmias.
Properties of Beta Blockers
Beta blockers are sometimes divided into arbitrary generations. First-generation agents, such as propranolol, non-selectively block all the beta receptors (beta 1 and beta 2 ) Second-generation agents such as atenolol, metoprolol, acebutolol, bisoprolol and others, have relative selectivity when given in low doses for the beta 1 (largely cardiac) receptors. Third-generation agents have vasodilatory properties, acting through the following three mechanisms: (1) agents with added α-adrenergic blockade, as in the case of labetalol and carvedilol; (2) nitric oxide donation as in the case of nebivolol (see section on nitric oxide donors); and (3) a group now less used with added intrinsic sympathomimetic activity, including pindolol. Other nonvasodilatory beta blockers tend to promote systemic vascular and coronary vasoconstriction by unopposed α-adrenergic activity.
There are other marked differences between beta blockers in pharmacokinetic properties with widely varying half-lives and different lipid and water solubility. There is little compelling evidence that any of these properties confers significant therapeutic advantage. Simple clinical logic would favor the use of short-acting agents in the hemodynamically unpredictable ACS but paradoxically much of the available evidence of benefit is with longer acting agents.
Properties of Calcium Channel Blockers
CCBs are conventionally divided into the following: (1) predominantly vascular-active dihydropyridines (DHPs), of which nifedipine is an example of the first generation and amlodipine and felodipine are referred to as the second-generation; and (2) the more cardioactive non-DHPs, which are also called the heart rate-slowing agents. Both types of CCBs, but particularly the DHPs, inhibit the vascular long-lasting calcium channels to diminish calcium ion entry and to cause vasodilation. Another vascular action, well studied experimentally, is increased production of nitric oxide by the vascular endothelium, a process that can be expected to be protective by the vasodilatory and antiplatelet properties of nitric oxide. Verapamil and diltiazem have modest heart rate lowering effects and negative inotropic effects which when coupled to peripheral vasodilatation reduce myocardial oxygen consumption. With the DHPs, particularly short-acting nifedipine, the more marked peripheral vasodilatation stimulates adrenergic reflexes and tachycardia, which could account for the adverse effects of nifedipine capsules in the ACS.
Beta Blockers in Clinical Practice in Acute Coronary Syndromes
Beta Blockers in ST-Elevation Acute Coronary Syndromes
The overall evidence for the benefits of beta blocker treatment in reducing morbidity and mortality is considered to be best for patients with ST-segment elevation myocardial infarction (STEMI). A comprehensive systematic review and meta regression analysis published in 1999 identified a 29% reduction in the odds of death in long-term trials with a relatively modest 4% reduction in the short-term trials. The mortality benefit is in part due to a lower rate of sudden cardiac death. Beta blocker prescription remains a primary recommendation in most guidelines for the management of patients after myocardial infarction. , The contemporary evidence base and practical considerations involved in implementation of beta blocker therapy after infarction have been comprehensively reviewed. Many of the key studies on which the recommendations are based were performed in the era prior to routine administration of antiplatelet agents, thrombolysis, and primary percutaneous coronary intervention (PCI). The evidence that beta blockers confer benefit after myocardial infarction has been considered to be so good that their prescription within 7 days of hospital discharge has been used as a marker of quality of care. This practice is now so well-accepted and implementation so widespread that it no longer is useful as such a marker.
Despite the favorable findings of the earlier studies and widespread use later after the onset of infarction in the convalescent stage, the key following questions remain:
- 1
What is the role of early intravenous administration of beta blocker?
- 2
Do patients undergoing primary percutaneous intervention benefit from beta blocker therapy?
- 3
What is the role of beta blockers in the face of heart failure early after myocardial infarction (MI)?
- 4
Should the traditional contraindications to beta blocker therapy still be applied to patients after STEMI?
- 5
If the data on early oral beta blockade are indeed applicable to current practice, what is the agent of choice and in which dose?
Early Administration of Beta Blockers
The early treatment of patients with suspected acute myocardial infarction with intravenous followed by oral beta-blockade was studied in many trials in the 1980s ( Table 23-1 ). Overall, the results of these studies have been interpreted as indicating that the treatment is safe and moderately effective in a group of relatively low-risk patients, preventing six deaths per thousand patients treated (ISIS-1). There has been persistent uncertainty about the addition of early beta blocker therapy, particularly intravenous therapy, to standard treatment; opinions differ , and practice varies widely. There has been no large trial testing the effects of early oral beta blockade versus placebo (see Table 23-1 ).
| Trial (Date) | Entry Criteria | Drug and Dose | Outcome |
|---|---|---|---|
| Ryden (1983) | 1395 patients with suspected or later proven MI | Metoprolol 15 mg IV (3 × 5 mg), then 100 mg every 12 h for 3 months | Less ventricular fibrillation ( P < .05) |
| Norris (1984) | 735 patients with suspected MI within 4 h of onset | Propranolol 7 mg IV over 5 min (weight adjusted); oral 40 mg 1, 3, 7, 11, 15, 19, 23, 27 h (after start) | Less ventricular fibrillation ( P = .006) |
| MIAMI (1985) | 5778 patients with definite or suspected acute MI | Metoprolol 15 mg IV (3 × 5 mg), then 100 mg every 12 h until day 16 | No overall difference, but in high-risk group (retrospective) 29% fall in deaths |
| ISIS-1 (1986) | 16,027 patients within 12 h of onset of suspected MI | Atenolol 5-10 mg IV at once, then 100 mg/day orally for 7 days | Vascular mortality on first day reduced, P < .003; days 1-365, P < .01 |
| HINT (1986) | 338 patients with unstable angina | Metoprolol, 100 mg twice a day | MI at 48 h; odds ratio 1.07 (95% CI 0.54-2.09) |
| Kirshenbaum (1988) | 16 patients with acute MI or unstable angina with wedge pressure 15-25 mm Hg | Esmolol up to 300 µg/kg/min IV up to 48 h | Rate pressure product fell, wedge pressure the same, drug effect over by 30 min. In 4 of 16, drug stopped (oliguria, hypotension) |
| Roberts TIMI II-B (1991) | 1434 patients; beta blockade given early as IV then oral to 720, deferred for 6 days in 714 patients; all t-PA early | Early: Metoprolol 15 mg IV (3 × mg), then 100 mg in first 12 h, then 200 mg/day in split doses;Deferred: on day 6, start 50 mg then 100 mg, both twice daily | Mortality and ejection fraction at discharge unchanged; less early reinfarction and recurrent pain in early group; trend toward fewer intracranial bleeds |
| Van de Werf (1993) | 292 patients with acute MI ≤5 h duration (divided atenolol, placebo, alinidine) | Atenolol group: 5-10 mg IV then 25 to 50 mg twice daily | No clinical differences except 6% nonfatal pulmonary edema in atenolol vs. 0% in placebo group |
| COMMIT (2005) | 45,852 patients within 24 h of suspected MI; note metoprolol CV effects heterogeneous | Metoprolol up to 15 mg IV then 200 mg/day orally for mean of 15 days | Mortality equal (7.7%); per 1000 treated, 5 less reinfarction and 5 less ventricular fibrillation, versus 11 more cardiogenic shock |
COMMIT Trial
Those considerations prompted the conduct of the COMMIT trial, which randomized 45,852 patients within 24 hours of onset of symptoms to intravenous and continued oral metoprolol or placebo.
The majority of patients had STEMI or left bundle branch block and approximately half received thrombolytic therapy. Patients with “moderate” heart failure were allowed to be enrolled and 20% were estimated to be in Killip class II and 5% in class III at entry. Prior beta blocker use was not an exclusion. Up to 15 mg of metoprolol was administered intravenously in 5-mg aliquots at 2- to 3-minute intervals provided the heart rate was above 50 beats/min and systolic blood pressure above 90 mm Hg. Following this, 50 mg of metoprolol was administered orally and repeated every 6 hours for the first day followed by 200 mg in sustained-release formulation daily thereafter.
In this, the largest trial of early intravenous beta-blockade in acute myocardial infarction neither of the co-primary outcomes of (1) death or (2) a composite of death, reinfarction or cardiac arrest, were reduced by allocation to metoprolol. For every thousand patients on treatment for a mean of 15 days, metoprolol was associated with one fewer deaths (7.7% vs. 7.8%), five fewer reinfarctions, and five fewer episodes of ventricular fibrillation. This was counterbalanced by increased cardiogenic shock, heart failure, persistent hypotension and bradycardia (in total 88 serious adverse events). Shock occurred most frequently during the first 24 hours of treatment and rates of cardiogenic shock were greater for those older than 70 years of age, with systolic blood pressure less than 120 mm Hg, with a heart rate of greater than 110 beats/min, or with any heart failure. The authors pointed out that it was not possible to identify reliably any particular category of patients in which the beneficial effects of early beta blocker therapy clearly outweighed the adverse effects, although there was a tendency toward net benefit in those at lower risk of developing shock. The effects were time-dependent and in contrast with the early risk of cardiogenic shock, the reductions in the risk of reinfarction and of ventricular fibrillation emerged more gradually. The overall net effect of metoprolol on the combined efficacy and safety outcome changed from being significantly adverse during days 0 and 1 to being significantly beneficial thereafter.
The results of this very large placebo-controlled, double-blind investigation and the observational analysis of GUSTO-I have led to suggestions that early intravenous beta-blockade should be removed from standard recommendations and replaced by the introduction of a beta blocker only once hemodynamic stability is ensured , This is despite contemporary experimental evidence showing that intravenous beta blocker reduces infarct size.
However, it can be argued that the outcome of COMMIT does not justify all the conclusions that have been drawn and that some aspects of the trial are open to criticism. In COMMIT, high doses of both intravenous and oral metoprolol were given to all patients including some with heart failure and others already on treatment with a beta blocker. These patient characteristics and the policy of continued administration of intravenous beta blocker provided systolic blood pressure was not lower than 90 mm Hg and heart rate was above 50 beats/min may have led to harm and the consequent inability to demonstrate benefit. Prudent clinical practice is not to administer intravenous beta blockers to patients with STEMI who have clinical heart failure, extreme bradycardia, or hypotension nor to those already on treatment with beta blockers. Guidelines for both STEMI and non–ST-elevation myocardial infarction (NSTEMI) , advise against acute use of beta blockers in patients with rales or an S3 gallop and most clinicians would avoid intravenous administration of beta blockers to patients in pulmonary edema (Killip III). The most recent guidelines for the management of STEMI continue to emphasize the importance of attempting to introduce beta blocker therapy as early as possible. However, in the only study comparing early intravenous beta blockade at a mean delay of 3.3 hours after the onset with later oral administration at 6 days, there were no substantial differences in mortality at 1 year, although early reinfarction and recurrent chest pain were reduced. Hence the guidelines do not recommend routine intravenous administration, while emphasizing the great importance of carefully screening patients for contraindications to beta blockade before its introduction, the necessity of continued monitoring of patients for complications, and careful and prudent dose titration. , , The use of ultra-short-acting beta blockers such as esmolol is attractive but has also not been tested in large-scale outcome trials and has not achieved widespread clinical implementation.
Primary Percutaneous Coronary Intervention (PCI) and Beta Blockade
The excellent results of primary PCI have made it the treatment of choice for patients with STEMI-ACS when patients are seen early and the necessary personnel and facilities are available. The necessary urgency in obtaining shortened “door-to-balloon” times may mean that potentially beneficial therapies not directly linked to PCI are inadvertently omitted. Additionally the shortened hospitalization times and perception of both physician and patient that the condition has been cured may lead to omission of important prophylactic therapies. While there is no good evidence from prospective randomized trials of whether or not beta blocker therapy is beneficial in the setting of primary PCI for STEMI, observational analyses suggest that it is and should be administered intravenously before PCI and continued orally after the procedure. Retrospective analysis of the CADILLAC trial of primary PCI showed that 30 mortality was reduced from 2.8% to 1.5% by pre-procedural administration of intravenous beta blockade and improvement in left ventricular function between baseline and 7 months was greater after intravenous beta blockade. These benefits were limited to patients not being treated with beta blockers prior to infarction. Pre-procedural beta blockers may protect patients undergoing primary PCI against ventricular tachycardia and ventricular fibrillation during the procedure. Beta blockade after successful primary PCI reduced 6-month mortality from 6.6% to 2.2% in observational studies. The greatest benefit was seen in patients with low ejection fraction or multi-vessel disease. These observational studies suggest that the advent of a new and effective form of treatment for STEMI is a stimulus to fully investigate the combination with beta blockade to obtain maximum patient benefit in appropriately selected patients.
Beta Blockade and STEMI-Related Left Ventricular Dysfunction and Heart Failure
The beneficial effects of beta blockers after STEMI in the trials of an earlier era (see Table 23-1 ) were shown well before the introduction of current standards of reperfusion, and also before the benefit of the angiotensin converting enzyme inhibitors (ACE-Is) in heart failure and left ventricular dysfunction, and the marked benefits of beta blocker therapy in chronic heart failure were established. Many patients with heart failure or asymptomatic left ventricular dysfunction were almost certainly excluded by cautious physicians evaluating beta blockers after STEMI in the early trials. Three retrospective analyses—SAVE, SOLVD, and AIRE —showed that patients treated with a beta blocker had lower rates of events than those not so treated and indicate that beta blockers can and should be used in patients with treated heart failure and left ventricular dysfunction after STEMI. The results of the CAPRICORN trial reinforce this opinion. This investigation randomized patients with reduced ejection fraction (<40%) within 21 days after myocardial infarction who were treated with an ACE-I to carvedilol in increasing dose or placebo. Carvedilol reduced all-cause mortality and nonfatal infarction. The all-cause mortality rate was 12% on carvedilol versus 15% on placebo at an average follow-up of 1.3 years. Approximately half of all participants had experienced reperfusion with thrombolytics or primary PCI. The effects were seen early and the carvedilol group experienced a reduction in mortality in the first 30 days, which is the period of greatest risk for recurrent infarction, sudden death, and all-cause mortality. The effects within the first 30 days were similar in direction and magnitude to those observed during the prolonged follow-up period.
Guidelines recommend early introduction and continued treatment with beta blockers for all patients without contraindications after STEMI But concern remains that they are underused, particularly in patients with heart failure. , This may reflect physicians’ concerns that these agents may worsen heart failure. The results of CAPRICORN should allay these fears and encourage more widespread use of beta blockers in addition to all other appropriate therapy for heart failure after MI. Beta blockers can worsen heart failure and are generally considered contraindicated in hemodynamically unstable patients. Specific agents, such as carvedilol, when used appropriately with careful up-titration of dose in addition to other appropriate treatment in stable patients in the convalescent phase of MI, are safe and confer benefit. The only side effect found during up-titration of carvedilol started in the convalescent phase was hypotension necessitating withdrawal in some patients.
Relative contraindications and potential harmful effects in some groups of patients are often cited by clinicians as reasons not to prescribe beta blockers after STEMI and may be responsible for under-use and under-dosing. Survival benefit with beta blocker therapy has been demonstrated in observational registry analyses of large numbers of patients after MI with such relative contraindications as chronic lung disease, diabetes, peripheral vascular disease, as well as heart failure and left ventricular dysfunction.
Where cocaine use is considered a possible precipitant of STEMI, beta blocker therapy is generally considered to be contraindicated.
Beta Blockers in Non–ST-Elevation Acute Coronary Syndromes
In contrast to the situation in patients with STEMI where there is a considerable reported experience with beta blockers and fair evidence of benefit in trials from an earlier era, there is a remarkable lack of good information from randomized trials on the use of these agents in patients with unstable angina and NSTEMI. Despite the lack of contemporary published evidence of benefit, oral beta blockers are recommended to be started early in the absence of contraindications in current guidelines and intravenous administration is advised in patients with ongoing rest pain, especially with tachycardia or hypertension. ,
Observational data suggest that acute beta blockade, given within 24 hours of onset, but not specifically intravenously, is underused especially in the elderly and in those with heart failure. These recommendations are based on expert opinion, clinical experience and old, small, and inconclusive studies that would be unlikely to survive the careful scrutiny to which current therapies are subjected. The HINT trial, published two decades ago, was the largest study evaluating beta blockers in NSTEMI. In that study 338 patients, not previously treated with a beta blocker, were randomized to placebo, nifedipine, or metoprolol. Metoprolol-treated patients experienced fewer ischemic events but the effect was not statistically significant. A more recent but smaller study evaluated carvedilol compared to placebo in addition to aspirin, nitrates, and heparin. Carvedilol reduced the number and duration of ischemic episodes and the number of patients experiencing ischemic episodes during 48 hours of ambulatory monitoring. The clinical relevance of this benefit is unclear. The totality of evidence of benefit for beta blocker therapy in NSTEMI-ACS is far from convincing. A dated review of double-blind randomized trials in patients considered to have threatening or evolving myocardial infarction suggests that such therapy offers an approximately 13% reduction in the risk of progression to myocardial infarction.
Some good observational evidence that is available to guide practice in the current era comes from the analysis of results of several trials of a variety of antiplatelet agents in patients with ACS who were undergoing percutaneous intervention. After 1 month, there were more deaths (2%) in patients not receiving beta blocker therapy than in those treated with beta blockers (0.6%). This mortality benefit persisted to 6 months by which time 3.7% of patients not treated with beta blockers versus 1.7% of those treated with beta blockers had died. Current practice as evaluated in large registries indicates that beta blockers are used in the majority of patients within the first 24 hours of presentation with symptoms of NSTEMI. Such use is correlated with both lower in-hospital mortality and lower mortality at 6 months. Failure to institute beta blockade within the first 24 hours was associated with lower rates of subsequent beta blocker therapy and the use of evidence-based therapies.
Analysis of beta blocker use in usual practice in a very large registry of 72,054 patients with NSTEMI at 509 U.S. hospitals between 2001 and 2004 showed that acute beta blocker use, implemented in more than 80% of such patients, was associated with lower in-hospital mortality (3.9% vs. 6.9%, P < .001) and the beneficial effects were seen in patients with and without signs of heart failure. The authors concluded that the majority of NSTEMI patients in usual practice receive acute beta blocker therapy, but some subgroups remain undertreated. Given the improved clinical outcomes in nearly all subgroups assessed, broader use in such patients appears warranted, albeit lacking prospective trial evidence. A similar frequent use of beta blockers in international practice is reflected in an early review and in the GRACE registry.
Thus, the overall evidence base for the use of beta blockers in patients with unstable angina or NSTEMI, in contrast to much other evidence on which important therapeutic decisions are based in cardiology, is virtually nonexistent apart from registry studies. Yet almost all guidelines advise the use of beta blockers. Given the demonstrated benefit of long-term beta blockade after MI and the excellent symptomatic relief they provide in patients with stable angina, it is unlikely that the current recommendations will be tested in any randomized trial and will remain standard in patients without major contraindications.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
