Other Adjunctive Drugs for Coronary Intervention: Beta-Blockers, Calcium-Channel Blockers, and Angiotensin-Converting Enzyme Inhibitors

Key Points

β-Blockers provide long-term mortality reduction after myocardial infarction (MI).
Although β-blockers are beneficial, they should be used carefully immediately after MI to avoid cardiogenic shock in susceptible patients.
Calcium-channel blockers are reasonable alternatives to β-blockers after MI in the few patients with strong contraindications to β-blockers.
Angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients after MI, especially in those with left ventricular (LV) dysfunction.
Genomic studies have demonstrated differential response of some populations to these agents, and further studies might help us target individuals with specific agents in the future.

Introduction

For several decades, β-blockers, calcium-channel blockers, and angiotensin-converting enzyme (ACE) inhibitors have been beneficial in a wide spectrum of coronary artery disease (CAD)—stable and unstable angina, ST-elevation myocardial infarction (STEMI), and non–ST-elevation myocardial infarction (NSTEMI). Multiple clinical trials since the 1980s have demonstrated benefits of these agents, which work either by reducing myocardial oxygen demand or by promoting favorable myocardial remodeling.

This chapter will discuss the basic pharmacology of these agents, followed by an in-depth discussion of randomized trials that have used them. Finally, we will discuss ongoing research and will also provide treatment recommendations.

β-Adrenergic Receptors

β-Receptors belong to a well-characterized family of receptors known as G protein-coupled receptors . The pathway involves binding of an agonist, such as catecholamines for β-receptors, to an extracellular receptor. Receptor activation causes a coupled G protein to stimulate adenylyl cyclase, which increases intracellular concentrations of cyclic adenosine monophosphate (cAMP). In turn, cAMP activates several AMP-dependent protein kinases, which phosphorylate other proteins and result in a cellular response.

The cellular response for β-receptors differs according to three major subtypes: β ₁ , β ₂ , and β ₃ . Whereas stimulation of β ₂ -receptors causes bronchodilation and peripheral vasodilation, stimulation of β ₁ -receptors predominantly affects the heart, increasing contractility, heart rate, and lipolysis. The β ₃ -receptor increases heat production in brown adipose tissue and increases lipolysis in both brown and white adipose tissue. Notably, the β ₃ -receptor likely plays a role in obesity and insulin resistance and may promote endothelial nitric oxide synthase and nitric oxide bioavailability.

β-Adrenergic Receptor Blockers

β-Blockers act by directly competing with binding of catecholamines to β-adrenergic receptors. These agents differ in their selectivity, lipid solubility, metabolism, and partial-agonist ability (intrinsic sympathomimetic ability [ISA]; Table 13.1 ). Although some data suggest that these differences might impact efficacy in certain conditions, such as chronic congestive heart failure (CHF), these differences mainly affect side effects, contraindications, and frequency of dosing. For example, nonselective agents may increase bronchospasm in asthmatic patients, whereas lipophilic agents may have more central nervous system (CNS) effects such as sedation and depression. Type of metabolism will affect plasma half-life in patients with renal or hepatic insufficiency. β-Blockers with ISA slow heart rate less than β-blockers without ISA; also, β-blockers with ISA are less likely to decrease high-density lipoprotein cholesterol (HDL-C) or to increase triglycerides.

TABLE 13.1

β-Blockers

Adapted from Griffin B, Topol E, Nair D, et al. Manual of Cardiovascular Medicine . 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

Type	Dose (mg)	Frequency (Q)	Excretion	Lipid Solubility	ISA
Selective β ₁
Acebutolol	200–600	12 h	Kidney	Moderate	Low
Atenolol	25–200	24 h	Kidney	None	None
Betaxolol	20–40	24 h	Kidney	Moderate	Low
Metoprolol Long-acting metoprolol	50–400	12 h 24 h	Liver	Moderate	None
Nonselective β
Labetalol (α, β ₁ , β ₂ )	600–2400	6–8 h	Liver	None	None
Nadolol	80–240	24 h	Kidney	Low	None
Pindolol	15–45	8–12 h	Kidney	Moderate	Moderate
Propranolol Long-acting propranolol	80–320	4–6 h 12 h	Liver	High	None
Timolol	15–45	12 h	Liver	Moderate	None

ISA , Intrinsic sympathomimetic ability.

Despite these pharmacokinetic differences, efficacy in CAD arises primarily from β ₁ -receptor antagonism. In acute MI, for example, the catecholamine storm decreases the fibrillation threshold, increases myocardial oxygen consumption, and promotes myocardial necrosis. By decreasing heart rate and contractility, blockade of the β ₁ -receptor lowers myocardial stress, which decreases necrosis. β-Blockade also raises the fibrillation threshold. By antagonizing lipolysis, β-blockers reduce concentrations of free fatty acids and cause greater use of glucose and less use of oxygen. Although controversial, β-blockers—in particular, carvedilol and nebivolol—may also inhibit platelet aggregation, but the mechanism could be membrane interaction instead of β-receptor antagonism.

Given these beneficial effects, it is not surprising that numerous clinical trials have demonstrated the benefits of β-blockers in acute coronary syndromes (ACSs). Nonetheless, prudence is still required because β-blockers decrease inotropy and slow atrioventricular conduction, which can harm certain subgroups of patients.

Unstable Angina Pectoris

Because β-blockers potently reduce myocardial oxygen demand and possibly reduce inflammation in ACSs, treating unstable angina with β-blockers has much intuitive appeal. A few small randomized trials have supported this. Gottlieb and colleagues randomized patients with unstable angina to 4 weeks of propranolol or placebo. All patients received calcium-channel blockers and/or nitrates. Although incidence of death, myocardial infarction (MI), or need for urgent coronary artery bypass grafting (CABG) did not differ between the groups, propranolol significantly reduced frequency and severity of recurrent ischemia. In the Holland Interuniversity Nifedipine and Metoprolol Trial (HINT), 338 patients with unstable angina not pretreated with a β-blocker randomly received nifedipine alone, metoprolol alone, or nifedipine and metoprolol. The odds ratios (ORs) for recurrent ischemia or MI by 48 hours were 1.15 for nifedipine (95% confidence interval [CI], 0.83 to 1.64), 0.76 for metoprolol (95% CI, 0.49 to 1.16), and 0.80 for both (95% CI, 0.53 to 1.19). Not surprisingly, small numbers limited the power of this study, and these differences were not statistically significant. Hohnloser and associates examined effects of esmolol, a short-acting (half-life 9 minutes) intravenous (IV) β-blocker in a randomized, placebo-controlled trial of 113 patients. Investigators increased esmolol until they reduced the double-product by about 25%; thereafter, the esmolol infusion continued for up to 72 hours. Acute MI or urgent revascularization occurred in 9 patients treated with placebo compared with 3 patients treated with esmolol ( P = .06). In a more recent randomized trial, Brunner and colleagues randomized 116 patients with unstable angina to placebo or carvedilol at 25 mg twice a day. Patients received 48-hour Holter monitoring to document ischemia. Carvedilol reduced ischemic time by 76% (204 vs. 49 minutes, P < .05) with a 66% reduction in number of ischemic episodes (24 vs. 8, P < .05).

Some retrospective data from recent studies also demonstrate benefit of β-blockers in unstable angina. Ellis and associates pooled data from five randomized trials of abciximab during percutaneous coronary intervention (PCI): Evaluation of the 7E3 for the Prevention of Ischaemic Complications (EPIC) trial, Evaluation in percutaneous transluminal coronary angioplasty (PTCA) to Improve Long-Term Outcome With Abciximab GP IIb/IIIa Blockade (EPILOG), Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT), c7E3 FAB Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), and ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT). Except for RAPPORT, which had STEMI patients, the other four trials included patients with unstable angina or NSTEMI. All-cause mortality by 30 days occurred in 0.6% of patients receiving β-blockers compared with 2.0% for patients who did not receive β-blockers. After adjusting for baseline characteristics and propensity score to receive β-blockers, β-blockers remained predictive of lower mortality (hazard ratio [HR], 0.25; 95% CI, 0.11 to 0.57; P = .001). This mortality difference persisted at 6 months (1.7% vs. 3.7%; adjusted HR, 0.53; 95% CI, 0.29 to 0.94; P = .03). Among patients with unstable angina, β-blockers reduced mortality at 3 months (1.6% to 0.6%, P = .029) and at 6 months (3.1% to 1.4%, P = .009).

Similarly, investigators found a mortality benefit of β-blockers in patients enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines (CRUSADE) initiative. In 72,054 patients with NSTEMI at 509 U.S. hospitals from 2001 through 2004, acute β-blocker use was associated with a lower hospital mortality (adjusted OR, 0.66; 95% CI, 0.60 to 0.72; P < .01). Notably, nearly all patient subgroups benefited, including patients aged 80 years and older.

Percutaneous Coronary Intervention

Although trials have evaluated adjunctive β-blockade in patients with unstable angina or MI undergoing PCI, fewer data exist for effect of β-blockade as a specific adjunct to PCI. In fact, most data for adjunctive benefit arise from nonrandomized registries.

Sharma and colleagues evaluated 1675 consecutive patients undergoing PCI, none of whom had a previous MI; the authors did not specify how many patients presented with unstable angina. Creatine kinase myocardial band (CK-MB) elevation occurred in 13.2% of patients on β-blockers before the procedure compared with 22.1% of patients not on β-blockers ( P < .001). On multivariate analysis, β-blockers remained an independent predictor of lower CK-MB release. Over a mean 15 months of follow-up, patients on preprocedural β-blockers had a mortality of 0.8% compared with 2.0% for patients not on preprocedural β-blockers ( P = .04). Chan and colleagues evaluated 4553 consecutive patients without acute or recent MI who underwent PCI according to whether they had been treated with β-blockers at the time of the PCI. Of these patients, 2056 (45%) were on β-blockers at the time of the intervention. Mortality was lower at 30 days for patients who received β-blockers (1.3% vs. 0.8%, P = .13) and at 1 year (6.0% vs. 3.9%, P = .0014). After adjusting for differences in the baseline characteristics by propensity analysis, β-blocker therapy remained independently predictive of 1-year survival (HR, 0.63; 95% CI, 0.46 to 0.87; P = .0054).

Along with these mortality data, other data suggest a benefit of β-blockers on restenosis. Jackson and colleagues followed 4840 people who underwent PCI according to whether they received β-blockers on discharge. Patients treated with β-blockers had a 5-year clinical restenosis rate of 12% versus 14% (adjusted OR, 0.83; P = .046). These data are controversial, however, because a small randomized trial of adjunctive carvedilol failed to reduce restenosis in patients undergoing atherectomy.

In another small randomized trial, Wang and colleagues examined the effect of intracoronary (IC) propranolol during PCI. In this trial, investigators randomized 150 patients undergoing PCI to placebo or propranolol (15 μg/kg) injected into the distal coronary artery via the balloon catheter positioned across the stenosis. CK-MB elevation occurred in 17% of propranolol patients compared with 36% of placebo patients ( P = .01). The incidence of death, MI, or urgent revascularization by 30 days occurred in 18% of propranolol patients compared with 40% of placebo patients ( P = .004). The relative risk (RR) of MI did not differ between patients on prior β-blocker therapy and those not on prior therapy.

Uretsky and colleagues also examined the effect of IC β-blockers during PCI by randomizing 400 patients to IC propranolol or placebo combined with systemic eptifibatide. At 1 year, the composite end point of death, postprocedural MI, urgent target-lesion revascularization (TLR), or MI after hospitalization occurred in 21.5% of propranolol patients and in 32.5% of placebo patients ( P < .01), driven primarily by lower periprocedural MI (12.5% propranolol vs. 21.5% placebo; RR reduction 0.43; 95% CI, 0.08 to 0.65; P = .018).

In a unique study design, Park and colleagues randomly assigned 70 patients undergoing elective PCI to either placebo or the short-acting β-blocker landiolol as a 1-minute IC infusion before and after first balloon inflation, followed by a 6-hour IV infusion. The troponin I (TnI) level at 24 hours trended lower in the landiolol group compared with placebo (0.5 ± 1.14 vs. 1.27 ± 2.48, P = .07), although it is unclear whether this difference, if verified in a larger cohort, would be clinically meaningful.

Acute Myocardial Infarction

Early Trials: The MIAMI and ISIS-1 Trials

The data for β-blockade in acute MI come from 26 small trials and two large trials: the First International Study of Infarct Survival (ISIS-1) trial and the Metoprolol in Acute Myocardial Infarction (MIAMI) trial.

The MIAMI Trial

Patients with acute MI within 24 hours of symptom onset ( n = 5778) were randomized to receive IV metoprolol (15 mg) or placebo followed by oral metoprolol (200 mg daily) or placebo for 15 days. β-blockade reduced Q-wave infarction significantly, from 53.9% to 50.9% ( P = .024), with a nonsignificant reduction in mortality (4.9% to 4.3%, P = .29). However, the MIAMI trial was significantly limited in its applicability to the modern era; patients enrolled in MIAMI were low risk (e.g., all Killip class I), and the trial occurred in the pre-reperfusion era before routine ACE inhibition and statin treatment.

The ISIS-1 Trial

Although ISIS-1 was similarly limited by lack of reperfusion, its larger size and power are important. ISIS-1 randomized 16,207 patients with suspected acute MI (mean 5-hour symptom onset) to control or to IV atenolol (5 to 10 mg) followed by 100 mg oral atenolol daily for 7 days. Treatment with atenolol significantly reduced vascular mortality from 4.57% to 3.89% ( P < .04) from day 0 to day 7. Atenolol-treated patients also had a significantly lower vascular mortality by 1 year (10.7% vs. 12.0%, P < .01), although much of this late difference might have arisen because patients randomized to atenolol were more likely to be discharged on β-blockers compared with controls.

COMMIT and Other Trials

Given that most data for β-blockade in acute MI are several decades old, benefit for β-blockade in the current era—with aggressive use of antiplatelet therapy, thrombolysis, or primary angioplasty, statin therapy, and antialdosterone therapy—has remained uncertain, and physicians have hoped for trials with modern background therapy to assess the true value of β-blockade. This uncertainty has remained relevant because of persistent fears that β-blockers may exacerbate the condition of some acute MI patients, particularly those with signs and symptoms of CHF.

Ibanez and colleagues randomized 270 patients of Killip class II or less with anterior STEMI to receive an IV β-blocker or a placebo before primary PCI. In this small group of selected patients, infarct size estimated by creatine kinase curves was smaller in the IV β-blocker group.

More definitive data come from the large-scale randomized trial Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT). In fact, COMMIT was the largest trial ever to investigate β-blockers in acute MI. As such, it is exceptionally important to understand the trial in depth and its implications for patient management.

The COMMIT trial, also known as the Second Chinese Cardiac Study (CCS-2), was a placebo-controlled randomized trial with a two-by-two factorial design that randomized acute MI patients to metoprolol or placebo, as well as to clopidogrel or placebo, with a background therapy of aspirin, anticoagulant therapy (mostly unfractionated heparin [UFH]), and thrombolysis.

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