Distinctions in Class: Considerations for the Use of β‐Blockers in Cardiovascular Disease

There is little dispute that hypertension therapy should be customized to an individual patient's needs and that, as physicians, we must aggressively treat hypertension to avoid its long‐term complications. The nuances of selecting a medication for hypertension therapy, however, often go underappreciated. Physicians are charged not only with choosing the class of agent that is best suited for their patient, but also with artfully selecting the best agent within that class.

In that regard, there are innumerable medication classes to select from when opting for an antihypertensive medication. Angiotensin receptor blockers, angiotensin‐converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), and diuretics continue to be used with some regularity in the initial phases of hypertension treatment. The primary use of β‐blockers in the treatment of hypertension, however, has been questioned in the face of considerable debate about their utility.

Many physicians believe that the age of β‐blocker use in the first‐step treatment of hypertension is all but over; however, such a view is overly restrictive. β‐Blockers remain desirable first choices for various forms of sympathetically driven hypertension and continue to be suitable complementary therapies in the patient with hypertension who requires 3 or 4 medications. Moreover, there is a not insignificant body of positive outcomes data that supports β‐blocker use in patients with hypertension and compelling indications such as heart failure (HF), the post‐myocardial infarction (MI) circumstance, and/or a high coronary artery disease (CAD) risk. ¹

As with most other antihypertensive drug classes, the question of class effect with β‐blockers arises with their use both for compelling indications and as primary hypertension treatment. The β‐blocker drug class is one characterized by considerable diversity, with abundant pharmacokinetic and pharmacodynamic differences that go well beyond the issue of whether a compound is cardioselective (β₁) or noncardioselective (β₁/β₂). One such intraclass difference receiving much play of late is that of combined α‐/β‐blockade, which is addressed in some detail throughout this supplement.

In this supplement, we review the current landscape of β‐blocker therapy in hypertension as well as in cardiovascular disease in general. The first article, “β‐Blockers in Hypertension: A Reassessment of the Benefit of Combined α‐/β‐Blockade,” addresses the issue of class effect among β‐blockers. Most β‐blockers lower cardiac output and do not decrease peripheral vascular resistance; there may also be negative metabolic consequences to their use that can influence the development of CAD; however, vasodilating β‐blockers differ in that regard. One such compound is carvedilol, which is a β‐adrenergic blocker with αblocking effects and many other intraclass distinguishing features. ²

There is a paucity of data from large‐scale clinical trials regarding the benefits of β‐blockade in patients with essential hypertension compared with other antihypertensive therapies. This theme is addressed in the paper “A Modern Perspective on β‐Blocker Use in Hypertension: Clinical Trials and Their Influence on Clinical Practice.” ³ Clinical trials in patients with hypertension have shown that β‐blockers successfully lower BP, but recent data have questioned their effectiveness in reducing the risk of morbidity and mortality when compared with other antihypertensive agents such as diuretics, ACE inhibitors, and CCBs. Accordingly, national guidelines now recommend β‐blockers as second‐line agents after diuretic therapy in patients without compelling indications. ¹

Drs Black and Sica use both historical data and recent clinical trials to underscore the importance of β‐blockade in specific patient populations and to help demarcate those circumstances where β‐blocker use is most appropriate. As such, in high‐risk patients with hypertension (ie, people who have had an MI or have diabetes, HF, or CAD), β‐blockers have been shown to reduce the risk of cardiovascular mortality and are, therefore, a warranted choice of therapy. In patients with HF or post‐MI patients, β‐blockers have been shown to reduce event rates apart from what might be ascribed to BP lowering alone. ³

Dr Frishman provides a wide‐ranging review in his article, “A Historical Perspective on the Development of β‐Adrenergic Blockers.” ⁴ This article provides the context and chronology of the introduction of β‐blocking agents, along with the subsequent applications of this therapeutic class to a wide variety of cardiovascular and noncardiovascular conditions. The advent of β‐adrenergic‐blocking drugs is one of the most significant advances in pharmacology, and their use has helped uncover the role of the sympathetic nervous system in the pathophysiology of a wide variety of disorders. As Dr Frishman notes, “the therapeutic efficacy and safety of β‐adrenergic‐blocking drugs has been well established after 40 years of use.” This paper allows the reader to follow the β‐blocker story step‐by‐step, and, as such, the reader gains a keen understanding of how β‐blockers became mainstream therapy.

In a departure from the hypertension focus of this supplement, Dr Yancy provides the rationale and importance of β‐blockade in patients with HF. ⁵ Hypertension is a well‐recognized risk factor for the development of HF and, thus, a discussion on HF matters is relevant. The American College of Cardiology and American Heart Association recognize patients with hypertension as having stage A heart failure (ie, “at high risk for the development of heart failure”). ⁶ Hypertension, together with aligned risk factors such as diabetes and CAD, can lead to left ventricular hypertrophy and diastolic and/or systolic HF.

In the Systolic Hypertension in the Elderly Program (SHEP), ⁷ , ⁸ treatment with the diuretic chlorthalidone and the β‐blocker atenolol decreased HF rates by almost 50%. Unfortunately, despite their important life‐sustaining effects in HF, β‐blockers remain underutilized. Strategies to improve processes of care and increase the use of evidence‐based therapies are needed. Simplifying dosing is one such consideration that ultimately encourages patient adherence to prescription regimens. ⁹ A new controlled‐release formulation of carvedilol, a non‐cardioselective α‐/β‐blocker, has been approved for once‐daily use in patients with systolic HF and post‐MI left ventricular dysfunction. ¹⁰ The availability of once‐daily HF medications may improve patients' compliance with prescribed treatments and thereby promote better clinical outcomes. ¹¹

This supplement provides a comprehensive look at where β‐blockade currently fits in hypertension management and whether β‐blockers will remain an important part of this treatment paradigm. We encourage readers to weigh the evidence for β‐blocker use and arrive at their own conclusions regarding the use of β‐blockade in their practice. No matter what class of agent or drug within a particular class is used, it is imperative that physicians treat hypertension early and aggressively to slow, and possibly prevent, progression to cardiovascular disease.