Beta-Blockers for Treatment of Hypertension: Where Do They Fit?

Prescribing cascade occurs when the side effects of a prescribed drug are misinterpreted as a new medical condition, leading to the subsequent addition of another drug to treat these side effects.1 This phenomenon deserves close attention from clinicians. Two forms of prescribing cascades have been described: intentional and unintentional.2 Intentional or “unavoidable” prescribing cascades are not uncommon in medicine. Potassium chloride supplement for patients on loop diuretics is one example. However, the unintentional prescribing cascades represent opportunities to reduce the burden of polypharmacy and the resulting increase in patients’ morbidity and healthcare expenditure. When side effects of a drug ensue, the optimal approach is to recognize them for what they are and potentially change the drug or reduce its dose. The 2 essential steps in avoiding a drug prescribing cascade are being aware of the drug side effects and recognizing the drug indications and alternatives. In this issue of the American Journal of Hypertension, Vouri et al. present their findings of studying a large prescription database to evaluate beta-blockers (BBs)—edema—loop diuretics prescribing cascade.3 Edema is a common side effect of certain antihypertensive classes, including calcium channel blockers and direct vasodilators like hydralazine. However, it is not a widely recognized side effect of BBs. The authors applied a pharmacovigilance approach called “prescription sequence symmetry analysis”4 to test a hypothesis that patients are more likely to be prescribed loop diuretics after initiating BBs due to the development of edema. Among BBs initiators, authors estimated 1.72 excessive initiations of loop diuretics per 100 patient-years. This rate was higher among individuals older than 65 years (4.09 vs. 1.25), with the use of metoprolol tartrate (4.0) and with metoprolol succinate (2.11). It is important to note that this study aimed to focus on patients prescribed BBs for the treatment of hypertension and excluded patients who may have other indications for BBs like atrial fibrillation or who may require loop diuretics for congestive heart failure. Raising awareness of edema as a side effect of BBs is important in avoiding the described prescribing cascade. But could one argue that such prescribing cascade is “unavoidable” for patients with hypertension? The remaining of this paper will take a closer look into the role of BBs in treating hypertension. Following several trials in the 1970s and 1980s, BBs benefits in improving cardiovascular outcomes following acute myocardial infarction became clear.5 Soon, this class of drugs became the standard of care in secondary cardiovascular disease (CVD) prevention. In the absence of contraindications, BBs have a clear benefit in the long-term management of patients with acute coronary syndrome or heart failure with reduced ejection fraction.6 They are also often used for rate control in patients with certain tachyarrhythmias like atrial fibrillation.7 With time, BBs use crossed over from secondary CVD prevention to primary prevention, and they became a widely used class of drugs in patients with hypertension. At one point, almost 35% of US adults with hypertension were prescribed BBs, making them the third most prescribed class of drugs to treat hypertension.8 However, a close review of available evidence reveals the inferiority of BBs as an antihypertensive class compared with diuretics, ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers. In a recent update from Cochrane Library, 13 studies comparing BBs to placebo, diuretics, calcium channel blockers, and renin–angiotensin–system inhibitors were reviewed. The authors concluded that BBs offered modest CVD reduction with little or no effect on mortality, and as a class, BBs were inferior to the other antihypertensive drugs reviewed.9 In their meta-analysis, Lindholm et al. showed that the relative risk of stroke was 16% higher for BBs than other antihypertensive drugs.10 This limited benefit may, in part, be related to an unfavorable hemodynamic effect on central aortic pressure. For example, compared with amlodipine, atenolol was associated with significantly higher central systolic and diastolic blood pressure at the same level of brachial blood pressure.11 Similar findings were seen when BBs were compared with ACEIs.12 This phenomenon, described as “pseudo antihypertensive effect,”13 may explain why BBs did not reduce the risk of stroke or regress left ventricular hypertrophy as effectively as other classes of antihypertensive drugs.14 Pseudo antihypertensive effect becomes especially important when treating isolated systolic hypertension. The heart rate reduction from BBs results in a compensatory increase in stroke volume, which may worsen central aortic systolic pressure further.13 In addition to what Vouri et al. described in their study,3 BBs have other important side effects. They are associated with an increase in the risk of new-onset diabetes mellitus with a relative risk of 1.22 (95% confidence interval 1.12–1.33) compared with nondiuretic antihypertensive drugs.15 This risk is further augmented when BBs are combined with thiazide diuretics.16 The effect was pronounced enough for Mason et al. to conclude that “the increased risk of developing diabetes may exceed the benefit of blood pressure lowering” in certain patients.16 When this risk is combined with BBs adverse effect on lipoprotein metabolism17 and their tendency to limit exercise tolerance, the use of BBs in treating hypertension, especially in patients who will be on treatment long-term, becomes troublesome. As a result of these findings, it is not surprising to see many hypertension management guidelines consider BBs as fourth or fifth line hypertension therapy in the absence of compelling indications. The 2017 Guidelines for High Blood Pressure in Adults do not recommend the use of BBs in the treatment of hypertension unless the patient has compelling indication such as ischemic heart disease or heart failure.18 Current National Institute for Health and Care Excellence (NICE) guidelines only recommend BBs after initiation of ACEIs, ARBs, calcium channel blockers, or thiazide-like diuretics.19 Furthermore, BBs are only recommended for those with blood potassium of more than 4.5 mmol/l; spironolactone is preferred for those with lower potassium levels. No discussion of BBs is complete without acknowledging the heterogeneity of this class when it comes to the individual drug exact mechanism of action. This class includes cardioselective BBs, nonselective BBs, combined BB and α1-blocker, and BBs with intrinsic sympathomimetic activity. As a result of this heterogeneity, the effect on blood pressure, cardiovascular benefits, and side effect profile may differ from one individual drug to another. Among BBs, carvedilol, which has BB and α1-blocker activity, and nebivolol, a selective BB with the ability to increase nitric oxide bioavailability, are both considered “vasodilatory BBs.” Vasodilating BBs tend to reduce peripheral vascular resistance and are more effective in lowering central aortic pressures. This unique property makes these 2 drugs preferred choices when BBs must be added to treat hypertension.20 In conclusion, in the absence of compelling indications such as ischemic heart disease, heart failure with reduced ejection fraction, or atrial fibrillation, BBs should be kept as an add-on fourth or fifth line hypertension therapy. When BBs are added for the treatment of hypertension, vasodilatory drugs like carvedilol or nebivolol are preferred. Close attention to potential side effects should be maintained. When one or more side effects occur, the drug or its dose should be changed when possible to help prevent a prescribing cascade and reduce the risks associated with polypharmacy. The authors declared no conflict of interest.