Time to Retire Beta-Blockers in Uncomplicated Hypertension?

Beta-blockers were one of the first modern medications used for the treatment of blood pressure. Before 1950, treatment options for hypertension were limited. The alphabet soup of medications -reserpine, pentaquine, hydralazine, and guanethidine -were notorious for inducing orthostasis, sedation, constipation, impotence, or blurry vision. Then in the 1960s, propranolol and chlorothiazide were developed. Initially designed to treat angina pectoris, propranolol was serendipitously discovered to also lower blood pressure. Oddly, propranolol, like the other beta-blockers in its generation and thereafter, did not act directly on the blood vessel to lower blood pressure. Instead, its purported mechanism of action was via inhibition of beta-adrenergic receptors, reduction of cardiac output, and decrease in sympathetic outflow. Despite beta-blockers' odd mechanism of action, they were (and still are) as effective as the earlier anti-hypertensive agents in decreasing blood pressure. Beta-blockers became extremely popular once they were found to have many fewer side effects than the older generation of drugs. Since then, many derivatives and generations of the beta-blocker have come into use and have become the mainstay in the treatment of hypertension. In the subsequent 40 years, beta-blockers battled high blood pressure in the front lines. But in 2014, researchers appointed to the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) released what was called the 8th guideline on treating hypertension. In these new recommendations, beta-blockers were relegated to second-line treatment, behind thiazide diuretics, calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEi), and angiotensin II receptor blockers (ARBs). After being the crux of hypertension treatment for decades, are beta-blockers becoming obsolete? Several studies from the early 2000s rendered the beta-blocker a less attractive treatment option for hypertension. In 2002, rallying more than 30,000 hypertensive individuals, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that treatment with the thiazide diuretic chlorthalidone decreased the rate of heart failure (HF) significantly more than an ACEi and a CCB. Additionally, African Americans treated with chlorthalidone were less likely to have a stroke. A smaller trial published around the same time, Intervention as a Goal in Hypertension Treatment (INSIGHT), also showed a reduction in HF rates. In contrast, these outcomes have not been demonstrated with beta-blockers. Thus, ALLHAT and INSIGHT brought thiazide diuretics to the forefront of hypertension treatment. A second hit befell beta-blockers in 2004, when a meta-analysis published in The Lancet suggested that atenolol did worse than other hypertension medications in reducing the risk of stroke (relative risk 1.13; 95% CI 1.02-1.25). Subsequent studies and larger meta-analyses confirmed this relationship, and exposed propranolol as also having this deficiency. Based on the mounting evidence, the JNC-8 guidelines relegated beta-blockers to second-line therapy for high blood pressure. Several theories have been proposed to explain this observed risk of stroke. One theory that is gaining strength is based on the idea of pulse wave dyssynchrony, whereby pressure waves are prematurely reflected back from the periphery by older and stiffer arteries, resulting in increased central systolic pressures. Because beta-blockers increase the length of systole, they exacerbate pulse wave dyssynchrony thereby increasing central aortic pressures. Using pressure sensors designed to calculate central pressures from the radial artery (called radial artery applanation tonometry), one study showed that not only did higher central aortic pressures lead to worse cardiovascular outcomes, but that beta-blockers were less capable of lowering central blood pressure when compared to CCBs. Atenolol, in particular, could further worsen this dyssynchrony by causing relative peripheral vasoconstriction. Keep in mind, however, that not all beta-blockers are created equal. For instance, the newer