Beta-blockers in hypertension: Exactly how cardioprotective?

In patients with primary hypertension, beta-blockers as a class are not as effective as other antihypertensive drug classes in the prevention of cardiovascular events.

Hypertension affects an estimated 50 to 60 million Americans and is one of the major epidemics of the modern era. The management of hypertension has undergone major changes in recent years, with the utility of traditional antihypertensives like beta-blockers being questioned.

In fact, as of this year, the British Hypertension Society, the American Heart Association Council for High BP Research and the European Society of Hypertension/ European Society of Cardiology are no longer endorsing beta-blockers as first-line treatment for uncomplicated hypertension.

Franz H. Messerli

Misperceptions

Unfortunately, physicians still perceive beta-blockers as exceedingly efficacious antihypertensive drugs. In a recent survey in which physicians were asked “Which of the following class of drugs have been proven to reduce the risk for stroke in hypertensive patients?” beta-blockers were by far considered the most effective class.

Similarly, when asked, “Which of the following classes of drugs have been proven to reduce mortality in hypertensive patients?” beta-blockers were rated highest. These perceptions or misperceptions are unfortunate and probably the result of deceptive marketing by the pharmaceutical industry that beta-blockers were “cardioprotective” no matter what the underlying disorder.

Use in primary hypertension

Data from various clinical trials show that beta-blocker therapy may be associated with worse clinical outcomes compared with other currently available agents, especially in the elderly.

Even when compared with placebo, beta-blockers did not result in any significant risk reduction for the end points of all-cause mortality, cardiovascular mortality and nonfatal MI. They were associated with a 19% to 20% reduction in the risk for stroke.

However, this risk reduction for stroke is far less than the 38% relative risk reduction seen with other antihypertensive agents (compared with placebo) for the same degree of BP control. When compared with other antihypertensive agents, beta-blockers provide no benefit for the end points of all-cause mortality, cardiovascular mortality and MI, and have a 16% increased risk for stroke.

Reasons for ineffectiveness

The reason for the lack of cardiovascular morbidity and mortality benefits of beta-blockers in the treatment of hypertension could be the result of a number of factors.

For the same fall in brachial BP, beta-blockers are less efficacious at reducing central aortic pressure when compared with renin angiotensin aldosterone system (RAAS) blockers, diuretics and calcium antagonists. Hence their antihypertensive efficacy can be best described as a “pseudo antihypertensive efficacy.”

Metabolic side effects — new onset diabetes: Beta-blockers have been shown to increase insulin resistance and predispose patients to diabetes. In a meta-analysis of 12 studies evaluating 94,492 patients, beta-blocker therapy resulted in a 22% increased risk for new-onset diabetes compared with nondiuretic antihypertensive agents. The results of our analyses let us calculate that treatment of 1,000 patients with beta-blockers for 4.4 years will result in 14 excess cases of diabetes, three excess deaths, and 4.7 excess strokes — hardly an acceptable risk-benefit ratio!

Metabolic side effects — dyslipidemia: Study data have shown that diuretics and beta-blockers used for the treatment of hypertension can cause dyslipidemia. Chronic administration of beta-blockers may increase triglyceride levels by 20% to 50% and decrease HDL by 10% to 20%.

Decreased compliance: Beta-blockers are often not well tolerated, and the compliance rate with these medications is dismal. In a meta-analysis of randomized, controlled trials, the risk for treatment withdrawal was 80% and 41% higher with beta-blockers compared with diuretics and RAAS blockers. The study’s results allow us to calculate that for every MI or stroke prevented, three patients treated with atenolol (Tenormin, AstraZeneca) withdrew from the study secondary to impotence, and another seven withdrew because of fatigue.

Cost effectiveness: Previously, the guideline committees endorsed thiazides and beta-blockers as first-line agents given the actual cost of medication. However, such an approach does not take into consideration the efficacy and effectiveness of medication.

An ideal cost-effectiveness analysis should consider the relative effectiveness of different drugs on clinical outcomes, the direct and indirect cost associated with long-term sequelae with the medications (like development of diabetes and the cost associated with this disease), and the actual cost of the drug itself.

Such a formal cost-effectiveness analysis was performed by the National Institute for Health and Clinical Excellence. Based on their economic model, they concluded that thiazide diuretics were the most cost-effective agent, followed by calcium antagonists. Beta-blockers were the least cost-effective option.

Other indications

For many years, beta-blockers have been touted as being cardioprotective no matter what the underlying disease. Thus, their “cardioprotectiveness” in post-MI patients was uncritically extrapolated to a whole spectrum of other cardiovascular conditions.

Most recently, some of the indications for beta-blockade have been scrutinized, and it has become clear that this class does not offer universal cardioprotection. The only outcome study data showing that beta-blockers reduce morbidity and mortality are in patients who have had an MI and those with congestive HF (see table). For symptomatic relief, beta-blockers are useful in angina pectoris and hypertrophic obstructive cardiomyopathy.

Many of the myths about the putative benefits of beta-blockade for the patient with hypertension have been blown away by recent outcome trial data and meta-analyses. In patients with primary hypertension, beta-blockers as a class are not as effective as other antihypertensive drug classes in the prevention of cardiovascular events.

Furthermore, the prevalence of adverse effects and the cost associated with beta-blocker treatment are too high to use this class of medicine without the evidence of it benefits, especially given the availability of more potent and more efficacious new antihypertensive agents like calcium antagonists and RAAS blockers. Unfortunately, it has been difficult to remove the physicians’ comfort blanket founded on the notion that beta-blockade will protect and stabilize the heart in patients with hypertension.

Franz H. Messerli, MD, is Director, Hypertension Program, Division of Cardiology, St.Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, and Section Editor of the Hypertension and Vascular Disease Section of Cardiology Today’s Editorial Board.

Sripal Bangalore, MD, MHA, is Fellow in Cardiovascular Medicine, Division of Cardiology, St.Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons.

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