Large clinical trials published in recent years, such as the ASCOT and LIFE studies, as well as a meta-analysis published by Lindholm et al. in 2005 [1], have questioned the efficacy of beta-blockers in the treatment of hypertension and the effects of long-term use on glucose and lipid metabolism. In June 2006, the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) jointly published an updated version of the Guidelines for the Treatment of Hypertension in Adults (hereinafter referred to as the British Guidelines), which for the first time proposed that “β-blockers are no longer the first choice of antihypertensive treatment for most patients with hypertension” [2]. Since β-blockers are very widely used drugs in the clinical treatment of hypertension at present, and they occupy a rather important position in the treatment of coronary heart disease and heart failure, many domestic experts have also paid great attention to the revision of the British guidelines concerning β-blockers, and reached a consensus through extensive discussions.
I. The rationality of beta-blocker application from the perspective of the pathogenesis of hypertension
Over-activation of the sympathetic nervous system is one of the important mechanisms leading to increased blood pressure in patients with essential hypertension [3-5]. It is manifested by increased output of central sympathetic activity, increased release of norepinephrine from the heart and kidneys, increased muscle sympathetic tone, and decreased reuptake of norepinephrine by nerve endings. Activation of the sympathetic nervous system ① first promotes renin release by increasing renal vascular resistance, which further activates the renin-angiotensin system (RAS); in addition, increased secretion of antinociceptive hormone leads to water and sodium retention; ② increases peripheral vascular resistance by increasing the tone of the vascular wall and its permeability to sodium and increasing the sensitivity of the vessels to vasoconstrictive substances; ③ in addition to the positive chronotropic and variable force effect on the heart causing altered hemodynamics, they also cause proliferation and hypertrophy of cardiac myocytes and vascular smooth muscle cells, leading to remodeling of the myocardium and blood vessels, thus playing a role in the regulation and maintenance of blood pressure [3].
Beta-blockers not only counteract excessive activation of the sympathetic nervous system and exert antihypertensive effects, but also prevent the cardiotoxic effects of catecholamines by reducing sympathetic tone, inhibit excessive neurohormonal and RAS activation and exert comprehensive cardiovascular protection, including improving myocardial remodeling, reducing arrhythmias, increasing ventricular fibrillation threshold and preventing sudden death. Therefore, the use of β-blockers for the treatment of hypertension has a solid theoretical basis.
The 2006 British guidelines for the treatment of hypertension in adults on β-blockers
The 2006 UK guidelines clearly suggest that beta-blockers are no longer the first choice of antihypertensive treatment for most patients with hypertension. The guideline recommends that: in the initial pharmacological treatment of patients with hypertension, calcium antagonists (CCB) or thiazide diuretics are preferred for patients over 55 years of age, while ACE inhibitors (ACEI) are preferred for patients under 55 years of age; if monotherapy is unsatisfactory, the second step should be CCB + ACEI or diuretics + ACEI treatment; the third step will be ACEI, CCB and diuretics in combination; if the three-drug combination is still not controlled, a fourth step of treatment is considered, which includes increasing the diuretic dose, switching to other diuretics, β-blockers or selective α-blockers [2]. Meanwhile, the UK Guidelines Working Group conducted a health economic modeling analysis and the price-effectiveness analysis of the five drug classes showed no statistical differences in clinical outcomes, although β-blockers were, however, at a relative disadvantage. As a result, beta-blockers are not recommended as initial drug therapy for hypertension. However, the UK guidelines also state that beta-blockers should be considered in younger patients with hypertension, contraindications to ACEI/ARB use, significantly elevated sympathetic nervous system activity, or pregnancy. The guidelines also note that because the vast majority of data from previous studies of beta-blockers have been derived from atenolol, and there are few studies of other beta-blockers for hypertension, there is uncertainty in extending the conclusions from atenolol to all beta-blockers, and therefore well-designed clinical studies of the use of other beta-blockers for hypertension are needed to update the current guidelines.
Evidence-based medical evidence on the clinical use of β-blockers
The recommendations of the UK guidelines for β-blockers for the treatment of hypertension are mainly based on a meta-analysis by Lindholm et al. published in Lancet in 2005 [1]. This article collected 20 clinical studies of β-blockers for hypertension and showed that β-blocker therapy increased the relative risk of stroke by 16% compared with other blood pressure-lowering drugs and significantly increased the development of type 2 diabetes. However, this meta-analysis has several problems: (i) the studies included are somewhat limited. 17 of the 20 studies were clinical studies of atenolol and only 3 were clinical studies of non-atenolol; a part of the studies (e.g., MRC and MRC-O) were single-blind studies [6,7]; (ii) MAPHY was excluded because it was part of the HAPPHY study, and the MAPHY study was a study that included 3234 patients on the prevention of atherosclerosis in hypertensive patients with metoprolol compared with diuretics, and metoprolol treatment significantly reduced the incidence of morbidity and mortality, sudden cardiovascular death, and coronary events in patients compared with diuretics [8]. (iii) An analysis of 17 clinical studies of atenolol in a meta-analysis showed that atenolol significantly increased the relative risk of stroke by up to 26% and all-cause death by 8% compared with other antihypertensive drugs; the incidence of cardiovascular endpoints, including stroke, was not significantly different compared with other blood pressure-lowering drugs because there were too few clinical trials of non-atenolol β-blockers. In fact, a meta-analysis by Carlberg et al. 2004 comparing atenolol with placebo or other blood pressure lowering drugs [10] has shown that water-soluble atenolol does not reduce the incidence of cardiovascular events and mortality while lowering blood pressure and stated that atenolol should no longer be used as the active reference drug in antihypertensive studies. Therefore, Lindholm et al. arbitrarily extended the conclusions obtained from the clinical studies of atenolol to other β-blockers. ④ The ASCOT-BPLA study enrolled in the meta-analysis was a comparison between two treatment regimens of β-blockers + diuretics versus ACEI + calcium antagonists [9]. Only 14.3% and 8.8% of patients were receiving amlodipine or atenolol monotherapy, respectively, at the end of that study, so the study was not a head-to-head comparison between beta-blockers and other antihypertensive agents.
Beta-blockers for the treatment of hypertension
Beta-blocker therapy for hypertension improves long-term clinical outcomes for patients, including reduced rates of death, stroke, and heart failure. Many large-scale clinical treatment trials, such as the STOP-H, MAPHY, UKPDS, CAPP, and STOP-2 studies [8,10,11,12,13], have provided sufficient evidence. Both the first and second rounds of prospective BPLTTC meta-analyses organized by the International Society of Hypertension showed that β-blockers did not differ significantly from calcium antagonists or angiotensin-converting enzyme inhibitors (ACEIs) in lowering blood pressure and reducing cardiovascular risk [14,15]. In the MAPHY study, a mean follow-up of 4.2 years in 3234 patients with mild to moderate hypertension showed that metoprolol had the same antihypertensive efficacy as diuretics, but overall mortality, cardiac death, and sudden cardiac death occurred significantly less in the metoprolol group than in the diuretic group (all P < 0.05) [8]. Based on the large body of evidence-based medical evidence of β-blockers for the treatment of hypertension over the years, both domestic and foreign guidelines for the treatment of hypertension have identified β-blockers as the first-line hypotensive agent for the treatment of hypertension. ⑤ The UK guidelines themselves clearly state that they do not include Chinese and Asian populations and that further evidence-based medical evidence is needed to support this.
Use of beta-blockers after myocardial infarction
The clinical efficacy of β-blockers in the treatment of acute myocardial infarction (AMI) has been confirmed by a large number of clinical studies. Data from the PAMI, Stent-PAMI, Air-PAMI, and CADILLAC studies suggest that β-blockers used prior to reperfusion therapy can significantly reduce morbidity and mortality [16,17]. Therefore, various national or regional guidelines have identified β-blockers as the first-line agent for life-saving treatment in patients with AMI. 2004 ACC/AHA guidelines for the early use of β-blockers in infarction state that oral β-blockers (I, A) should be given immediately if there are no contraindications, regardless of whether the patient receives thrombolytic therapy or direct PCI; in patients with ST-segment elevation infarction The 2004 ESC Expert Consensus made the same recommendation and stated that β-blockers can reduce infarct size, reduce life-threatening arrhythmias, relieve pain, and reduce morbidity and mortality (including sudden cardiac death) if there are no contraindications.
The role of β-blockers in secondary prevention of infarction is also well recognized. 1998 American Cardiovascular Collaborative Program, which included 201 752 post-infarction patients followed for up to 2 years, found that long-term treatment with β-blockers reduced morbidity and mortality in all groups of patients [19]. Analysis of a series of large, long-term studies including 35,000 post-infarction survivors found that β-blockers improved patient survival by 20-25% in post-infarction patients by reducing cardiac death, sudden cardiac death, and recurrent myocardial infarction. A meta-analysis of 82 randomized clinical studies (31 with long-term follow-up) found that long-term use of beta-blockers significantly reduced morbidity and mortality and the incidence of cardiovascular events, and that the benefit persisted even with concomitant use of aspirin, thrombolytic drugs, and ACEIs. In-depth analysis of these studies revealed positive results only with treatment with lipid-soluble β-blockers such as propranolol and metoprolol, while this effect was not seen with water-soluble β-blockers such as atenolol.
Beta-blockers for heart failure
Beta-blockers slow the heart rate and inhibit the cardiotoxicity of catecholamines by suppressing the over-activated sympathetic nervous system, and in several clinical trials in systolic heart failure (including CIBISII, COPERNICUS and MERIT-HF) [20,21.22], have shown that treatment with beta-blockers significantly reduces the morbidity mortality of patients by up to 35%. In patients with combined mild to moderate impaired left ventricular systolic function after myocardial infarction, β-blocker therapy also significantly improves the long-term prognosis of patients. In the treatment of heart failure, beta-blockers in combination with ACEIs have been shown to reduce the prevalence and mortality of heart failure and are an important component of the pharmacological regimen for chronic heart failure.
National and international guidelines for heart failure consistently recommend β-blocker therapy for all patients with stable chronic systolic heart failure due to ischemic or nonischemic cardiomyopathy, NYHA class II-IV, without contraindications (I, A). Long-term beta-blockers should be used in all patients with impaired left ventricular systolic function after acute infarction, with or without symptoms of heart failure, to reduce mortality (I, A).
Prevention of sudden cardiac death
Animal experiments suggest that the effect of β-blockers in preventing ventricular fibrillation depends on the amount of β-blockers entering the central nervous system, so fat-soluble β-blockers (such as bisoprolol, metoprolol and propranolol) may be better than water-soluble β-blockers (atenolol) in preventing sudden death. In contrast, lipid-soluble β-blockers have been shown to significantly reduce prevalence and mortality in large-scale clinical studies of hypertension, acute myocardial infarction and secondary prevention after myocardial infarction, and chronic heart failure. And beta-blockers are the only drugs that have been shown to reduce sudden death like no other.
In the treatment of myocardial infarction and heart failure, the reduction in morbidity and mortality is mainly due to the reduction in the incidence of sudden death. 26 years of prospective studies by Framingham showed that 90% of sudden cardiogenic deaths were associated with arrhythmias, and 80% of arrhythmic sudden deaths were associated with ventricular tachyarrhythmias [23]. The mechanisms of anti-ventricular fibrillation and reduction of sudden death by β-blockers The mechanisms of β-blockers against ventricular fibrillation and reducing sudden death include: (i) increasing the ventricular fibrillation threshold by 60% to 80%; (ii) blocking central sympathetic nerves, reducing peripheral sympathetic excitability and increasing vagal excitability; and (iii) reducing heart rate and stabilizing electrical activity.
Beta-blockers are used as primary and secondary prevention drugs for sudden cardiogenic death in various clinical guidelines and treatment principles. For patients with a high incidence of sudden death such as acute myocardial infarction, heart failure, and hypertrophic cardiomyopathy, β-blockers are the drugs of choice for the prevention of sudden cardiac death.
From the above evidence-based medical evidence of the widespread use of β-blockers in the cardiovascular field, it is clear that lipid-soluble β-blockers have a comprehensive cardiovascular protective effect, especially the prevention of sudden cardiac death, a role that cannot be replaced by any existing drugs. The goal of anti-hypertensive therapy is not only to control blood pressure levels, but also to reduce the incidence of cardiovascular events and long-term morbidity and mortality in patients. The efficacy of β-blockers (especially fat-soluble β-blockers) in myocardial infarction, heart failure, and sudden death prevention, in addition to their recognized antihypertensive effects, has become indisputable. In today’s scientific development, the efficacy and safety of drugs need to undergo the test of evidence-based medicine. The efficacy and side effects of similar drugs with different physicochemical properties may vary; even different dosage forms of the same drug may have different therapeutic effects. There is no scientific basis for eliminating all beta-blockers as first-line antihypertensives simply because the water-soluble atenolol has been shown to have no cardioprotective effect.
IV. Consensus and recommendations of Chinese experts
Through a review of previous large-scale clinical studies on the use of β-blockers in the treatment of hypertension and its related diseases, an analysis of meta-analyses of clinical trials in recent years, and an understanding of the UK NICE/BHS guidelines on adult hypertension, Chinese experts have reached the following consensus on the use of β-blockers in the treatment of hypertension.
1. b-blockers are still clinically effective and safe drugs for the treatment of hypertension, and are among the commonly used drugs for lowering blood pressure in clinical practice. However, in view of the problems exposed by water-soluble beta-blockers such as atenolol in clinical trials, they are not recommended as the drug of choice for hypotensive treatment.
2.Patients who are currently being treated with beta-blockers should continue to use them and should not change their medication.
3, beta-blockers have an irreplaceable status and should be preferred for patients with the following combined conditions: rapid arrhythmias, coronary artery disease (stable/unstable angina, post-myocardial infarction), heart failure combined with hypertension; patients with increased sympathetic activity (those with increased heart rate early in the onset of hypertension, those with psychosocial stress, those with increased mental stress such as anxiety, perioperative hypertension, high circulatory power state such as hyperthyroidism, plateau life, etc.) and pregnancy hypertension; young hypertensive patients who are contraindicated to use or cannot tolerate ACE inhibitors or ARB
4, in the clinical use of drugs, pay attention to the use of beta-blockers without intrinsic sympathomimetic activity, high selectivity for beta1 receptors, or both alpha-blocking effect, in order to reduce the adverse effects of long-term drug use. Selective β1 receptor blockers and β-blockers with α-blocking effects are different from traditional non-selective β-blockers in that their effects on glucose and lipid metabolism and peripheral vascularity are relatively small and can be used more safely and effectively in patients with diabetes combined with hypertension.
The combination of β-blockers and other drugs is of great significance in the treatment of hypertension. β-blockers in combination with long-acting dihydropyridine calcium antagonists or α-blockers can not only obtain synergistic hypotensive effects, but also inhibit the reflex sympathetic excitation caused by calcium antagonists or α-blockers; from the perspective of target organ protection, the combination of β-blockers and ACEI/ARB is currently recommended for hypertension combined with cardiovascular disease. is currently recommended as standard treatment for hypertension combined with heart failure and myocardial infarction. The beneficial effects of ACEI/ARB on glucose metabolism can counteract the potential adverse effects of β-blockers on glucose metabolism.
6, In patients without heart failure, the separate combination of high-dose β-blockers and thiazide diuretics should be avoided to reduce the possibility of causing disorders of glucose and lipid metabolism.
7. In hypertensive patients with heart attack and heart failure who have combined glucose and lipid metabolism disorders or metabolic syndrome, β-blockers are not recommended as the drug of choice for initial treatment.
V. Summary
Sympathetic hyperactivation is one of the important pathogenesis of hypertension, and evidence-based medical evidence suggests that β-blockers have clear antihypertensive efficacy and cardioprotective effects. Meta-analyses have shown that water-soluble β-blockers such as atenolol do not reduce the incidence of cardiovascular events and morbidity and mortality while lowering blood pressure compared with other hypotensive drugs; therefore, atenolol should no longer be used as an active reference drug in antihypertensive studies and as a routine agent for treatment. The arbitrary extension of the adverse effects of atenolol to so beta-blockers is lacking in scientific evidence. Given the clear protective effects of beta-blockers on the cardiovascular system, until further research evidence is available, beta-blockers other than atenolol may remain an option for the pharmacological treatment of new or young patients with hypertension, especially in patients with combined post-myocardial infarction, angina pectoris and heart failure.
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