The continuing role of beta-blockers in hypertension

When a joint collaboration was announced last year between the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) to produce updated guidelines on blood pressure control, many within the medical profession breathed a huge sigh of relief. The collaboration also promised to help interpret the results of the Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) trial whose conclusions have been reported as sounding the death knell for many widely used antihypertensive treatments³. Indeed, with ASCOT swiftly followed by Lars Lindholm’s highly critical meta-analysis of beta-blocker therapy⁴, it has been a confusing time for those of us trying to offer the best possible therapy for our hypertensive patients.

The move brought an end to almost a year of confusion over their differing recommendations after they launched contradictory guidelines in 2004^1,2.

The question many have been asking is whether we should continue prescribing beta-blockers in the light of the ASCOT and Lindholm studies as both recommend that beta-blockers should no longer be considered first-line treatments for hypertension. This article will look at the results of these studies and assess the future for beta-blockers use in the management of hypertension in the elderly and also the likely impact on future guidelines.

ASCOT study and beta-blockers

ASCOT included more than 19,000 men and women with high blood pressure who were at a moderate risk of strokes and heart attacks. To control their blood pressure, they received either the newer drugs – a calcium antagonist, amlodipine and the ACE inhibitor, perindopril – or a traditional combination of a beta-blockers, atenolol and a diuretic. Additionally, 10,000 patients were also treated with the cholesterol lowering drug atorvastatin or a placebo. This is the only major European study to-date to combine these two treatment strategies.

The final results of ASCOT, which was conducted in the UK, Ireland and the Nordic countries, showed that the combination of newer blood pressure lowering drugs reduced the risk of strokes by about 25 per cent, coronaries by 15 per cent, cardiovascular deaths by 25 per cent and new cases of diabetes by 30 per cent compared with the standard treatment. Clearly its findings cannot be ignored.

Of the 25 per cent of patients in both groups who stopped therapy early because of adverse events, significantly fewer did so because of serious adverse events in the amlodipine group compared to the atenolol group (1.7 per cent versus 2.6 per cent, p<0.0001) but numbers were few and there was no significant difference in cessation from non-serious adverse events.

Lars Lindholm’s meta-analysis

In their meta-analysis, Lars Lindholm and colleagues included 13 randomised controlled trials (n=105 951) comparing treatment with beta-blockers with other antihypertensive drugs. They also included seven studies (n=27 433), which compared beta-blockers with placebo or no treatment⁴.

The meta-analysis found that the relative risk of stroke was 16 per cent higher for beta-blockers (95 per cent CI 4-30 per cent) than for other drugs. There was no difference for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19 per cent for all beta-blockers (seven to 29 per cent), about half that expected from previous hypertension trials. There was no difference for myocardial infarction or mortality.

It concluded that in comparison with other antihypertensive drugs, the effect of beta-blockers is less than optimum, with a raised risk of stroke. The investigators added that beta-blockers should not therefore remain first choice in the treatment of primary hypertension and should not be used as reference drugs in future randomised controlled trials of hypertension.

The future?

Beta-blockade has long been regarded as a safe and effective therapy for hypertension. It has been clearly established that, after myocardial infarction and in patients with heart failure, treatment with selected beta-blockers prevents re-infarction, reduces hospitalisation for heart failure, and cuts the risk of premature death^5-8. Both the guidelines from NICE and, to a lesser extent from the BHS, recommend beta-blockers as a first or second line therapy in patients with hypertension.

NICE/BHS guidelines

Whether the NICE/BHS Expert Advisory Group, set up to produce the updated guidelines, and chaired by past-BHS President Professor Bryan Williams, agrees with this interpretation remains to be seen. A number of meetings are planned and it is hoped that draft recommendations will be available for consultation by stakeholders soon with publication of the final joint NICE/BHS document by June. However, before we abandon what has, after all, been a tried and trusted approach to anti-hypertension therapy for many years, it is important that we ensure that these new findings are truly applicable to our own patients and the treatments we currently prescribe.

The first thing to point out is that atenolol, as used in ASCOT and in many of the Lindholm trials, can no longer be considered a typical beta-blockers. It is now 30 years old and lacks the cardioselectivity and vasodilatory properties of more modern beta-blockers such as nebivolol and carvedilol.

This distinction is especially important when we consider that many of our hypertensive patients, and especially our more elderly patients, present with considerable cardiovascular co-morbidity. These patients require careful risk assessment and management so that their overall risk of a major coronary event is not increased and their quality of life is maintained. Many elderly patients with hypertension have overt coronary heart disease. Others may have underlying coronary disease that is not clinically evident because they are taking a ÃŸ-blocker. Sudden discontinuation of a beta-blocker, particularly from high doses, could cause rebound hypertension, rebound angina or even precipitate a myocardial infarction.

Trial data for beta-blockers

The potential benefits of using beta-blockers in elderly patients with chronic heart failure have been clearly demonstrated. Sin-Don D, et al observed observed in a retrospective study of 11,942 patients over 65 years with heart failure (1,162 taking beta-blockers), that beta-blocker use was associated with substantial reductions in all-cause mortality, heart failure mortality and hospitalisations due to heart failure9.

These endpoints were less frequent in patients treated with beta-blockers than in untreated patients in all examined subgroups. In the study, all doses of beta-blockers were associated with benefit, but there was a trend towards greater benefit in patients prescribed higher doses.

Furthermore, in the SENIORS trial, the randomisation of over 2,000 patients, with a mean age of 76.1 years and a clinical diagnosis of chronic heart failure, to receive either nebivolol or placebo showed a significantly reduced all-cause mortality or rate of hospitalisation for cardiovascular events among the nebivolol-treated patients¹⁰.

The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). This occurred in 332 patients (31.1 per cent) on nebivolol compared with 375 (35.3 per cent) on placebo (hazard ratio (HR) 0.86, 95 per cent CI 0.74-0.99; P=0.039). There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on this primary outcome. Death (all causes) occurred in 169 (15.8 per cent) on nebivolol and 192 (18.1 per cent) on placebo (HR 0.88, 95 per cent CI 0.71-1.08; P=0.21). The study, therefore, concluded that nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

Results such as this demonstrate that there remains a place for modern, cardioselective beta-blockers within the management of hypertension. While the results of ASCOT and the Lindholm meta-analysis are likely to change the guidance on first-line use of beta-blocker, we should recognise that many patients will continue to need beta-blocker therapy and that rapid discontinuation could be particularly dangerous for patients with cardiovascular co-morbidities.

Conclusion

We must remember that successful treatment of hypertension frequently requires the use of several types of drugs. For reasons of effectiveness and tolerability (indeed 25 per cent of patients in the ASCOT trial did not tolerate the drugs), a variety of alternative and adjunctive treatments are needed to effectively manage hypertension, including beta-blockers.

References

Williams B, Poulter NR, Brown MJ, et al. British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary BMJ 2004; 328: 634-40
North of England Hypertension Guideline Development Group. Essential Hypertension: managing adult patients in primary care. August 2004. www.nice.org.uk/page. aspx?o=217976 (date last accessed: 20/01/06)
DahlÃ¶f B, Sever P, Poulter N, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet 2005; 366: 895-906
Lindholm LH, Carlberg B, Samuelsson O. Should ÃŸ-blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005; 366: 1545-53
Freemantle N, Cleland J, Young P, et al. After myocardial infarction: systematic review and meta regression analysis. BMJ 1999; 318: 1730-37
CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive heart failure (MERIT-HF). Lancet 1999;353: 2001-07
Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002; 106: 2194-99
Sin DD, McAlister FA. The effects of beta-blockers on morbidity and mortality in a population-based cohort of 11,942 elderly patients with heart failure. Am J Med 2002; 113(8): 650-6
Flather MD, Shibata MC, Coats AJS, et al. Randomised controlled trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). European Heart Journal Heart Journal 2005;26(3): 215-25