Hypertension
ASCOT-BPLA : An Overview of Largest European Hypertension Trial Results
By Sanjukta Acharya, Editor
Sep 5, 2005, 16:53

Combination of effective, modern antihypertensives with cholesterol lowering drugs can abolish most strokes and heart attacks in people with high blood pressure by reducing the risk of strokes by about 25%, coronaries by 15%, and cardiovascular deaths by 25% and new cases of diabetes by 30% compared with the standard treatment. The success of this treatment strategy has been shown for the first time in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) - which was presented at the congress of the European Society of Cardiology on 4 September 2005 and is published online in The Lancet. ASCOT is the largest study of high blood pressure treatment ever conducted in Europe. Also, it is the only major European study to-date to combine these two treatment strategies.

What is already known on this topic?
Previous studies have suggested that newer agents would confer advantages over diuretics and Beta-blockers. However, no individual trial using standard diuretic or Beta-blocker therapy, or both has shown a significant reduction in coronary heart disease.

Results
The final results of the Blood Pressure Lowering Arm (BPLA) of Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), a large randomised controlled trial with sample size of 19000 and prospective randomised open blinded end point design (PROBE), 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%, coronaries by 15%, and cardiovascular deaths by 25% and new cases of diabetes by 30% compared with the standard treatment. The addition of the cholesterol lowering drug, atorvastatin, still further reduced the remaining risk irrespective of the patient's original cholesterol level. Indeed, the ASCOT patients only had average or below average levels of cholesterol at the outset of the study.

As a result of the reductions in heart attacks and strokes in patients receiving the cholesterol lowering drug and those treated with the modern blood pressure lowering drugs, both parts of ASCOT were terminated early by the independent Data Safety Monitoring Board.

Methodology
The investigators recruited 19257 patients aged between 40�79 years with high blood pressure who had a least three other risk factors for cardiovascular events (moderate risk) such as smoking, non-insulin dependent diabetes, history of a cerebral vascular or a peripheral vascular disease and microalbuminuria.

Therapeutic targets of the study are a blood pressure of less than 140/90 in non-diabetics and less than 130/80 in diabetics with no fixed target for the lipid-lowering limb. Half of the patients were assigned the atenolol based regimen (traditional combination: a beta-blocker, atenolol and a diuretic) and half the amlodipine-based regimen (newer drugs: a calcium antagonist, amlodipine and the ACE inhibitor, perindopril ). After 5 years the investigators found those allocated the amlodipine-based regimen had lower blood pressure values than those on the atenolol -based regimen.

Comments
"The patients treated in ASCOT were those generally seen in everyday practice. They had high blood pressure plus three additional risk factors, e.g. aged over 55, male gender, smoker. They were seen as being at moderate risk.� Said Professor Peter Sever, Professor of Clinical Pharmacology and Therapeutics, Imperial College London, International Centre for Circulatory Health, London, UK, Co-Chairman of the ASCOT Steering Committee. He continued �Compared with patients receiving standard blood pressure lowering therapy of a beta-blocker and diuretic, the combination of the contemporary blood pressure lowering drugs, amlodipine and perindopril, plus effective lowering of cholesterol abolished about half the risk of strokes and heart attacks - the most important causes of death in millions of men and women with high blood pressure."

"High blood pressure is a major public health problem. Despite the availability of effective blood pressure lowering drugs, many people who are being treated still suffer strokes, heart attacks and other related diseases, such as diabetes. Now, the evidence from ASCOT offers us a simple and effective combination of treatments which both control the blood pressure and lower cholesterol to more effectively reduce this risk. This is very important news for patients and their physicians." said Professor Bjorn Dahlof, Associate Professor in the Department of Medicine at Sahlgrenska University Hospital/Ostra, University of Gothenburg, Sweden and Co-Chairman of the study.

�On balance, the ASCOT results endorse the European guidelines for the treatment of hypertension, which leave the responsibility to choose the drug class to initiate antihypertensive to the doctor. ASCOT also supports the use of newer drugs, especially in patients with complicated hypertension, associated risk factors and/or metabolic disturbances . . . Governments and health care insurers will have to accept that the use of antihypertensive drugs cannot be rationed.� - Jan Staessen (University of Leuven, Belgium)

The investigators believe that international recommendations for managing high blood pressure may need to be reviewed after the publication of these results. Additionally, they suggest that most patients with hypertension should also be considered for a cholesterol lowering drug.

Professors Sever and Dahlof concluded: "Diuretics and beta-blockers are an effective and proven combination for lowering blood pressure and its associated risks. What ASCOT has shown is that for many patients the combination of newer drugs may be an even better option. Patients should discuss the implications of ASCOT with their physicians before any modification of treatment is considered."

The Lancet in January 2005 reported that more than 330 million adults in Europe and North America suffer from high blood pressure which also affects a further 639 million men and women in the rest of the world. According to World Health Organization about 80% of people with high blood pressure have additional uncontrolled cardiovascular risks.

Explanations for the benefits seen from this study are reviewed in a separate paper also published in The Lancet online with the title �'Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)� In this paper Neil Poulter (Imperial College London, UK) and colleagues looked at differences in blood pressure and other variables in patients assigned the newer drugs versus those allocated the standard drugs. They found that a reduction in blood pressure was the single biggest contributor to the effect on stroke events, but other factors, such as differences in cholesterol, were more important for coronary events.

Background of ASCOT Trial
ASCOT (The Anglo-Scandinavian Cardiac Outcomes Trial) commenced patient recruitment in 1998. It was designed as a randomised controlled trial of the prevention of coronary heart disease (CHD) and other vascular events by blood pressure lowering, and uses a factorial design to assess the same endpoints by cholesterol lowering. The impetus for ASCOT was the lack of outcome data on newer types of blood pressure lowering agents, the absence of data on the evaluation of specific combination treatment regimens in hypertension, and the shortfall of CHD prevention using standard therapies based on diuretics and β-blockers. It was also felt that there was a need to evaluate multiple risk factor intervention in the prevention of CHD, as there were few data on the benefits of lipid lowering among hypertensive patients. Pre-study discussions focused on two major issues. Firstly, previous trials investigated the efficacy of diuretic and/or β-blocker-based treatment (together with older drugs, such as methyldopa and hydralazine) in reducing cardiovascular events in hypertensive patients. However, no outcome data was available with two classes of drugs that were being readily accepted into common clinical practice, namely calcium channel blockers and ACE inhibitors.

The second issue focused on the observation from individual studies and subsequent meta-analysis that there was a shortfall in protection against CHD events in hypertensives treated primarily with β-blockers and diuretics. This was in contrast to the impressive evidence for protection against stroke. It quickly became apparent that new trials were needed to compare two or more active treatments. These would require a very large number of patients to address whether CHD outcome depends on the type of drugs used to lower blood pressure. Discussions centred around the comparison of individual drugs as first line treatments, with other drugs added to control blood pressure, or comparing specific treatment regimens using combination therapies. Similar discussions in the USA led to ALLHAT, a study which compares individual drugs with a uniform add-on drug for the treatment of inadequate blood pressure control. The other obvious need was for a trial to compare the standard treatment regimen of diuretic + beta-blocker with a combination of newer agents. So, following on from earlier discussions, the possibility of a factorial design trial was considered, in which additional hypotheses could be tested, such as the benefits of lipid lowering and anti-platelet agents in the hypertensive population. These initial plans did not progress any further until 1991 when a British Hypertension Society Working Party was set up to re-visit the question of such a trial and to seek financial support for the study. The Working Party readdressed the issues discussed previously and proposed a trial design to the annual meeting of the British Hypertension Society in September 1993. This was broadly similar to the earlier proposal for a comparison of individual drugs with a common add-on antihypertensive agent for those patients who failed to achieve adequate blood pressure control with first line therapies. They also ratified the earlier proposal for a factorial design study. At the same time on-going discussions were being held in Scandinavia along the same lines.

In 1995, following discussions between Peter Sever and Neil Poulter (London), and Bjorn Dahl�f and Hans Wedel (Gothenburg), a joint proposal for an outcome study was submitted to Pfizer, who agreed to support a study which later became known as ASCOT. The study outline was announced in 1996 and a Steering Committee was formed. After several meetings a working protocol was agreed and formed the basis of the study which began in early 1998. The primary objective of ASCOT is to assess and compare the long-term effects on non-fatal myocardial infarction and fatal coronary heart disease of a standard anti-hypertensive regimen of a beta-blocker � a diuretic with a more contemporary regimen of a calcium channel blocker � an ACE inhibitor. The study also aims to compare the effects of a statin vs placebo among patients with a total cholesterol of 6.5mmol/l on non-fatal myocardial infarction and fatal coronary heart disease. For those with higher cholesterol levels it was felt that contemporary clinical practice dictated the recommendation of lipid lowering therapy, and it would be considered unethical to randomise such patients to placebo, even though in fact they were not receiving active lipid-lowering therapy. The study was designed with large number of secondary and tertiary objectives including, in both the BP and lipid lowering limbs of the trial, an evaluation of the effects of the different treatment regimens on stroke, all cause mortality, heart failure, cardiovascular events and procedures.

It also studied the development of diabetes and renal impairment and focus on major study endpoints in ethnic minority groups and other important subgroups. ASCOT has a prospective randomised open blinded end point design (PROBE). A total of about 19,000 patients have been recruited into a 2X2 factorial trial of an antihypertensive first line regimen of atenolol vs amlodipine to which a thiazide diuretic or the ACE inhibitor perindopril respectively may be added, with cholesterol lowering using atorvastatin vs placebo. It was predicted that 1,150 primary events will occur over a five year follow up period (an annual total CHD event rate of approximately 2%). In the hypertensive limb the study has >80% power at a significance level of 5%, to demonstrate a relative 20% additional benefit of the "new" drug regimen over the older treatment. In the lipid lowering limb there is >90% power with a significance level of 1%, to detect a 30% relative risk reduction on coronary end points of statin vs placebo.

In order to achieve the desired event rate in the trial, hypertensive patients had three additional risk factors for cardiovascular disease, such as smoking, non-insulin dependent diabetes, history of a cerebral vascular or a peripheral vascular disease and microalbuminuria. Therapeutic targets of the study were a blood pressure of less than 140/90 in non-diabetics and less than 130/80 in diabetics with no fixed target for the lipid-lowering limb.

ASCOT Investigators
Peter Sever MB, BChir (Cambridge), MA (Cambridge), MRCP (UK), Ph.D (London), FRCP (London) , FESC � 1990, is Professor of Clinical Pharmacology and Therapeutics at Imperial College London, Honorary Consultant Physician at St Mary�s Hospital, London, and Director of the International Centre for Circulatory Health. After graduating from Cambridge, Professor Sever completed his training at St Mary�s Hospital Medical School. Following a succession of appointments in general medicine, cardiology and chest diseases, followed by lectureships in medicine and pharmacology, he became an Honorary Consultant Physician and Senior Lecturer in Medicine in the Medical Unit at St Mary�s Hospital in 1976. In 1980 he was appointed Professor of Clinical Pharmacology and Therapeutics at St Mary�s Hospital Medical School, which was subsequently incorporated into the Imperial College School of Medicine. During the past decade he established a major research programme in the pathogenesis and treatment of cardiovascular disease. He is Joint Editor in Chief of the Journal of the Renin-Angiotensin-Aldosterone System. He has been a member of the editorial boards of several journals, including the Journal of Hypertension, Journal of Human Hypertension and Clinical Science. Professor Sever is a past-president of the British Hypertension Society and the European Council for Blood Pressure and Cardiovascular Research. He is also a Fellow of the European Society of Cardiology and Chairman of the Fellowships Committee of the British Heart Foundation. His current research interests include all aspects of cardiovascular disease, including the pathophysiology of vascular disease, the evaluation of anti-hypertensive drug therapy and multiple risk factor intervention in hypertensive populations. He is also interested in the epidemiology of hypertension with particular reference to environmental influences on blood pressure, and ethnic differences.

Bjorn Dahlof MD, PhD, FACC, is presently Associate Professor of Medicine at Sahlgrenska University Hospital/�stra in G�teborg, Sweden. Also holds a position as Vice President of the University based clinical trials company Scandinavian CRI AB. Married with 1 child. Studied medicine at University of G�teborg and became MD 1978. Member of the Hypertension Research Group at Sahlgrenska University Hospital/�stra, G�teborg, since 1982. Naval certificate for practising hyperbaric medicine. Research experience mostly in the field of CV medicine in particular hypertension with a special interest in CV disease prevention. A thesis on Pathogenesis and Regression of Structural Cardiovascular Changes in Hypertension, in particular LVH, was defended 1992, became PhD 1994 and FACC 1995. Have published around 200 peer reviewed scientific papers. Previous and present involvement in large mortality-morbidity studies: coordinator of the the two STOP-Hypertension studies, secretary SC of the CAPPP and HOT studies and participated as a SC member of the NORDIL study. Currently chairman of LIFE, co-chairman of ASCOT and SC member in the JIKEI Heart study, ACCOMPLISH study and PRoFESS.

Neil Poulter MBBS MSc FRCP, Professor of Preventive Cardiovascular Medicinis a Director of the International Centre for Circulatory Health, Imperial College London and President of the British Hypertension Society. He co-authored the 1998 and 2005 Joint British Recommendations on Prevention of CHD; 2003 WHO-ISH Statement on Management of Hypertension; 2003 ESH-ESC guidelines for the management of arterial hypertension; 2004 BHS guidelines for management of hypertension. Research interests include the optimal investigation and management of essential hypertension and dyslipidaemia, the association between birth weight and hypertension, the cardiovascular effects of exogenous oestrogen and progesterone, and ethnic differences in cardiovascular disease.

Hans Wedel is Professor of Epidemiology and Biostatistics at the Nordic School of Public Health since the early 1980ies. His special research area is cardiovascular epidemiology and clinical trials. He was the responsible statistician for several large cohort studies in Goteborg during the1970ies. He has been a member of the Steering Committee for 4S, MERIT, CONSENSUS-2, HOT, DIGAMI 1+2, CORONA and ASCOT. He was a member of the Data Safety and Monitoring Committee for STOP I+II, IDEAL, ALERT and EXPRESS.

References

1. '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 randomised controlled trial' Bjorn Dahlof, Peter S Sever, Neil R Poulter, Hans Wedel, D Gareth Beevers, Mark Caulfield, Rory Collins, Sverre E Kjeldsen, Arni Kristinsson, Gordon T McInnes, Jesper Mehlsen, Markku Nieminen, Eoin O'Brien, Jan Ostergren, for the ASCOT investigators. Lancet 2005, Volume 366, DOI:10.1016/S0140-6736(05) - 67185-1

2. 'Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)' Neil R Poulter, Hans Wedel, Bjorn Dahlof, Peter S Sever, D Gareth Beevers, Mark Caulfield, Sverre E Kjeldsen, Arni Kristinsson, Gordon T McInnes, Jesper Mehlsen, Markku Nieminen, Eoin O'Brien, Jan Ostergren, Stuart Pocock, for the ASCOT investigators Lancet 2005, Volume 366, DOI:10.1016/S0140-6736(05) - 67186-3

3. 'ASCOT background: An International Perspective', by Professor Peter Sever & Professor Bj�rn Dahl�f

4. the ASCOT website: www.ascotstudy.org

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