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  » Medical Topic Archive  »  Heart Protection Studies - Medicines Research


Atenolol study- new study questions the use of atenolol
The VALUE Trial -
study comparing valsartan with amlodipine
The ‘Polypill’
A new way of preventing heart disease and stroke?
The ALLHAT Study -
Large general study on medications for high blood pressure
The Heart Protection Study -
study on medications to reduce cholesterol
The LIFE Study -
study on the medicines losartan and atenolol
The Progress Study -
study on the medicine perindopril and stroke

New study questions use of beta-blocker

A study published in November 2004 has questioned the effectiveness of atenolol; a beta-blocker widely used to control blood pressure by slowing down the heart rate.
Researchers in Sweden reviewed five studies that compared atenolol with placebo (dummy medicine) and four that compared it with other groups of medicines used to treat high blood pressure. In all, the studies looked at the results from almost 25,000 people.
The results showed that there were the same number of deaths and heart attacks in those people taking atenolol as those taking the placebo. In addition atenolol was found to be no more effective at lowering blood pressure than any other group of medicines for treating high blood pressure. In fact there were more deaths from cardiovascular disease (stroke, heart attack, heart failure) in those that took atenolol than in those who took medicines from other groups. The authors of the study said that the results cast doubt on atenolol as a suitable drug for people with high blood pressure.

Article: Atenolol in hypertension: is it a wise choice?
Publication:The Lancet, Volume 364, Issue 9446, 6 November 2004, Pages 1684-1689
Authors: Bo Carlberg, Ola Samuelsson and Prof Lars Hjalmar Lindholm

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The VALUE Trial

The VALUE trial aimed to find out whether Valsartan (an angiotensin receptor blocker) is more effective than amlodipine (calcium channel blocker) in preventing heart attack and heart failure in people with high blood pressure.
The trial included over 15,000 people from 31 countries and lasted for over 4 years. Those included in the study were already at risk of a heart attack or heart failure, because they already had diabetes or had already had a stroke or heart attack. Those taking part in the study were randomly given either Valsartan or Amlodipine as their initial treatment and then monitored to see how they progressed. Other medications were added in order to ensure effective blood pressure lowering and control.
The results showed that the group treated with amlodipine did slightly better than those treated with valsartan. However, blood pressure was better controlled in the group who took amlodipine, particularly in the first six months of the trial. The authors conclude that the findings emphasise the importance of prompt blood pressure control, ie, that it is how well the blood pressure is controlled and lowered, rather than the medicines used to do so that is important.
Article: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial
Publication: The Lancet 2004, Volume 363 (19 June) Pages 2022-2031
Authors: S Julius, S Kjeldsen, M Weber and others
The ‘Polypill’ – A new way of preventing heart disease and stroke?
A study published in the British Medical Journal has set out to determine the combination of medications and vitamins, and their respective doses, for use in a once daily pill to prevent heart disease and stroke.
The authors of the study looked at research about a number of different medications and vitamins to determine which would be the most effective in reducing the risk of heart disease a stroke. They concluded that a combination of five medications and one vitamin could prevent 80% of stokes and nearly 90% of heart attacks. This ‘Polypill’ would include aspirin, a statin to lower cholesterol levels, folic acid to regulate homocysteine levels and three medications to lower blood pressure – for example, bendrofluazide, a beta blocker and an ACE inhibitor. The authors recommended that it should be offered to everyone over the age of 55 and people younger than 55 who are at high risk of stroke or heart disease.
The Polypill has yet to be made or tested on people to see how effective it is and it may be years before it is available to the general public.

Article: A strategy to reduce cardiovascular disease by more than 80%
Publication: The British Medical Journal, 2003, Volume326 June 28th

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The ALLHAT study stands for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and is the largest study ever undertaken in hypertension. The results of the study were announced and published at the end of 2002.
30,000 people with high blood pressure in North America took part and the study included women and black people who had not been included in studies in such large numbers before. To enter into the study people needed to have high blood pressure plus another risk factor for heart disease, for instance smoking or diabetes.
The aim of the study was to compare whether there was any difference in the success of first-line therapy (the first medicines your doctor starts your treatment with). The medications that were compared were
- Diuretic (chlorthalidone) (not frequently used in the UK but similar to bendrofluazide)
- Calcium antagonist (amlodipine)
- ACE inhibitor (lisinopril)
- Alpha blocker (doxazosin)
People in the study were randomly put into one of these four groups as first-line therapy. Other tablets were added in, as necessary, to control blood pressure. As far as possible people did not have any of the other medicines ion the study added to their treatment. This is a major disadvantage to the study, as it does not follow what is normally done. For example, many people had a beta-blocker added to their initial treatment. However, beta blockers do not very effective when added to certain medications, such as an ACE inhibitor. Some of the older kind of medications were also added to this if blood pressure was not controlled.
Those taking the alpha blocker, doxazosin, as first-line therapy were stopped before the end of the trial. More people in this group were thought to have developed heart failure and there were more heart attacks and strokes compared to the other treatment regimes, almost certainly due to the fact that the blood pressure was not as well controlled in the group taking doxazosin. The three other groups completed the trial.
What does this study tell us?
At the end there was no difference between starting treatment with a diuretic, calcium antagonist or ACE inhibitor in reducing the risk of coronary heart disease. However, the ACE inhibitor was slightly less effective than the diuretic or calcium channel in reducing strokes. This, again, was probably due to the fact that the blood pressure was higher on the ACE inhibitor than in the other two groups.
This study confirms that it does not matter which treatment you start on, whether it is either a diuretic, calcium antagonist or ACE inhibitor. Based on cost alone, it would appear that a diuretic would be a good first line choice as these are the cheapest tablets. However, they are associated with some changes in blood biochemistry, particularly in the lowering in potassium and may cause difficulties with erections in men.
The average age in the study was 67. For younger people and those who have restricted their salt intake, it may be more sensible to start with a medication that blocks the renin-angiotensin system, i.e. an ACE inhibitor or an angiotensin receptor blocker.
The most important message is the realisation that many in the study did not reach the target blood pressure and that getting blood pressure to the target level, i.e. controlled, is far more important than what type of tablet is used first.

Article: Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic
Publication: Journal of the American Medical Association, 2002 Volume 288, Pages 2981-2997
Author: The ALLHAT Officers and Co-ordinators for the ALLHAT Collaborative Research Group

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The Heart Protection Study

The results of the largest trial in the world investigating the use of cholesterol-lowering therapy, and its effect on heart disease, were published in the Lancet in July 2002.

The MRC/BHF Heart Protection Study was designed to be large, to involve a substantial reduction in blood LDL cholesterol levels and a substantial increase in antioxidant vitamin levels, and to include a wide range of people at risk from heart disease and other causes.

Between 1994 and 1997, 20,536 people were recruited in 69 hospitals from various groups; those with coronary disease, arterial disease, diabetes and hypertension women, the elderly, and those with average or below average cholesterol levels.

Half of those in the study were randomly allocated to receive 40mg daily simvastatin to lower blood cholesterol levels, and half to receive dummy "placebo" tablets. These groups were then split again with half receiving antioxidant vitamins (600 mg E, 250 mg C and 20 mg beta-carotene daily), and half receiving placebo capsules.

The results showed large average reductions in blood levels of total cholesterol (1.3 mmol/l) and LDL cholesterol (1.0 mmol/l), and large increases in antioxidant vitamin levels. This led to a reduction in the risk of a stroke or heart attack by one third.

The study also showed that cholesterol lowering treatments were worthwhile in women as well as men; in people over the age of 70 as well as younger people; in those with an existing heart problem, diabetes or stroke; in people with total cholesterol levels below 5mmol/l or LDL (bad) cholesterol below 3mmol/l.

Article: MRC/BHF Heart Protection Study of cholesterol lowering with Simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial.
Publication: The Lancet 2002; 360: 7-22M
Author: Heart Protection Study Collaborative Group.
(MRC= Medical Research Council BHF= British Heart Foundation)

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The LIFE study

A study published in the Lancet in March 2002 has shown that the drug Losartan, which is an Angiotensin II Receptor Antagonist, can reduce the number of strokes and heart disease in people with high blood pressure, compared to the beta blocker Atenolol.

The study, called the LIFE study (Losartan Intervention For Endpoint Reduction), followed over 9000 people with high blood pressure, and a thickening of the left side of the heart, over a period of at least 4 years. These people were randomly given either Losartan or Atenolol to take during the study and at the end of the study the number of people who had had a stroke or a heart attack was analysed.

Both those people taking the Atenolol and those people taking Losartan saw similar reductions in their blood pressure but fewer people who took Losartan went onto have a stroke or heart attack. Those people who took Losartan were also less likely to develop diabetes (Type 2 or non-insulin dependent diabetes). Those who took Losartan also tended to have fewer side effects from their medication than those taking Atenolol.

Article: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE: a randomised trial against Atenolol.
Publication: The Lancet, 23 March 2002
Authors: B Dahlof, R Devereux, S Kjeldsen and others

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A study, published in the Lancet October 1st 2001, has shown that the drugs Perindopril and Indapamide when taken together can reduce the risk of a stroke by 43%, in those who have had a previous stroke or TIA (Transient Ischaemic Attack or mini stroke).

The study, called the Perindopril Protection Against Recurrent Stroke (or PROGRESS for short) study followed 6000 people in 172 hospitals for four years. All of the people in the study had already had a stroke or a TIA. People were randomly put into two groups when they entered the trial, about half receiving active medication and half receiving a placebo (dummy medication). Those that received the active medication all had Perindopril but were also given Indapamide if their doctor felt that it was appropriate. Perindopril is an ACE inhibitor and Indapamide is a diuretic.

The results after four years showed that those who were receiving both Perindopril and Indapamide showed the biggest reduction in risk of a further stroke, more than those who were treated with just Perindopril. This was true for people with high blood pressure and for those without. The researchers involved believe that this treatment should be routinely considered for patients who have had a stroke or a TIA, regardless of whether they have high blood pressure or not.

Article: Randomised trial of a Perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.
Publication: The Lancet, 29 September 2001 (Volume 358)
Authors: PROGRESS collaborative group.

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