Key Trials

Question 1

Describe the Women’s Health Initiative(WHI) Trial and it’s findings.

Answer 1

• The Women’s Health Initiative (WHI) trial began in 1991 and lasted for 15 years. Over 160,000 American women took part in the randomised-controlled study. The two main arms of WHI were:
  
  • oestrogen-progestogen in healthy post-menopausal women
  • oestrogen in women post-hysterectomy
• Main results
  
  • in 2002 the oestrogen-progestogen arm was stopped prematurely as it was found that women on HRT had a significantly increased risk of stroke, deep vein thrombosis and breast cancer
  • in 2004 the oestrogen only arm was also stopped following an increased stroke risk being identified
  • the WHI trial led to a dramatic reduction in the use of HRT as the risks became better understood

Question 2

Describe the Million Women Study and it’s findings.

Answer 2

• The Million Women Study was launched in the UK in 1996 and, as the name suggest, involved over one million women. It is a cohort study linked to the Breast Screening programme
• Main results
  
  • Women currently using HRT are more likely to develop breast cancer than those who are not using HRT
  • Past users of HRT are not at increased risk
  • The risk is significantly greater for combined (oestrogen-progestogen) HRT than for oestrogen-only HRT
  • There is an increased risk of endometrial cancer in women taking oestrogen-only HRT or tibolone
  • There is a slightly increased risk of ovarian cancer in women who take HRT

Question 3

Describe the findings of the HERS trial.

Answer 3

• The Heart and Estrogen/Progestogen Replacement Study (HERS) looked at women with established coronary heart disease
• Main results
  
  • HERS was the first study to challenge the widely held belief that oestrogen was protective against cardiovascular disease. No difference in coronary events was shown in the groups taking HRT or placebo

Question 4

Describe the UKPDS trial and its findings.

Answer 4

• The United Kingdom Prospective Diabetes Study was a seminal trial of over 5,000 patients with type 2 diabetes mellitus. Patients were followed for an average of 10 years to establish whether control of blood glucose levels was associated with clinical benefits (reduced macrovascular and microvascular complications) and whether there was an advantage to any particular type of drug treatment. UKPDS also had a blood pressure control arm to establish whether this had an impact on complication rates.
• Main results
  
  • UKPDS confirmed the importance of tight glycaemic and blood pressure control in type 2 diabetics
  • Both macrovascular and microvascular complications were reduced in patients with tight glycaemic control

Question 5

Describe the DCC Trial and its findings.

Answer 5

• The Diabetes Control and Complications Trial involved 1,400 patients with type 1 diabetes mellitus in the US and Canada between 1983 and 1993.
• Main results
  
  • DCCT showed a significant reduction in microvascular complications for patients who had tight glycaemic control
  • There was a higher incidence of hypoglycaemia in the group who had tight glycaemic control

Question 6

Describe the DREAM trial and its findings.

Answer 6

• The Diabetes Reduction Assessment with ramipril and rosiglitazone Medication trial looked at whether patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) could be stopped from developing type 2 diabetes by using either ramipril and rosiglitazone.
• The study showed that the onset of type 2 diabetes may be delayed by rosiglitazone therapy.

Question 7

Describe the STOP-2 Study and its findings.

Answer 7

• The 1999 Swedish Trial in Old Patients with Hypertension-2 study looked at whether older drugs (beta-blockers or thiazides) or newer drugs (ACE inhibitors or calcium channel blockers) were better at preventing fatal cardiovascular disease.
• Main results
  
  • Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events
  • Decrease in blood pressure was the most important factor in the prevention of cardiovascular events in this age group
  • Supports the NICE approach to using older agents first-line in the elderly population

Question 8

Describe the ALLHAT Trial and it’s findings.

Answer 8

• The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial was a large randomised controlled trial that was started in 1994 and reported in 2002. ALLHAT compared amlodipine, chlorthalidone (a thiazide), lisinopril and doxazosin. Over 40,000 patients aged 55 years or older who had hypertension with one other risk factor (for example diabetes) were included in the trial.
• ALLHAT is seen as a landmark trial due to the large size and inclusion of minority groups such as people of Afro-Caribbean descent.
• Main results
  
  • Chlorthalidone outperformed lisinopril in preventing cardiovascular disease, a surprising finding which has been debated since (particularly in relation to the large number of black patients in the trial (ACE inhibitors are known to be less effective in this group)
  • The doxazosin arm was stopped prematurely due to a higher incidence of heart failure
  • 60% of patients reached the target blood pressure of 140/90 mmHg (it was generally thought prior to the trial that blood pressure targets were more difficult to achieve)

Question 9

Describe the ASCOT Trial and its findings.

Answer 9

• The 2003 Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm was a double-blinded, randomised controlled trial of around 20,000 patients with hypertension and other risk factors. Patients were randomised to either atenolol (with the addition of bendroflumethiazide if needed) or amlodipine (with the addition perindopril if needed). The primary outcome was non-fatal myocardial infarction (MI) and fatal ischaemic heart disease (IHD).
• Main results
  
  • The study was stopped prematurely because of a higher death rate in the atenolol assigned group
  • The group receiving amlodipine-based regimes had a non-significant 10% reduction in primary outcomes (non-fatal MI plus fatal IHD) and significant reductions in nearly all secondary cardiovascular endpoints and new-onset diabetes
  • The trial resulted in a major shift away from the use of beta-blockers in the management of hypertension

Question 10

Describe the 4S trial and its findings.

Answer 10

• The 1994 Scandinavian Simvastatin Survival Study was a double-blinded randomised controlled trial looking at the secondary prevention of cardiovascular disease.
• Patients who had ischaemic heart disease and a cholesterol between 5.5 and 8.0 mmol/l were given either simvastatin or a placebo.
• Main results
  
  • Total mortality decreased by 30% with death related to ischaemic heart disease decreased by 42%
  • No increase in non-cardiovascular death

Question 11

Describe the WOSCOPS trial and its findings.

Answer 11

• The 1995 West of Scotland Coronary Prevention Study was a randomised controlled trial of men aged 45-64 years with no history of ischaemic heart disease and with a raised cholesterol ( > 6.5 mmol/l). Participants were given either pravastatin or a placebo.
• Main results
  
  • total mortality decreased by 22% with death related to ischaemic heart disease decreased by 31%

Question 12

Describe the Heart Protection Study and it’s findings.

Answer 12

• A large randomised controlled trial of just over 20,000 patients funded by the Medical Research Council. Initial results were published in 2002. Patients were included if they were between 40 - 80 years and were considered to have a substantial 5-year risk of death from ischaemic heart disease due to a history of vascular disease or risk factors such as diabetes or hypertension.
• Patients were randomly allocated either simvastatin 40mg, antioxidants (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene daily), placebo or a combination.
• Main results
  
  • number needed to treat (NNT) to prevent all cause death = 57
  • NNT to prevent death related to ischaemic heart disease = 85
  • NNT to prevent a vascular event = 19, NNT to prevent a major coronary event = 33, NNT to prevent a stroke = 73
  • vascular events were reduced by around 25%
  • antioxidants did not affect clinical outcome