ASCOT TRIAL

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ASCOT TRIAL

• Abbas Zaidi
• 20/09/05

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• Hypertension is one of the most prevalent risk
  factors for cardiovascular disease, affecting as
  many as 800 million people worldwide.
• It is estimated that at least 80 percent of
  people with high blood pressure may also have
  other uncontrolled cardiovascular risk factors
  with elevated cholesterol being the most common.

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• In a typical Western country with a population of
  50 million people, about eight million receive
  treatment for high blood pressure beta-blockers
  and diuretics.

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• The NICE guideline advises that first-line
  treatment should be
• A low-dose thiazide diuretic
• Except in patients under 55 with moderately
  raised blood
• pressure, for whom a beta-blocker may be more
  effective and should be considered as an
  alternative first-line therapy.
• If monotherapy is unsuccessful, a beta-blocker
  should be added.
• The combination of a thiazide and a beta-blocker
  may still be effective in patients under 55 but
  is associated with a slightly increased risk of
  diabetes.

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Introduction

• Several randomized clinical trials in
  hypertension have documented that most of the
  antihypertensive drug classes reduce major
  cardiovascular end points such as heart attack,
  stroke, and congestive heart failure to a similar
  extent. Therefore, most authoritative guidelines
  have time and again recommended to preferentially
  use b-blockers and diuretics because they are
  less expensive than the newer drugs, such as
  calcium antagonists and blockers of the
  renin-angiotensin system (ARBs).
• The rationale for the design of the
  Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
  was the lack of outcome data for the two most
  commonly used newer drug classes--that is,
  calcium antagonists and ACE inhibitors, and to
  compare this combination with a
  b-blocker/diuretic combination.

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Aim

• The primary objective of ASCOT was to compare the
  long-term effect on non-fatal myocardial
  infarction (MI) and fatal coronary heart disease
  of a standard antihypertensive regimen
  (b-blockers and diuretic) with a more
  contemporary combination of a calcium antagonist
  blocker and an ACE inhibitor.

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• It was conducted in more than 650 general
  practices and 32 regional medical centers across
  the United Kingdom, Ireland, and the 5
  Scandinavian countries (Denmark, Finland,
  Iceland, Norway, and Sweden).

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• The ASCOT results predicted that, if the
  amlodipine and perindopril combination were
  prescribed in only half of the patients currently
  receiving a beta-blocker/diuretic combination for
  the treatment of high blood pressure, over a 5
  1/2 year period
• There would be nearly 100 000 fewer
  cardiovascular events and procedures, nearly 40
  000 fewer strokes and 35 000 fewer deaths from
  cardiovascular disease. There would also be over
  90 000 fewer patients who develop type 2
  diabetes.

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• Method ASCOT was an independent, multicenter,
  randomized study designed to evaluate the
  separate and combined effects of antihypertensive
  and lipid-lowering therapy on cardiac outcome in
  patients (n 19,342) with hypertension and no
  history of coronary heart disease.
• The study used a prospective, randomized, open,
  blinded end point (PROBE) design to compare the
  effects of a calcium antagonist-based regimen
  (amlodipine) plus an ACE inhibitor (perindopril,
  if necessary) versus a b-blocker-based
  regimen (atenolol) (plus a diuretic,
  bendroflumethiazide-K, if necessary).

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ASCOT LLA

• A subset of patients were further randomized to
  receive atorvastatin 10 mg/d (n 5168) or
  placebo (n 5137) in a double-blind fashion.

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• The trial protocol called for bringing
  nondiabetic patients to blood pressure targets of
  lt 140 mm Hg systolic blood pressure and lt 90 mm
  Hg diastolic blood pressure
• Diabetic patients to targets of lt 130 mm Hg SBP
  and lt 80 mm Hg DBP.

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• The 2 antihypertensive regimens were administered
  in 6 incremental steps, depending on whether
  patients achieved their blood pressure goals.
  First-line drugs were increasing doses of
  amlodipine or atenolol, followed by combination
  with perindopril or BFZ, respectively, to bring
  patients to goal. If this was not sufficient, the
  alpha-blocker, doxazosin could be added as a
  third drug, at the discretion of the physician,
  to either of the 2 drug combinations

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Table 1. ASCOT-BPLA Antihypertensive Regimens
BFZ bendroflumethiazide GITS
gastrointestinal therapeutic system K
potassium
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• In October 2004, the independent Data Safety
  Monitoring Board (DSMB) recommended stopping
  ASCOT due to benefits in favor of
  amlodipine/perindopril-based antihypertensive
  therapy compared with atenolol/bendroflumethiazide
  -K-based antihypertensive therapy.
• .
• The data safety monitoring board determined that
  there was a higher event rate in the atenolol
  arm.

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Blood pressure was well controlled in both arms
of the study (Table 2). At the end of the study,
mean blood pressure was lower in the
amlodipine/perindopril group by 2.9/1.8 mm Hg.
Table 2. ASCOT-BPLA Mean Blood Pressure Over
Time
BFZ bendroflumethiazide DBP diastolic blood
pressure SBP systolic blood pressure
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• The combination reduced
• Major cardiovascular events by 16 (Plt0.001),
• Stroke by 23 (P0.003)
• Cardiovascular mortality by 24
• Total mortality by 11 (P0.025) compared with
  the regimen of the beta-blocker atenolol with or
  without bendroflumethiazide.
• There were significantly fewer new cases of
  diabetes, 567 versus 799 (Plt0.0001)

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• What Were the Reasons for These Results?
• Several possible explanations for the results
• Better blood pressure lowering with
  amlodipine/perindopril
• An adverse interaction between atenolol/thiazide
  and the statin
• A beneficial interaction between
  atenolol/thiazide and the statin
• Extra blood pressure-lowering benefits of
  amlodipine/perindopril and
• Non-blood pressure-lowering disadvantages for
  atenolol/thiazide.

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• The ASCOT researchers said that the blood
  pressure by itself can only explain 15 to 35 of
  the positive outcomes in the amlodepine arm.

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Conclusion

• The results of ASCOT are substantial and
  important.
• We must consider whether the much-used regimen of
  beta-blockers followed by thiazides is the
  automatic choice for our patients.