Clinical Trial Commentary

1
Clinical Trial Commentary
ALLHAT

• Dr Eric Topol
• Chairman and Professor, Department of Cardiology
• Director of the Joseph J Jacobs Center for
  Thrombosis and Vascular Biology at the Cleveland
  Clinic
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

2
ALLHAT

• The Antihypertensive and Lipid-Lowering
  treatment to prevent Heart Attack Trial
• Eligibility
• - Men and women gt 55 years with systolic
  BP gt 140 mmHg and/or diastolic BP gt 90 mm Hg, or
  medicated for hypertension
• - at least one additional risk factor for
  coronary heart disease (CHD)
• Risk factors for CHD
• -myocardial infarction, stroke, left ventricular
  hypertrophy by ECG or echo, type II diabetes,
  smoking, low HDL

3
ALLHAT

• Patients
• 42 448 participants recruited from 625 centers
• Patients were randomized to the following
  antihypertensive treatments (relative number of
  patients per group in parentheses).
• chlorthalidone (1.7) amlodipine (1)
• lisinopril (1) doxazosin (1)
• A substudy looks at lipid-lowering using
  pravastatin.
• Treatment goal
• BP systolic lt 140 and diastolic lt 90 mm Hg

4
ALLHAT

• Primary endpoint
• composite fatal CHD and nonfatal MI
• Secondary endpoints
• (1) all-cause mortality
• (2) combined CHD (death, nonfatal MI,
  revascularization, hospitalization for angina)
• (3) stroke
• (4) combined CVD
• The doxazosin arm was discontinued in January
  2000 based on the recommendations of an
  independent review committee.
• For the remaining treatment arms, follow-up is
  scheduled to end in March 2002.

5
ALLHAT doxazosin vs chlorthalidone
Outcomes for blood pressure control
Year of study chlorthalidone doxazosin
Baseline 145/83 145/84
1 137/79 140/79
2 136/78 138/78
4 135/76 137/76
Mean blood pressure, seated Mean blood pressure, seated Mean blood pressure, seated
ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. JAMA
20002831967-1975
6
ALLHAT doxazosin vs chlorthalidone
Outcomes for primary and secondary
endpoints Relative risk (RR) for doxazosin shown
Endpoint RR 95 CI p value
CHD 1.03 (0.9 - 1.17) 0.71
all-cause mortality 1.03 (0.9 - 1.15) 0.56
Combined CVD 1.25 (1.17-1.33) lt0.0001
CHF 2.04 (1.79-2.32) lt0.0001
Non-CHF events 1.13 (1.06-1.21) lt0.001
Stroke 1.19 (1.01-1.40) 0.04
ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. JAMA
20002831967-1975
7
ALLHAT

• Study outcome
• Compared with doxazosin, chlorthalidone reduces
  the risk for combined CVD events, particularly
  CHF, in high-risk hypertensive patients.
• The study did not have a placebo arm, so the
  effect of doxazosin compared to no treatment
  cannot be determined.
• The use of blood pressure as a surrogate marker
  in the treatment of hypertension, without regard
  for the antihypertensive drug used, is called
  into question.

8
ALLHAT

• To me the take home message to the practitioner
  is that if you have a patient on an alpha-blocker
  alone or doxazosin alone in particular, and
  there's an alternative, and it hasn't been a
  complicated step to get where you are in the
  antihypertensive regimen, then switch to the
  other alternative.
• Dr Robert Califf
• Professor of Cardiology
• Associate Vice Chancellor for
• Clinical Research at Duke University

9
ALLHAT

• So it's ironic too that here is a men's health
  drug, to improve quality of life for patients
  with large prostates, and coming out the same
  week as the Women's Health Initiative for
  estrogen replacement. You wonder all kinds of
  things that are in the pharmacologic environment
  that because they haven't been adequately tested
  when they get to large scale trials you start to
  learn about the truth.
• Dr Eric Topol
• Chairman and Professor
• Department of Cardiology
• Cleveland Clinic

10
Demographics in cardiology

• The average American can now be expected to live
  until age 76.4 (80 years for females, 73 years
  for males).
• In 1995, 737 000 deaths were secondary to heart
  disease (HD). 615 000 or 84 of these deaths
  occurred in people 65 years or older.
• The population is projected to increase 43.4
  and deaths attributable to HD are projected to
  increase by 112.7 over the next 50 years.

Foot DK, et al. J Am Coll Cardiol
20003510667-1081