1. ANBP2: ACE inhibitors vs diuretics for hypertension in the elderly
Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH
Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

2. ANBP2: Trial design Second Australian National Blood Pressure Study
6083 elderly (65-84) hypertension patients from 1594 family practices
Randomized to ACE inhibitor or diuretic (enalapril or hydrochlorothiazide recommended but not mandated)
Primary end point: any cardiovascular event or death from any cause

3. ANBP2: Results Event Hazard ratio* 95% CI p Primary end point 0.89
0.05
Primary end point in men
0.83
0.02
Primary end point in women
1.00
0.98
*ACE inhibitor vs diuretic
Wing LMH et al. N Engl J Med 2003;348:

4. Questions raised Did ALLHAT get the right answer?
Is ACE inhibitor really the first drug of choice, not a diuretic?
Trial population almost exclusively Caucasian
Califf

5. Soft methodology
ALLHAT was large and rigorous and the secondary end points clearly favored chlorthalidone; this is opposite
The methodology in ANBP2 is "loosey goosey"
Open label
No restrictions on the drugs
Difficult to interpret soft methodology
Topol

6. ALLHAT stroke risk: Lisinopril vs chlorthalidone
Subgroup
Relative risk
95% CI
Nonblack
1.00
Black
1.40
JAMA 2002; 288:

7. Effectiveness study
Is this a better model of how this works in real practice?
ALLHAT restricted your choices of second drug
This could be viewed as an effectiveness study
Califf

8. Proper trial design
A trial should be uniform, blinded, and rigorous, even though it limits some choices
"There's a choice of a very non- restrictive approach vs one that is much rigorous, much larger and much more extrapolatable to a broader population."
Topol

9. Dead or alive GUSTO I was unblinded, but the end point was mortality
"I don't think blinding changes death rate."
"A lot of things that are not dead or alive can be influenced by the unmasked nature of the drug."
Topol

10. Biochemistry experiment
Masking can interfere with getting a real-world result
"It might be a great biochemistry experiment but it might not have anything to do with what's going to happen when you use the drugs in practice."
Califf

11. Unspecified drugs Problems with ANBP2 methods
Small numbers of patients
Unblinded study drug with soft end points
Lack of uniformity of the drug
"How can you do a trial where you don't even have those darn drugs specified? That's really weak."
Topol

12. Fatal CHD or nonfatal MI
Race effect?
Trial
Primary end point
Hazard ratio*
ALLHAT (whites only)
Fatal CHD or nonfatal MI
0.94
ANBP2
Any CV event or all- cause mortality
0.89
*ACE inhibitor vs diuretic

13. The right answer?
Black patients with good kidney function should be given a diuretic and perhaps a calcium channel blocker
White patients may be better off with an ACE inhibitor or at least not worse off
Califf

14. Race effect The differences may be affected by race
Race isn't even reported in this trial but presumably wasn't blinded
"There's a lot of things about this report and the methodology that make it surprising it would surface in a high-impact journal."
Topol

15. The export of clinical trials?
Clinical trials are getting more and more expensive and take a long time to do
"It's been said that clinical trials will be nonexistent in the US in the near future. They will all be exported to other countries where they're not consumed by all the regulatory burden."
Califf

16. Burden of clinical research
The burden of clinical research is dramatically increasing
IRBs are overzealous
HIPAA will make malfeasance a criminal penalty
Payments aren't keeping up
"We're just not going to have the evidence for practice unless we do more clinical research, not less."
Califf

17. Informed consent
Only 18% of patients in HERO-2 actually read the information sheet before giving or refusing consent
CPR research was stopped due to considerations like these; at least AMI patients are awake
"It's certainly suboptimal with somebody in the midst of pain and fear to try to get a true informed consent."
Topol

18. Necessity of clinical trials
"[There is] increasing evidence that unless we do the studies we simply don't know what we're talking about."
At the NIDDK they have done two clinical trials
"No matter how much we believe something based on 'experience' life is pretty confounded."
Califf

19. Human research
There is pressure to go through extreme hurdles before you can do research on humans
Research needs to regain public trust
"A lot of really great clinical trial work has come from inside the US and hopefully it can be sustained."
Topol

20. Eastern Europe
Several large trials where most of the enrollment is in Eastern Europe and Russia
Can we trust the results if they are done in a country that can't afford the other forms of treatment common in the US?
Califf

21. Comparing medical systems
It can be hard to determine whether the difference in a trial is due to the drug or the medical system of the countries the studies are performed in
"You want to have a trial that's global but truly representative."
Topol

22. Dietary supplements
Dietary supplement sales: $17.8 billion, 3 billion doses consumed by 12 to 17 million Americans (2001)
Ephedra accounted for 0.82% of US herbal supplement sales but 62% of all herb-related reports to US poison control centers (2001)
"I still don't understand, why is ephedra on the market? There's nothing good about this drug."
Topol

23. Dietary supplements
Patients in clinic request coenzyme Q10 to replace their statin
None of these supplements are FDA reviewed but they can criticize statins, which have more evidence supporting it than almost any other therapeutic in cardiovascular medicine
"This befuddles me how this can keep continuing."
Topol

24. Lack of regulation
FDA hasn't been allowed to regulate dietary supplements
Supplements are presumed safe until proven otherwise
Drugs are not presumed safe until they are proven to be
"It's your congress at work."
Califf

25. Alternative medicine
Andrew Weil was pushing natural estrogens after the dangers of hormone replacement therapy became known
Alternative-medicine proponents without evidence hurt clinical research by blurring the boundaries of good and bad research
Topol

26. Approaches to hypertension
In light of ALLHAT and ANBP2
Blood pressure is inadequately treated
Diuretic is probably the drug to start with
ACE inhibitors do look good
Amlodipine is not as bad as some people thought it was and may even be pretty good
Califf

27. Furthering confusion
Amlodipine is still questionable due to the heart failure excess
The methodological problems with ANBP2 add to the confusion
We need a standard, rigorous approach for important clinical trials
In elderly patients of Caucasian origin ACE inhibitors might not be so bad
Topol

28. Thumbs
Topol: "I would give it two thumbs down because the methodology was very poor."
Two thumbs down
Califf: "We need effectiveness trials and they create good discussions."
One thumb up

29. ANBP2: ACE inhibitors vs diuretics for hypertension in the elderly
Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH
Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC