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

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

ANBP2: Results Event Hazard ratio* 95% CI p Primary end point 0.89 0.71-1.00 0.05 Primary end point in men 0.83 0.71-0.97 0.02 Primary end point in women 1.00 0.83-1.21 0.98 *ACE inhibitor vs diuretic Wing LMH et al. N Engl J Med 2003;348:583-592.

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

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

ALLHAT stroke risk: Lisinopril vs chlorthalidone Subgroup Relative risk 95% CI Nonblack 1.00 0.85-1.17 Black 1.40 1.17-1.68 JAMA 2002; 288:2981-2997

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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