1. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT: Optimal first-step therapy for hypertension 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. Thumbs up/Thumbs down – Feb 2003 ALLHAT Randomized design of ALLHAT High-risk hypertensive patients Consent / Randomize (42 418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid- lowering Not eligible for lipid-lowering Consent / Randomize (10 355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yrs).

3. Thumbs up/Thumbs down – Feb 2003 ALLHAT A horse race Each class of antihypertensive is represented by a drug, and the losers drop out as events are accrued Primary end point: fatal CHD or nonfatal MI All major clinical end points were measured in minimal detail Califf

4. Thumbs up/Thumbs down – Feb 2003 ALLHAT Secondary drug protocol Step 2 agents:Dose 1*Dose 2*Dose 3* Reserpine0.05 qd or 0.1 qod 0.1 qd0.2 qd Clonidine (oral)0.1 bid0.2 bid0.3 bid Atenolol25 qd50 qd100 qd Step 3 agent: Hydralazine25 bid50 bid100 bid *All doses in mg

5. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT: Trial design 42 418 patients age >55 with hypertension and 1 additional risk factor 623 sites:  United States  Canada  Puerto Rico  US Virgin Islands

6. Thumbs up/Thumbs down – Feb 2003 ALLHAT Cumulative event rate Years of Follow-up doxazosin chlorthalidone C: 15,268 D: 9,067 12,990 7,382 9,443 5,285 4,827 2,654 2,010 1,083 Rel risk 1.25 z = 6.77, p < 0.0001 95% CI 1.17-1.33 JAMA. 2000;283:1967-1975 Doxazosin CVD end point

7. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Primary end point

8. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 Lisinopril secondary end points

9. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 Amlodipine secondary end points

10. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Fasting glucose levels

11. Thumbs up/Thumbs down – Feb 2003 ALLHAT Stroke risk: Lisinopril vs chlorthalidone SubgroupRelative risk95% CI Nonblack1.000.85-1.17 Black1.401.17-1.68 JAMA 2002; 288:2981-2997

12. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Glomerular filtration rate

13. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT-LLT: Primary results JAMA 2002; 288:2998-3007

14. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT-LLT: Disappointing Second largest statin trial after HPS "[It's] disappointing that it didn't provide true consistency and only with this bouillabaisse pooling stuff do you get the same relative effect." Topol

15. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT: Points of contention Why did lisinopril increase heart failure and stroke? This is directly opposite of the results from HOPE PEACE and EUROPA are looking at ACE inhibitors as a key preventive tactic "This backfired terribly in ALLHAT." Topol

16. Thumbs up/Thumbs down – Feb 2003 ALLHAT Active control trial The other drugs were only less effective than the diuretic, not increasing risks for the patients The "soft underbelly" of HOPE was whether the patients were being adequately treated with regard to their other risk factors If EUROPA and PEACE are negative, either HOPE was wrong or ramipril is "a magic potion" Califf

17. Thumbs up/Thumbs down – Feb 2003 ALLHAT Using less ramipril I've gone from requiring ramipril use to making it optional "I think we have to say this is a piece of data that moves back toward less radical enthusiasm about the ACE-inhibitor class." Califf

18. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Blood pressure

19. Thumbs up/Thumbs down – Feb 2003 ALLHAT Genetics of hypertension Studies suggest the genetic defect of essential hypertension alpha — adducin Gly460Trp would be particularly responsive to thiazide diuretic Topol

20. Thumbs up/Thumbs down – Feb 2003 ALLHAT Stroke risk: Lisinopril vs chlorthalidone SubgroupRelative risk95% CI Nonblack1.000.85-1.17 Black1.401.17-1.68 JAMA 2002; 288:2981-2997

21. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Blood pressure

22. Thumbs up/Thumbs down – Feb 2003 ALLHAT JAMA 2002; 288:2981-2997 Amlodipine secondary end points

23. Thumbs up/Thumbs down – Feb 2003 ALLHAT Edema or heart failure? There was no objective measure of function to diagnose heart failure A substudy was commissioned to have records independently reviewed All the results are not in, but so far the substudy suggests that there is more than just edema going on Califf

24. Thumbs up/Thumbs down – Feb 2003 ALLHAT Surprising increase in heart failure The increase in heart failure for both classes of drugs (ACE inhibitor and CCB) was a very surprising finding Lisinopril 19% increased risk Amlodipine 38% increased risk "You would have thought both drugs would not have done this." Topol

25. Thumbs up/Thumbs down – Feb 2003 ALLHAT Bad choice of second drug Critics say the second drug after ACE inhibitor would be a diuretic, forbidden by the trial Most doctors in the US probably don't use a diuretic as the second drug "I think no matter how you slice the loaf here the answer is that the underused diuretics, which are a lot cheaper, are at least as good and almost certainly better." Califf

26. Thumbs up/Thumbs down – Feb 2003 ALLHAT A class effect? Most doctors use hydrochlorothiazide as a diuretic This could be a chlorthalidone-specific result, you can't be sure "We have examples where drugs in the same class don't get the same results." Califf

27. Thumbs up/Thumbs down – Feb 2003 ALLHAT Striking secondary outcomes The media loved that a cheaper drug came out better I wasn't enthusiastic about the trial when I was on the NIH advisory committee reviewing the trial "The secondary outcomes made for all the spice here. If you were to just go by the primary outcome, though, you wouldn't be able to differentiate the treatments." Topol

28. Thumbs up/Thumbs down – Feb 2003 ALLHAT Public health Why not use a cheaper drug that is just as good? It's a dominant treatment A company trying to get labelling with this primary outcome might have trouble getting approval from the FDA "We have examples where drugs in the same class don't get the same results." Califf

29. Thumbs up/Thumbs down – Feb 2003 ALLHAT An easy choice There is a value judgment being made among the secondary outcomes "I think the majority of people, if you said, 'Look, I can give you this thing for 2 cents a day, or I can give you this thing for a buck and a half a day, and here are the expected outcomes, which would you buy?' I don't think that's a hard choice." Califf

30. Thumbs up/Thumbs down – Feb 2003 ALLHAT Inadequate treatment "None of these drugs are very good, they all have some untoward effects, unfortunately. You're picking your poison in some respects." This study reinforces that there is inadequate treatment of blood pressure. "A lot of people are walking around with very high blood pressure still, despite therapy." Topol

31. Thumbs up/Thumbs down – Feb 2003 ALLHAT Lowering blood pressure "I think that people that are most critical of doctors trying to lower blood pressure are people that have never actually worked in a clinic trying to get blood pressure down." It takes the doctor and patient working together to get blood pressure down We usually need more than 2 drugs Califf

32. Thumbs up/Thumbs down – Feb 2003 ALLHAT Genomics approach to hypertension Genomics will allow us to move past the trial and error approach "$37 billion a year it costs to treat hypertension and we're not even doing a very good job of doing it. We've got to have a better strategy and almost any strategy would be better than what we have today." Topol

33. Thumbs up/Thumbs down – Feb 2003 ALLHAT Interpersonal approach People will round numbers down for patients who are frustrated at not getting hypertension under control to avoid adding more drugs drugs Lowering blood pressure is very complicated and interpersonal Califf

34. Thumbs up/Thumbs down – Feb 2003 ALLHAT Two thumbs up Topol: "Don't you think this is as good as it gets for hypertension and clinical trials?" Two thumbs up Califf: "I think it's as good as it gets." Two thumbs up

35. Thumbs up/Thumbs down – Feb 2003 ALLHAT A new approach "The system we have now, where companies not only fund trials but decide what the questions are is not the right way to do it" Doctors and patients want to know which is the best choice among the treatments that work? Most companies avoid head-to-head trials and try to game them even when they agree Califf

36. Thumbs up/Thumbs down – Feb 2003 ALLHAT Honest broker NIH or other agencies as an honest broker is the model to pursue in the future "If a drug is a winner it ought to prevail in a direct comparison without the type of engineering that can occur with interested sponsors." Topol

37. Thumbs up/Thumbs down – Feb 2003 ALLHAT Pricing The price of a drug should be a function of how much it contributes "The way it is now, people are having to decide what to take and what to buy without any knowledge in many fields of which one is really better." In multiple sclerosis, for example, there are 4 drugs and no one knows which is really better Califf

38. Thumbs up/Thumbs down – Feb 2003 ALLHAT ALLHAT: Optimal first-step therapy for hypertension 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