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ALLHAT: Optimal first-step therapy for hypertension

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

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ALLHAT: Optimal first-step therapy for hypertension

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  1. ALLHAT: Optimal first-step therapy for hypertension Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

  2. Randomized designof ALLHAT Amlodipine Chlorthalidone Doxazosin Lisinopril High-risk hypertensive patients Consent / Randomize (42 418) Eligible for lipid-lowering Not eligible for lipid-lowering Consent / Randomize (10 355) Pravastatin Usualcare Follow for CHD and other outcomes until death or end of study (up to 8 yrs).

  3. 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. Secondary drug protocol

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

  7. ALLHAT: Primary end point JAMA 2002; 288:2981-2997

  8. Lisinopril secondary end points JAMA 2002; 288:2981-2997

  9. Amlodipine secondary end points JAMA 2002; 288:2981-2997

  10. ALLHAT: Fasting glucose levels JAMA 2002; 288:2981-2997

  11. Stroke risk: Lisinopril vs chlorthalidone JAMA 2002; 288:2981-2997

  12. ALLHAT: Glomerular filtration rate JAMA 2002; 288:2981-2997

  13. ALLHAT-LLT: Primary results JAMA 2002; 288:2998-3007

  14. 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. 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. 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. 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. ALLHAT: Blood pressure JAMA 2002; 288:2981-2997

  19. Genetics of hypertension • Studies suggest the genetic defect of essential hypertension alpha —adducin Gly460Trp would be particularly responsive to thiazide diuretic Topol

  20. Stroke risk: Lisinopril vs chlorthalidone JAMA 2002; 288:2981-2997

  21. ALLHAT: Blood pressure JAMA 2002; 288:2981-2997

  22. Amlodipine secondary end points JAMA 2002; 288:2981-2997

  23. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. ALLHAT: Optimal first-step therapy for hypertension Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

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