1. Heartbeat – Jan 2003 ALLHAT ALLHAT and ALLHAT-LLT Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, TX Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY

2. Heartbeat – Jan 2003 ALLHAT ALLHAT and ALLHAT-LLT Special Guest Commentator Thomas G Pickering MD, PhD Director, Integrative and Behavioral Cardiovascular Health Program And Hypertension Program Mount Sinai Medical Center New York, NY

3. Heartbeat – Jan 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).

4. Heartbeat – Jan 2003 ALLHAT ALLHAT: Trial design 33 357 patients age >55 with hypertension and 1 additional risk factor Randomized to:  chlorthalidone (12.5 mg to 25 mg/day, n=15 255)  amlodipine (2.5 mg to 10 mg/day, n=9048)  lisinopril (10 mg to 40 mg/day, n=9054) Primary end point: fatal CHD or nonfatal MI

5. Heartbeat – Jan 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Primary end point

6. Heartbeat – Jan 2003 ALLHAT Secondary outcomes: Amlodipine vs chlorthalidone End point Amlodipine (%) Chlorthalidone (%) Relative risk p 6-year rate of heart failure 10.27.71.38 (1.25- 1.52) <0.001 JAMA 2002; 288:2981-2997

7. Heartbeat – Jan 2003 ALLHAT Summary Why did diuretics do so well in this population, when we've all been talking about how great the ACE inhibitors are? How do we unravel this surprising finding? Fuster

8. Heartbeat – Jan 2003 ALLHAT A negative study "I was frustrated by the authors immediately portraying this paper in public policy and economic terms." "I am by no means convinced that this study is anything other than what you might normally call a negative study." "I'm not convinced the discrepancies between the drugs are as obviously apparent as claimed." Weber

9. Heartbeat – Jan 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Blood pressure

10. Heartbeat – Jan 2003 ALLHAT Heart-failure protection "I was astonished with the heart-failure result." It seems an ACE inhibitor would be a superior protector against heart failure Could the chlorthalidone be masking the symptoms of heart failure and resulting in missed diagnoses? Weber

11. Heartbeat – Jan 2003 ALLHAT Blood-pressure effect It is possible the blood-pressure difference explains some, if not most, of the final results There was a consistent difference throughout the trial ACE inhibitors have been shown to be more effective in younger patients, and the age of the trial participants may be a factor in ALLHAT Pickering

12. Heartbeat – Jan 2003 ALLHAT Blood-pressure difference Can the blood pressure have had significant impact when the difference was so small? Blood-pressure difference compared with chlorthalidone Amlodipine:+0.8 mm Hg Lisinopril:+2.0 mm Hg Fuster

13. Heartbeat – Jan 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

14. Heartbeat – Jan 2003 ALLHAT ALLHAT: Masking heart failure It is possible the diuretics were masking some of the clinical manifestations of heart failure "I don't think that [ALLHAT] means that we should throw out all the new forms of therapy and go back to treating everybody with diuretics." Ferguson

15. Heartbeat – Jan 2003 ALLHAT ALLHAT: Understanding the biology "Is it the blood-pressure control or is it the specific agents?" We have confounding results and don't have the absolute answer right now We haven't had a chance to examine all the different subgroups yet Ferguson

16. Heartbeat – Jan 2003 ALLHAT ALLHAT: Fundamental principles "We've been going along fat, dumb, and happy thinking we've got all these great new forms of therapy and they're so much better than what we had before. And now we've got to reexamine that." We need to apply the principles of risk stratification to the world of hypertension Ferguson

17. Heartbeat – Jan 2003 ALLHAT ALLHAT: A surprise "I think we were all somewhat surprised." Consensus of meta-analyses was CCBs are better at preventing stroke, while ACE inhibitors are better at preventing coronary events when compared to standard diuretic and beta-blocker treatment Pickering

18. Heartbeat – Jan 2003 ALLHAT ALLHAT: Elderly population ALLHAT had a relatively elderly population: mean age: 67 years 57% of patients >65 We don't have as many comparative trials in the elderly Pickering

19. Heartbeat – Jan 2003 ALLHAT ALLHAT: Heart failure Increased heart failure was a factor involved in stopping the doxazosin arm of ALLHAT "It may be that the diuretic tends to reduce sodium retention whereas some of these agents may be associated with sodium retention if not given in combination with a diuretic." Pickering

20. Heartbeat – Jan 2003 ALLHAT HOPE: Primary end points N Engl J Med 2000; 342(3):145-153

21. Heartbeat – Jan 2003 ALLHAT African American population There seems to be an inconsistency between HOPE and ALLHAT concerning ACE inhibitors ALLHAT was designed to have a large black population (35%) in the study ACE inhibitors may be less effective in this population Weber

22. Heartbeat – Jan 2003 ALLHAT Overinterpreting the findings? 30% to 40% of the benefit seen in HOPE may come from lowering blood pressure Can argue that in the white cohort in ALLHAT, ACE inhibitors may have reduced coronary events 5% to 8% once blood pressure is factored in "I am rather concerned that the authors of the study [ALLHAT] have perhaps overinterpreted their own findings" Weber

23. Heartbeat – Jan 2003 ALLHAT Biochemical changes Past studies with diuretics suggested that one of the problems with the drug was an effect on elements like fasting glucose, potassium, etc These may increase risk for people with hypertension Does ALLHAT tell us we should stop worrying so much about these things? Fuster

24. Heartbeat – Jan 2003 ALLHAT New-onset diabetes In SHEP, diabetics did well on chlorthalidone Beta blockers may help prevent new- onset diabetes ACE inhibitors have also been linked to prevention of new-onset diabetes Pickering

25. Heartbeat – Jan 2003 ALLHAT JAMA 2002; 288:2981-2997 ALLHAT: Fasting glucose levels

26. Heartbeat – Jan 2003 ALLHAT Three patients Which would be the first drug of choice? Patient 1: Age 65; BP 170/100; no evidence of atherosclerotic disease Patient 2: Age 65; BP 170/100; previous MI, good LVF Patient 3: Age 65; BP 170/100; previous stroke

27. Heartbeat – Jan 2003 ALLHAT First patient Patient 1: Age 65; BP 170/100; no evidence of atherosclerotic disease Patient 2: Age 65; BP 170/100; previous MI, good LVF Patient 3: Age 65; BP 170/100; previous stroke

28. Heartbeat – Jan 2003 ALLHAT First patient: First drug Weber: Start with calcium channel blocker, maybe a diuretic in a black patient Pickering: Diuretic Ferguson: Diuretic Cannon: Diuretic, maybe a generic ACE inhibitor Fuster: ACE inhibitor in the past–not sure now

29. Heartbeat – Jan 2003 ALLHAT Digesting ALLHAT We must teach our colleagues that the last word is not yet in on all this "This is a very complicated story, ALLHAT, we're going to have to take a few months to fully digest it." Weber

30. Heartbeat – Jan 2003 ALLHAT Second patient Patient 1: Age 65; BP 170/100; no evidence of atherosclerotic disease Patient 2: Age 65; BP 170/100; previous MI, good LVF Patient 3: Age 65; BP 170/100; previous stroke

31. Heartbeat – Jan 2003 ALLHAT Second patient: First drug Weber: ACE inhibitor Pickering: Beta blocker Ferguson: ACE inhibitor Cannon: Beta blocker, followed by ACE inhibitor Fuster: ACE inhibitor

32. Heartbeat – Jan 2003 ALLHAT Third patient Patient 1: Age 65; BP 170/100; no evidence of atherosclerotic disease Patient 2: Age 65; BP 170/100; previous MI, good LVF Patient 3: Age 65; BP 170/100; previous stroke

33. Heartbeat – Jan 2003 ALLHAT Third patient: First drug According to PROGRESS study, you should use a combination of ACE inhibitor and a diuretic Likely to start with diuretic for older patient and ACE inhibitor for younger, but will end up with both Pickering

34. Heartbeat – Jan 2003 ALLHAT Third patient: First drug This patient is a quandary right now, having both manifest atherosclerotic disease and hypertension I am still biased toward ACE inhibitors and will make that the first line of therapy Cannot lose sight of the underlying atherosclerotic disease Ferguson

35. Heartbeat – Jan 2003 ALLHAT Third patient: First drug I want to finish up with both ACE inhibitor and a diuretic (PROGRESS trial) so it doesn't matter which I start with "Someone who comes in with 170 systolic, you aren't going to get him down to 140 with 1 drug anyway." We all seem likely to end up with an ACE inhibitor and a diuretic as a combination Weber

36. Heartbeat – Jan 2003 ALLHAT Third patient: First drug Start with an ACE inhibitor for the vascular disease risk and then titrate to blood pressure with diuretic as a follow-up drug Cannon

37. Heartbeat – Jan 2003 ALLHAT Drug choice based on patient An ACE inhibitor followed by a diuretic Seems that for a patient age 65 with No manifestation of disease–start with a diuretic CAD with good VF–ACE inhibitor After a stroke–combination of ACE inhibitor and diuretic Fuster

38. Heartbeat – Jan 2003 ALLHAT Implications of ALLHAT ALLHAT suggested that all of these drugs are similar in their effect "Tragically, ALLHAT never examined the sorts of combinations that we use." ALLHAT is complicated by the fact the patients weren't treated in the way they would be in the real world Weber

39. Heartbeat – Jan 2003 ALLHAT ALLHAT mortality Cumulative mortality rate Years to death 01234567 0.05.1.15.2.25.3 HR (95% CI)p A/C0.96 (0.89-1.02)0.20 L/C1.00 (0.94-1.08)0.90 Chlorthalidone Amlodipine Lisinopril ALLHAT trial site

40. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Trial design 10 355 patients age >55 with hypertension and 1 additional risk factor and moderate hypercholesterolemia Randomized to:  pravastatin (40 mg/day, n=15 255)  usual care Primary end point: all-cause mortality

41. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Primary results JAMA 2002; 288:2998-3007

42. Heartbeat – Jan 2003 ALLHAT HPS: Mortality results Lancet 2002; 360:7-22

43. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Statin use JAMA 2002; 288:2998-3007

44. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Evolving standard of care "We've been going along thinking that the statins are the answer to all of our atherosclerotic disease problems, and they're not." If usual standard of care means 30% are on statins anyway, it's hard to improve on that with a statin Ferguson

45. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Open label ALLHAT-LLT was not a double-blind trial, it was open-label Lots of dropouts (22.6% of statin arm came off their drug over the course of the trial) The big difference with other statin trials lies in the study design Cannon

46. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Designing clean studies Must construct clean, well-designed studies that can give meaningful results even in the face of an improving standard of care ALLHAT-LLT was also underpowered due to lack of enrollment Cannon

47. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: Crossovers It may become more difficult to see differences in the future, the real danger is crossovers An unblinded trial makes it much easier to use the study drug as part of usual care Fuster

48. Heartbeat – Jan 2003 ALLHAT ALLHAT-LLT: LDL-C LDL-C in mg/dL 0246 100 110 120 130 140 150 Usual care Pravastatin Year of blood draw 7% * 11% 16% 23% 28% 30% * Percent decrease from baseline.

49. Heartbeat – Jan 2003 ALLHAT Summary: ALLHAT In a hypertensive population, a diuretic was as good as the use of amlodipine and lisonipril "Diuretics may not be as bad as I thought." The results may be due in part to blood- pressure effects Fuster

50. Heartbeat – Jan 2003 ALLHAT Summary: ALLHAT-LLT "It's not a good study." There was a lot of crossover, and that makes it difficult to draw conclusions It hasn't changed my opinion on statins Fuster

51. Heartbeat – Jan 2003 ALLHAT Final word: Ferguson In both studies our preconceived notions were wrong The studies reinforce which mechanisms we should be targeting ALLHAT: focus on blood pressure in hypertensive patients ALLHAT-LLT: should still be treating cholesterol is a priority Ferguson

52. Heartbeat – Jan 2003 ALLHAT Final word: Pickering ALLHAT makes me think people should be using diuretics more Current trends show diuretics being used less and less ALLHAT-LLT won't change the way I use statins in my practice Pickering

53. Heartbeat – Jan 2003 ALLHAT Final word: Cannon "One will be much more apt to turn to diuretics and include them as part of combination therapy." The lesson from LLT is that one wants to do a clean trial as the way to examine if something is beneficial Cannon

54. Heartbeat – Jan 2003 ALLHAT Next program AHA 2002 Part 2 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, MA James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, TX Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY