1. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Chronic therapy of cardiovascular disease Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, Ohio Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

2. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE and OVERTURE/OCTAVE LIFE Losartan Intervention For Endpoint Reduction in Hypertension OVERTURE Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events OCTAVE Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril

3. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Inclusion criteria Atenolol vs Losartan 9193 patients Age 55-80 years Previously treated or untreated hypertension Systolic BP 160-200 mm Hg or diastolic BP 95- 115 mm Hg ECG LVH Primary composite endpoint of cardiovascular morbidity and mortality, defined as stroke, MI, or cardiovascular death

4. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI ACC 2002 LIFE: Event rate p=0.021 p=0.491p=0.001p=0.206 11% 13% 4% 5% 7% 4% 5%

5. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Implications Beta-blockade had been on such a high pedestal and now this puts the sartans in a whole other light "I'm a little bit stunned about the results, not knowing exactly how to change practice." Topol

6. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Expectations Investigators expected the primary beneficial effect to be on the heart as a result of the animal data "The trial was done extremely well and measured the right things, but the result was unexpected. The benefit was in the direction the investigators had postulated but […] not for the outcome reason they had thought." Califf

7. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Head-to-head clinical trials As we get head-to-head trials, interpreting them will be very complicated. "The Evidence-Based Medicine Mafia […] has been extremely high on beta- blockers […], and I haven't lost any enthusiasm for beta-blockers from this trial but I've gained a lot of respect for ARBs and their potential to produce benefit." Califf

8. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Blood pressure follow-up (4.8 years) 061218243036424854 Study Month 40 60 80 100 120 140 160 180 Systolic Diastolic mm Hg Atenolol Losartan Atenolol 145.4 mm Hg Losartan 144.1 mm Hg Atenolol 80.9 mm Hg Losartan 81.3 mm Hg B Dahlof et al. Lancet 2002;359:995-1003

9. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Blood pressure The real role of blood pressure can be difficult to determine We don't have any information about the pulse wave, which is potentially important "Nor do we have quite yet the full sense of the distribution of blood pressure effects in the population or across time." Califf

10. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: How generalizable? This trial had an overwhelmingly white patient population. Can we generalize to the more heterogeneous population you would find in general practice? Topol "I wouldn't abandon the fundamental principles that you treat blood pressure with a low-dose thiozide diuretic and in someone who has a risk of MI [ …] you err toward beta-blocker and an ACE inhibitor." Califf

11. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Not cheap These are exciting new drugs with real potential but they are not cheap "For people who can take an ACE inhibitor and who don't cough and feel fine and can get them at a lower price, I'm all for that." Califf

12. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Stroke belt Source: CDC

13. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Applying the data There could be a genetic component to the stroke belt, making the LIFE data difficult to generalize "I've been using ARBs a fair amount, this will make me feel even better about using them more often but to make a radical change in the fundamental approach to blood pressure based on one trial, I think would be a mistake." Califf

14. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: New onset diabetes 6 Proportion of patients with first event (%) 18243036424854 Losartan Atenolol Dahlof et al. Lancet 2002;359:995-1003 60660 Intention-to-Treat 12 Adjusted Risk Reduction 25%, p=0.001 Study Month 8 7 6 5 4 3 2 1 0

15. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Lifestyle changes Walking 4 times a week for 30 minutes a day would be more effective than losartan "But the changes in lifestyle are hard to come by. Unfortunately, our society relies too much on some pill and potion rather than the discipline of exercise and diet." Topol

16. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Start with ARBs for hypertension? Maybe we could start with ACE inhibitors or ARBs in a newly diagnosed hypertensive patient Patients successfully on beta-blockers shouldn't be switched These patients are hypertensives with serious left-ventricular hypertrophy and have already tried diuretic therapy and failed This may all be rendered moot by advances in genomics, proteonomics, and tailored therapy Topol

17. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Multiple drugs The average person with real systolic hypertension will require 2.6 drugs at maximal FDA levels to get their pressure below 140 The ARB option is well-tolerated, making it very attractive ALLHAT does not include ARBs, but should give us the first real evidence about what drug you should start with Califf

18. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: The pocketbook We have to balance what we need to do and the pocketbook Economic factors get in the way of proper treatment "It's difficult to take someone who feels fine and has not had a stroke and convince them that they should take not one, and not two, but three drugs that cost 2 or 3 bucks a day apiece." Califf

19. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Diabetes Prevention Program Research Group. N Engl J Med 2002;346(6):393-403 LIFE: DPP 4.8 7.8 11.0

20. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Source: CDC LIFE: Obesity 12.0% 17.9% 18.9% 15.3% 19.8%

21. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: NAVIGATOR Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research Nateglinide (60mg before main meals) vs valsartan (160mg daily) vs placebo > 60 000 patients screened for impaired glucose tolerance (IGT) 7500 subjects to be enrolled 600-800 centers in 40 countries Age > 50 with at least 1 CV risk factor

22. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Outpatient cardiology Outpatient cardiology is really a metabolic clinic; we're seeing the classic lifestyle problems It is hoped we can integrate the diabetologists' understanding of glucose management "We're going to see much attention to focused metabolic clinics run by major cardiovascular centers." Califf

23. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Marinating the blood vessels Jay Cohn advocates we abandon measuring blood pressure; we should focus on getting patients on effective doses of drugs "The concept of marinating blood vessels with the right doses of drugs as opposed to trying to hit these targets, which have never really been proven to be correct, might be the way to go." Califf

24. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI LIFE: Diabetes prevention Diabetes prevention has been seen in 3 rigorous trials; there is a theme "I think it's more than just marinating the blood vessels. There must be an anti- inflammatory effect that's afforded by working on this neurohumoral axis of ACE and ARBs and I think it's fascinating." Topol

25. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Topol: 2 thumbs up for LIFE "Very provocative trial. I love to see trials where you get a surprise finding, shake the bushes. It's good for the field." "I hope this one does get the interest it deserves in the cardiovascular community." Topol

26. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE and OCTAVE "[OVERTURE and OCTAVE were] supposed to be the big trials to validate omapatrilat as a cornerstone of heart failure and hypertension therapy. And I guess that didn't exactly turn out to be the case." Topol

27. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Background Omapatrilat vs enalapril for heart failure An ACE-NEP inhibitor (works through angiotension converting enzyme and the neutral endopeptidase) More effective than straight ACE inhibitor in lowering systolic blood pressure Two phase 2 trials both trended to mortality reduction Califf

28. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI Packer et al. ACC 51st Annual Scientific Session. OVERTURE: Event rate HR=0.93 p=0.233 HR=0.91 p=0.024 HR=0.94 p=0.339 HR=0.93 p=0.187 *primary endpoint

29. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Negative perception Most portrayals seem overly negative "If your expectation was that omapatrilat was going to have to be way better than ACE inhibitor then it's definitely a negative. If your expectation was that we could make a modest incremental improvement, it may not have knocked omapatrilat out of the box, at least in the field of heart failure." Califf

30. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Event rate HR=0.91 p=0.024 In a head-to-head trial, how do you know either is better than placebo? If you use the ACE inhibitor mortality trial end point, you get a nominally significant result Califf

31. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Adverse events Eventenalaprilomapatrilat CHF25.6%22.6% Hypotension11.5%19.5% Dizziness13.9%19.4% Impaired renal function3.6%2.3% Angioedema0.5%0.8% Packer et al. ACC 51st Annual Scientific Session.

32. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Shades of benefit ACE inhibitors are generic now, making for an inexpensive reference standard "You have some shades of benefit but it’s going to be an expensive alternative and the benefit is not assured. […] And angioedema is not exactly a nuisance, it's life- threatening." Topol

33. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Interpreting the data "I think fundamentally, the most important point about the pragmatic interpretation of the data is that to replace an ACE inhibitor, you've got to really beat it. And this trial did not beat it." Califf

34. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: The future "For those more interested in research and its future implications, does this mean the death of the ACE/NEP combination? I don't think so. Yet." Califf "Unfortunately, though, for the expectations of the drug, which were far greater than validating it as an alternative, it was demonstrating its superiority, and it was far from that." Califf

35. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Before and after "Going into the ACC I would have thought most people would say, ARBs, that's a yawner. You know, they're nice to have around, but so what? ACE/NEP, that's where the action is." "Now after the ACC we say, Jeez, ARBs, they're phenomenal, and the ACE/NEP – well, you know, you've got a drug that's maybe a little better but has the same side effects or worse." Califf

36. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OVERTURE: Benefit of sartans "This whole class has been kind of clouded by lack of data showing precise benefits." "You're right, I think that was one of the major themes that came out of this meeting [is that] there were some big benefits that I guess were not fully expected." Topol

37. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Risk of angioedema Eventenalaprilomapatrilat All patients0.68%2.17% Blacks1.62%5.54% Nonblacks0.55%1.78% Smokers0.81%3.93% Nonsmokers0.66%1.79% The OCTAVE Study Group. ACC 51st Annual Scientific Session.

38. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Pharmacogenetics "This could be a great drug for managing blood pressure if you could just screen out the people who were gonna be getting angioedema. And that could be easily done by a SNP analysis." "This could be one of the earliest applications of pharmaco- genetics." Topol

39. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: At-risk patients We need a way to identify the population at high-risk for angioedema "Those who look on the rosy side say, 'Well, there's not been a death yet due to angioedema in the omaptrilat experience.' But the setting of a clinical trial is very different from the setting in a community health clinic where people with hypertension are being treated and sent out there." Califf

40. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Good blood pressure response No one has seen the full data from OCTAVE Blood pressure response was better with omapatrilat If blood pressure effects are important in hypertension, this could be of benefit for those with the worst levels of systolic hypertension Califf

41. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: How important is BP "I'm uncertain how much of it is really a pressure effect." A meta-analysis by Curt Furberg implies that 50% of the benefit of any hypertensive drug is based purely on the blood pressure lowering Califf

42. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Benefits of low BP I can't argue there is no benefit to lowering blood pressure per se "I can bleed you into a trash can and lower your blood pressure and it doesn't mean its good for you." "You've got to consider the full effects of a drug you're going to give people." Califf

43. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Screening Omapatrilat is a potent drug, but it has a relatively infrequent serious side effect we could screen out "Perhaps some day we'll see broad application but in a pharmacogenetic way. It only takes a few dollars to run a polymorphism and it could mean a very effective therapy in those patients who are not at risk." Topol

44. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Applying polymorphisms "How are you going to get doctors to run a polymorphism test when they can't even give the drug in the first place?" Califf

45. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: Genetics in cancer Cancer specialists are ahead of cardiovascular specialists in using pharmacogenetics Talking about specific genetic linkages used to design therapies Omapatrilat is an attractive case because we know the pathway and it is easy to find SNPs in particular genes By next year, it should be a "no- brainer" Topol

46. Thumbs up/Thumbs down – June 2002 Direct coronary intervention for MI OCTAVE: The big issue Getting the drugs to the people who benefit the most is the big issue "Oftentimes I'm afraid that people just assume that operationalizing a concept is automatic. We've got a lot of work to do." Califf