1. Thumbs up/Thumbs down – Dec 2003 AHA 2003: VALIANT and SPORTIF V under debate 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 – Dec 2003 VALIANT Valsartan in acute myocardial infarction SPORTIF V Ximelagatran in atrial fibrillation Topics

3. Thumbs up/Thumbs down – Dec 2003 Valsartan in Acute Myocardial Infarction VALIANT

4. Thumbs up/Thumbs down – Dec 2003 Background Valsartan, captopril, or both in myocardial infarction complicated by heart failure, LV dysfunction, or both N Engl J Med 2003; 349: 1893–1906 ACE inhibitors reduce the risk of death by 25% in post-MI patients with LV dysfunction Standard of care, but poorly adhered to ARBs cause fewer side effects VALIANT

5. Thumbs up/Thumbs down – Dec 2003 Design Objective: to test an ARB against standard therapy and combination therapy 14 703 patients with recent MI Valsartan (160 mg twice/day) vs captopril (50 mg three times/day) or combination (valsartan 80 mg twice/day + captopril 50 mg three times/day) Primary end point: all-cause mortality Two-year follow-up VALIANT

6. Thumbs up/Thumbs down – Dec 2003 N Engl J Med 2003; 349: 1893–1906 Results VALIANT

7. Thumbs up/Thumbs down – Dec 2003 Equal performance "Amazingly enough, the three treatment arms were identical in terms of mortality." Superiority test: "There wasn't a winner among the three treatments." Inferiority test: Valsartan is as good as captopril for the clinical outcomes Califf VALIANT

8. Thumbs up/Thumbs down – Dec 2003 N Engl J Med 2003; 349: 1893–1906 Adverse events 29.4 28.4 34.8* 5.8* 7.7 9.0* 0 5 10 15 20 25 30 35 Adverse events (%) Resulting in dose reduction Resulting in drug discontinuation ValsartanCaptoprilCombination *difference from captopril significant at p<0.05 VALIANT

9. Thumbs up/Thumbs down – Dec 2003 Concern Arm of interest with captopril plus valsartan showed no benefit whatsoever "The fact that valsartan came out the same as captopril seems like a major bust." The headline of this trial: "New life- saving alternative" Concern about exuberant interpretations of the results Topol VALIANT

10. Thumbs up/Thumbs down – Dec 2003 Importance ALLHAT Great that more people are treated with a diuretic, especially in the US JAMA 2002; 288: 2998-3007 VALIANT The news here: for the first time an ARB has been shown to be as good as an ACE inhibitor Important for patients who don't tolerate ACE inhibitors Califf VALIANT

11. Thumbs up/Thumbs down – Dec 2003 ARBs CHARM Candesartan highly effective for patients intolerant of ACE inhibitors Lancet 2003; 362: 759–66 People who developed a cough were often being told to stick with ACE inhibitors, because doctors didn't know the performance of ARBs in terms of mortality Califf VALIANT

12. Thumbs up/Thumbs down – Dec 2003 Presenting the results The benefit of a much more expensive substitute alternative was maybe not the most appropriate way to position the results Topol "You're responding more to the newspaper headlines than to the scientific presentation." The presentation didn't recommend either drug Califf VALIANT

13. Thumbs up/Thumbs down – Dec 2003 Captopril Small percentage of the US population gets generic captopril VALIANT showed that captopril is great Message from upcoming publications: "Captopril is king of the hill" Califf I didn't find this major conclusion in the primary publicationTopol N Engl J Med 2003; 349: 1893–1906 VALIANT

14. Thumbs up/Thumbs down – Dec 2003 Potency of ARBs In my interpretation the results are a bust, except that valsartan is a nice substitute for people not tolerating ACE inhibitors With respect to CHARM: Lancet 2003; 362: 759–66 Is there a difference in potency between candesartan and valsartan? Topol VALIANT

15. Thumbs up/Thumbs down – Dec 2003 CHARM and Val-HeFT Difference in potency is unknown, because candesartan wasn't compared with an ACE inhibitor Val-HeFT Reduction in hospitalization with valsartan, but no mortality benefit NEJM 2001; 345: 1667-75 CHARM/Val-HeFT vs VALIANT: ACE inhibitor not optimized Lower dose of the ACE inhibitor at baseline Califf VALIANT

16. Thumbs up/Thumbs down – Dec 2003 Clinical indication ACE given in the initial post-MI setting is effective Over time: ACE escape mechanism Chronic situation: ARB added to ACE inhibitor shows benefit No benefit if ACE inhibitor and ARB therapy are started together Total HF hospitalizations significantly lower in the combination arm Califf VALIANT

17. Thumbs up/Thumbs down – Dec 2003 Candesartan vs valsartan "If one wants to claim that candesartan is better than valsartan I'd say that's based on vaporware for the most part." Superiority of valsartan over candesartan has not been proven either Califf VALIANT

18. Thumbs up/Thumbs down – Dec 2003 Platinum standard Captopril: now the platinum standard Inexpensive Highly effective "Exceptionally well tolerated" "I hope that that message comes out from the VALIANT investigators at some point." Topol VALIANT

19. Thumbs up/Thumbs down – Dec 2003 Thumbs "I would give this trial itself the two thumbs up, but I would take one away for the dissemination phase." One thumb up VALIANT Topol

20. Thumbs up/Thumbs down – Dec 2003 Important message We were amazed to see: Only 52% of patients with documented systolic dysfunction or heart failure, who did not participate in the trial, were sent home on an ACE inhibitor Main public health message: "Almost everyone can get on one or the other drug." Califf SPORTIF V

21. Thumbs up/Thumbs down – Dec 2003 Drug problem In reference to Your Doctor's Drug Problem New York Times, Nov 18, 2003 "If two drugs came out the same, and one is pennies and the other one is dollars per day, I think we need to show that the doctor doesn't have a drug problem." Topol VALIANT

22. Thumbs up/Thumbs down – Dec 2003 Cost Would you advocate that people stop prescribing nongeneric ACE inhibitors also? Califf "Yeah, why not? We've got to tell it like it is. Our job is not just efficacy but also trying to help keep the cost down." Topol VALIANT

23. Thumbs up/Thumbs down – Dec 2003 Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation SPORTIF V

24. Thumbs up/Thumbs down – Dec 2003 Design Ximelagatran: direct thrombin inhibitor; powerful anticoagulant 3922 patients with nonvalvular atrial fibrillation Fixed dose ximelagatran, 36 mg twice/day, compared with dose-adjusted warfarin, target INR 2.0-3.0 End point: prevention of strokes and systemic embolic events SPORTIF V

25. Thumbs up/Thumbs down – Dec 2003 AHA 2003 Results SPORTIF V *SEE=systemic embolic event

26. Thumbs up/Thumbs down – Dec 2003 Lancet 2003; 362:1691-8 SPORTIF III: Primary events p=0.018p=NS SPORTIF V

27. Thumbs up/Thumbs down – Dec 2003 Noninferiority VALIANT Around 1000 events in each arm SPORTIF V 37 + 51 events "It's a little bothersome to put them in the same category." Califf "I agree with you. This trial does not demonstrate noninferiority." Topol SPORTIF V

28. Thumbs up/Thumbs down – Dec 2003 Spinning the results Troublesome that the experimental drug is going in the wrong direction "The gap there is something I would not be entirely comfortable with." Trial was misinterpreted Spin problem Trial did not ascertain favorable results with ximelagatran from earlier trials Topol SPORTIF V

29. Thumbs up/Thumbs down – Dec 2003 Story on heartwire TheHeart.org ran a positive story on the trial: SPORTIF V: Ximelagatran noninferior to warfarin for stroke prevention in AF Heartwire > News; Nov 11, 2003 Represents what was declared "I don't agree with that." Topol SPORTIF V

30. Thumbs up/Thumbs down – Dec 2003 The real world Ximelagatran Will be very expensive when on the market Substitute for those who cannot take warfarin Question: Can you go without measuring an INR, especially since the burden of disease is increasingly concentrated in older people with renal dysfunction? Califf SPORTIF V

31. Thumbs up/Thumbs down – Dec 2003 AHA 2003 Liver enzymes SPORTIF V

32. Thumbs up/Thumbs down – Dec 2003 FDA approval Will ximelagatran be approved? Not SPORTIF V but previous efficacy trials will "carry the day." "Overall, though, I think that this is disappointing." Trials not presented accurately SPORTIF V data do not suggest noninferiority SPORTIF V Topol

33. Thumbs up/Thumbs down – Dec 2003 Margin The trial did not have a prespecified margin One issue about inferiority: "If you have a drug that's a lot easier to use and therefore could be used in a lot more people, would you give up a little bit of the benefit for that increase in tolerance?" Califf SPORTIF V

34. Thumbs up/Thumbs down – Dec 2003 The future of ximelagatran The margin is somewhat arbitrary It remains to be seen how this liver- function-test abnormality is going to play out in the real world "Overall, though, I don't question that ximelagatran is an advance." Perhaps even the current drug of choice in the right population if it gets approved SPORTIF V Topol

35. Thumbs up/Thumbs down – Dec 2003 Thumbs Califf: "I would give this trial one thumb up, not two, because of the presentation and the fact that it's a noninferiority trial with very few events." One thumb up Topol: "I agree with the one-thumb- up assessment." One thumb up SPORTIF V

36. Thumbs up/Thumbs down – Dec 2003 Lancet editorial on rosuvastatin The Statin Wars: Why AstraZeneca must retreat Lancet 2003; 362: 1341 Response by AstraZeneca CEO McKillop: Vastly more patients in trials with rosuvastatin compared with trials with other statins on the market Committed to large outcome trials before drug entered the market "A spirited defense." Califf The Statin Wars

37. Thumbs up/Thumbs down – Dec 2003 The Lancet attack Horton's attack somewhat appropriate More data needed before a new drug is launched in a widescale population Editor's concerns about massive campaign before outcome trials understandable No editorial against Pfizer, despite similar problems with atorvastatin "It was a little surprising that there was a lashing at this juncture." The Statin Wars Topol

38. Thumbs up/Thumbs down – Dec 2003 Changing the system The editorial "A little bit late in sequence and maybe not directed at the primary offender." Topol Systemic reform of drug and device development necessary "The science has outstruck the logistics." "If we had to wait for outcomes before things got on the market, there wouldn't be any investment in industry." Califf The Statin Wars