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AHA 2003: VALIANT and SPORTIF V under debate

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

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AHA 2003: VALIANT and SPORTIF V under debate

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  1. AHA 2003: VALIANT and SPORTIF V under debate 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. Topics VALIANTValsartan in acute myocardial infarction SPORTIF VXimelagatran in atrial fibrillation

  3. Valsartan in Acute Myocardial Infarction VALIANT

  4. VALIANT 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

  5. VALIANT 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

  6. VALIANT Results N Engl J Med 2003; 349: 1893–1906

  7. VALIANT 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

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

  9. VALIANT 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

  10. VALIANT Importance • ALLHAT Great thatmore people are treated with a diuretic, especially in the USJAMA 2002; 288: 2998-3007 • VALIANTThe 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

  11. VALIANT ARBs • CHARM Candesartan highly effective for patients intolerant of ACE inhibitorsLancet 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

  12. VALIANT 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

  13. VALIANT 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 publication TopolN Engl J Med 2003; 349: 1893–1906

  14. VALIANT 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

  15. VALIANT CHARM and Val-HeFT • Difference in potency is unknown, because candesartan wasn't compared with an ACE inhibitor • Val-HeFTReduction in hospitalization with valsartan, but no mortality benefitNEJM 2001;345: 1667-75 • CHARM/Val-HeFT vs VALIANT: • ACE inhibitor not optimized • Lower dose of the ACE inhibitor at baseline Califf

  16. VALIANT 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

  17. VALIANT 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

  18. VALIANT 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

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

  20. SPORTIF V 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

  21. VALIANT Drug problem • In reference to Your Doctor's Drug ProblemNew 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

  22. VALIANT 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

  23. Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation SPORTIF V

  24. SPORTIF V 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

  25. SPORTIF V Results *SEE=systemic embolic event AHA 2003

  26. SPORTIF V SPORTIF III: Primary events p=NS p=0.018 Lancet 2003; 362:1691-8

  27. SPORTIF V Noninferiority • VALIANTAround 1000 events in each arm • SPORTIF V37 + 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

  28. SPORTIF V 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

  29. SPORTIF V Story on heartwire • TheHeart.orgran a positive story on the trial: • SPORTIF V: Ximelagatran noninferior to warfarin for stroke prevention in AFHeartwire > News; Nov 11, 2003 • Represents what was declared • "I don't agree with that." Topol

  30. SPORTIF V 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

  31. SPORTIF V Liver enzymes AHA 2003

  32. SPORTIF V 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 Topol

  33. SPORTIF V 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

  34. SPORTIF V 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 Topol

  35. SPORTIF V 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

  36. The Statin Wars Lancet editorial on rosuvastatin • The Statin Wars: Why AstraZeneca must retreatLancet 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

  37. The Statin Wars 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." Topol

  38. The Statin Wars 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

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