Heartbeat – Nov 2003 AHA 2003 AHA 2003: Exchanging knowledge Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Robert Harrington MD Professor of Medicine Duke University Medical Center Durham, NC 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

Heartbeat – Nov 2003 AHA 2003 VALIANT Valsartan in acute myocardial infarction SPORTIF V Ximelagatran in atrial fibrillation Topics

Heartbeat – Nov 2003 AHA 2003 Valsartan in Acute Myocardial Infarction VALIANT

Heartbeat – Nov 2003 AHA 2003 VALIANT: Design Valsartan, captopril, or both in myocardial infarction complicated by heart failure, LV dysfunction, or both (N Engl J Med 2003; 349: 1893–1906) patients with recent MI (<10 days) 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 2-year follow-up

Heartbeat – Nov 2003 AHA 2003 N Engl J Med 2003; 349: 1893–1906 VALIANT: Results

Heartbeat – Nov 2003 AHA 2003 VALIANT: Summary More side effects in the combination group Valsartan looks good compared to captopril Combination does not look as good as giving both agents alone Fuster

Heartbeat – Nov 2003 AHA 2003 VALIANT: Alternative option Ferguson "The glass is half full here." Very good alternative for patients who do not tolerate ACE inhibitors Going after the angiotensin side of things maybe not as productive as looking at aldosterone-receptor antagonists "It would have been nice if the combination were better, but it's not. I think we just sort of need to get over it and move on"

Heartbeat – Nov 2003 AHA 2003 VALIANT: ARB vs ACE inhibitor "The glass is three quarters full." "I was, to be quite honest, a little bit concerned about this study" The fact that the ARB is fully equal to a very effective ACE inhibitor is reassuring Weber

Heartbeat – Nov 2003 AHA 2003 VALIANT: Beyond post-MI heart failure Caution about broadly extending the results to the world beyond post-MI heart failure "There is almost an irresistible impulse to do so" Combination therapy might be different in a general HF population Ferguson

Heartbeat – Nov 2003 AHA 2003 VALIANT: Important message We have entered a phase where we have a lot of therapies that work Captopril is well tolerated and highly effective The fact that valsartan is "as good" is an important message for the practitioner ARB did add incremental benefit in a different HF population in CHARM "Results may not be extrapolated from one patient population to another" Harrington

Heartbeat – Nov 2003 AHA 2003 OPTIMAAL and ELITE-2: Recap Better outcome with the ACE inhibitor captopril compared to losartan (50 mg/day) in OPTIMAAL and ELITE-2 Did losartan not do well because the dose was too low ? Fuster

Heartbeat – Nov 2003 AHA 2003 OPTIMAAL and ELITE-2: Dose issue The low dose was definitely a problem 50 mg/day is a minimal antihypertensive dose 100 mg to 150 mg twice/day would be far more appropriate New studies with higher losartan doses will confirm this Weber

Heartbeat – Nov 2003 AHA 2003 CHARM and Val-HeFT: Recap Valsartan showed improvements in cardiovascular outcome when added to the ACE inhibitor Was the addition in these trials also better because of a dosing aspect? Fuster

Heartbeat – Nov 2003 AHA 2003 VALIANT vs CHARM & Val-HeFT: I "We are getting into a complicated era with regard to comparative therapies" VALIANT Mortality end point, definitive results; "no wishy-washiness" CHARM and Val-HeFT Smaller trials, weaker end points Difficult to extrapolate from one drug to another, let alone to guess equipotent dosages Harrington

Heartbeat – Nov 2003 AHA 2003 Good news We have pushed the dose of ARBs to levels where we get outcomes comparable to those with ACE inhibitors Bad news In the post-MI population there is no incremental benefit in terms of mortality Ferguson VALIANT vs CHARM & Val-HeFT: II

Heartbeat – Nov 2003 AHA 2003 CHARM Benefit with combination therapy If you don't want to push the dose to the maximum, there may be other opportunities for modification "But once you've got your dose maxed out, there's no additive benefit" Weber VALIANT vs CHARM & Val-HeFT: III

Heartbeat – Nov 2003 AHA 2003 Val-HeFT : Combination therapy "We are really opening up a very complicated can of worms here" Val-HeFT Group getting all drugs had the least benefit of valsartan Difficulty of how to properly combine drugs in clinical practice HF world Thrombosis world Harrington

Heartbeat – Nov 2003 AHA 2003 N Engl J Med 2003; 349: 1893–1906 VALIANT: Adverse events

Heartbeat – Nov 2003 AHA 2003 VALIANT: Summary Was the increased number of side effects in the combination group disappointing? Yes, this was disappointing We need to turn attention to different mechanisms for additional benefit Harrington

Heartbeat – Nov 2003 AHA 2003 VALIANT: Editorial Mann DL, Deswell A. Angiotensin-receptor blockade in acute myocardial infarction. (N Engl J Med 2003; 349: ) ACE inhibitors remain first-choice therapy post-MI Cost of valsartan at the study doses was 4 to 6 times higher than generic captopril

Heartbeat – Nov 2003 AHA 2003 VALIANT: Cost Valsartan is expensive because patients take two pills a day Not everyone is using generic captopril "Getting patients to take a medication that they like and tolerate is the secret of success, not looking to save a little bit of money" Weber

Heartbeat – Nov 2003 AHA 2003 VALIANT: ACE inhibitors vs ARBs We have a good standard, substantially less expensive than the additive therapy ARBs are equal in terms of mortality Cost is a bit higher compared to ACE inhibitors "Maybe that's the price you need to pay" Ferguson

Heartbeat – Nov 2003 AHA 2003 VALIANT: Conclusions A huge trial In a comparative trial you are not going to get better than that Harrington ARBs certainly play a role in MI Different patient populations and the issue of dosage need to be taken into account Fuster

Heartbeat – Nov 2003 AHA 2003 Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation SPORTIF V

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Design 3922 patients from 409 US and Canadian sites with nonvalvular atrial fibrillation and one other stroke risk factor Fixed-dose ximelagatran, 36 mg twice/day, compared to dose-adjusted warfarin, target INR Primary objective: noninferiority of ximelagatran to warfarin for prevention of all strokes and systemic embolic events

Heartbeat – Nov 2003 AHA 2003 End point Ximelagatran (%) Warfarin (%) p Any stroke or systemic embolic event NA Intracerebral hemorrhage 0.6 NS Major bleeding Major and minor bleeding 3747< SPORTIF V: Results AHA 2003

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Summary Ximelagatran No need for monitoring Noninferior, even superior to warfarin "I think this is quite remarkable" Fuster

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Excitement In placebo trials warfarin achieved a 50% to 70% risk reduction for stroke in AF Accepting something that is as good is an admirable goal "Overall I'm excited, but I want to have some discussion on the liver issue" Harrington

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Stroke protection A lot of AF patients drop out of warfarin therapy "This really does open a door" More patients can eventually be protected against strokes The better safety profile of ximelagatran in terms of major bleeding is exciting Weber

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Encouraging data In the pooled analysis ximelagatran was not superior to but as good as warfarin Ximelagatran was going against very well-managed warfarin therapy, as opposed to "real-world" warfarin therapy "It's very encouraging that it shows noninferiority" Ferguson

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Liver enzymes

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Antithrombins THRIVE, SPORTIF III, ESTEEM Antithrombins effective but caused increases in alanine transaminase How does the effectiveness of oral antithrombins weigh against increases in liver enzymes? Fuster

Heartbeat – Nov 2003 AHA 2003 Lancet 2003; 362: 789–97 ESTEEM: Alanine transaminase

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Concern Elevations of liver enzymes are often transitory SPORTIF V: one case of "full-fledged" hepatitis "Once we are getting the drug out to the community, treating hundreds of thousands of people, are we going to see fatal events as a regular part of this?" Weber

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Totality Totality of the data is important Ximelagatran a very good anticoagulant Eliminates some of the "baggage" associated with warfarin Further data needed on patient monitoring and liver enzymes "Let's not turn our backs on what might be an important limitation" Harrington

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Good and bad Ximelagatran: equal to warfarin in terms of efficacy One death, however, showed resolving hepatitis on biopsy 20 patients had liver enzyme elevations from 6 months onward "Encouraging data, but legitimate concerns about liver enzymes" Ferguson

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: ACS Oral antithrombins in acute coronary syndromes Fibrinolytic therapy Enoxaparin/LMWH vs heparin EXTRACT-TIMI 25 will address this issue Do you think oral antithrombins are going to be the answer for this? Fuster

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Oral agents "I am not convinced that an oral agent given to someone who is acutely ill, coupled with a potent fibrinolytic agent, would be the best strategy" Uncertainty with regard to absorption Need for rapid treatment Confounding needs of cath lab or surgery Oral agents are probably best reserved for subacute and chronic periods Harrington

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: ACS debate Oral antithrombins Rapid and predictable Long half-lives – Fuster Direct thrombin inhibitor overview (Lancet 2002; 359: ) "If we couldn't do it intravenously... I am less optimistic that we can do it orally" – Ferguson

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Stent patients Is there a role for oral antithrombins in stent interventions, instead of IIb/III inhibitors? Combination of antithrombins and antiplatelets offers best results Harrington

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: ACS debate We might in the end even get rid of aspirin and clopidogrel and use a drug with a lower bleeding incidence, ie, antithrombins – Fuster "I'll be betting rather heavily against that" Antiplatelets are more potent than indirect thrombin inhibitors in acute thrombotic prevention – Ferguson

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Secondary prevention Ximelagatran vs clopidogrel + aspirin in secondary prevention ESTEEM Safety and efficacy of ximelagatran post-ACS (Lancet 2003; 362: 789–797) Question "Are we going to feel confident putting our stent patients... not on aspirin and clopidogrel for at least some period of time?" Ferguson

Heartbeat – Nov 2003 AHA 2003 SPORTIF V: Oral agents Anticoagulants or antiplatelets? The question remains open in post-ACS as well as in post-MI – Harrington Warfarin Good, cheap therapy Dosing problems "That is why we are so excited to talk about oral antithrombins" – Fuster

Heartbeat – Nov 2003 AHA 2003 Final thought: Weber Ximelagatran may be a safer and more effective way of managing AF, despite concerns about the liver VALIANT reminds us that 3 to 4 years into a trial there is still an 80% survival of these very high-risk patients "That is something that we should congratulate ourselves about" Weber

Heartbeat – Nov 2003 AHA 2003 Final thought: Harrington Ischemic heart disease remains a major problem, with 20% mortality post-MI. "We still have work to do" Comparative trials with established therapies are going to become the norm in the evaluation of new agents "Our ability to identify potentially new targets for inhibition or stimulation is unprecedented" Harrington

Heartbeat – Nov 2003 AHA 2003 Final thought: Ferguson VALIANT Two generally accepted agents head- to-head: equal, but not additive "A superbly done study" SPORTIF V "A new kid on the block" Both good and bad news Ferguson

Heartbeat – Nov 2003 AHA 2003 Final thought: Fuster "Two superbly done studies with a lot of information" Fuster