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Heartbeat – Nov 2001 Opening doors at AHA 2001 Opening doors to new therapies: Clinical trials at AHA 2001 Valentin Fuster MD Director, Cardiovascular.

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Presentation on theme: "Heartbeat – Nov 2001 Opening doors at AHA 2001 Opening doors to new therapies: Clinical trials at AHA 2001 Valentin Fuster MD Director, Cardiovascular."— Presentation transcript:

1 Heartbeat – Nov 2001 Opening doors at AHA 2001 Opening doors to new therapies: Clinical trials at AHA 2001 Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, Massachusetts James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, Texas Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, New York

2 Heartbeat – Nov 2001 Opening doors at AHA 2001 INTERVENTIONAL REMATCH COPPA II PRESTO PHAMACOLOGICAL HPS IONA PENTUA Studies

3 Heartbeat – Nov 2001 Opening doors at AHA 2001 REMATCH Randomized Evaluation of Mechanical Assistance Therapy for Congestive Heart Failure 129 Class IV heart failure patients randomized to either Heartmate LVAD or medical therapy 2-year follow-up

4 Heartbeat – Nov 2001 Opening doors at AHA 2001 Time pointLVAD (n=68) medical therapy (n=61) p value 1 year52%25%0.002 2 years23%8%0.09 Kaplan-Meier estimates of survival at 1 and 2 years Rose EA et al. AHA 2001 REMATCH results

5 Heartbeat – Nov 2001 Opening doors at AHA 2001 Lessons from REMATCH Life expectancy among transplant-ineligible CHF patients is dismal An option for patients, but not for everyone Technical improvements will minimize device failures (35% failure at 24 months) Economic issues will become important if extended beyond transplant-ineligible patients "We are not saving lives here, we are prolonging life." Ferguson

6 Heartbeat – Nov 2001 Opening doors at AHA 2001 A year of life We are only giving these people 1 year of life, but that is not much different from pharmacological trials "Everything we are doing, which is fantastically statistically significant, in fact when you look at what we are accomplishing, it is really not much." Fuster

7 Heartbeat – Nov 2001 Opening doors at AHA 2001 Survival plateau We have hit a plateau in survival, but anything to improve quality of life is helpful "The real benefit isn't making people live that much longer, but hopefully improving their quality of life during whatever time is left to them." Weber

8 Heartbeat – Nov 2001 Opening doors at AHA 2001 REMATCH: quality of life 1-year quality of life assessment LVAD group Medical therapy groupp value Median NYHA functional class IIIV<0.001 #patients assessed /total # patients (%) 24/24 (100%) 7/11 (64%) Rose EA et al. AHA 2001

9 Heartbeat – Nov 2001 Opening doors at AHA 2001 Potential LVAD candidates Who would be getting this? Younger patients who had a massive MI and developed heart failure New options are needed because there are still too few donors Cannon

10 Heartbeat – Nov 2001 Opening doors at AHA 2001 Recovery on LVAD A feasible device that might be combined with cell transplantation to improve the heart muscle Fuster Some evidence for recovery of heart muscle function in some patients on LVADs Ferguson

11 Heartbeat – Nov 2001 Opening doors at AHA 2001 COPPA II Decrease atrial fibrillation post bypass 293 patients (half on beta-blockers, half on propafenone postoperatively)

12 Heartbeat – Nov 2001 Opening doors at AHA 2001 Postoperative atrial fibrillation Was 50% before beta-blockers 25% with beta-blockers COPPA II: 12.4% AF in propafenone group 22.7% AF in control group

13 Heartbeat – Nov 2001 Opening doors at AHA 2001 Caution A lot of AF goes away on its own Propafenone is not a totally benign drug "Maybe we should not necessarily be routinely prophylaxing these people all the time." Ferguson

14 Heartbeat – Nov 2001 Opening doors at AHA 2001 Red flags "I have big red flags that go off clinically in treating with anything other than amiodarone." We won't see anything until we get 2-4000 patients Every class IA or IC antiarrhythmic has been associated with sudden death when studied in a very large trial Cannon

15 Heartbeat – Nov 2001 Opening doors at AHA 2001 Are there real benefits? Issues to look at with propafenone Only the highest dose did anything No difference in hospital length of stay between groups Ferguson

16 Heartbeat – Nov 2001 Opening doors at AHA 2001 PREVENT 2 PRoject of Ex-Vivo Vein Graft ENgineering Via Transfection 2 200 patients undergoing CABG randomized to receive E2F Decoy- treatment of their autologous vein grafts or to receive their grafts untreated

17 Heartbeat – Nov 2001 Opening doors at AHA 2001 PREVENT 2 results Park S-J et al. TCT 2001 Graft failure at 1 year E2F DecoyControl >75% restenosis 27%38%

18 Heartbeat – Nov 2001 Opening doors at AHA 2001 Gene therapy "This has been one area where there has been almost nothing developed in the last 2 decades." Encouraging to have a more direct approach Cannon

19 Heartbeat – Nov 2001 Opening doors at AHA 2001 An exciting advance First major advance in years with real potential to impact the biology of the bypass graft "What has always been the real Achilles' heel of the procedure is the biology of venous conduits." Ferguson

20 Heartbeat – Nov 2001 Opening doors at AHA 2001 PRESTO Prevention of REStenosis with Tranilast and its Outcomes 11 500 patients were randomized 4 treatment arms with tranilast or 1 placebo arm "This is the largest trial I know with the largest disappointment." Fuster

21 Heartbeat – Nov 2001 Opening doors at AHA 2001 PRESTO results Patient groupno of MACE% p value vs placebo Placebo35815.7N/A 300 mg twice daily for 1 month 35215.40.815 450 mg twice daily for 1 month 35115.50.77 300 mg twice daily for 3 months 36316.00.815 450 mg twice daily for 3 months 36416.00.765 Holmes D et al. AHA 2001

22 Heartbeat – Nov 2001 Opening doors at AHA 2001 Problems with PRESTO What data led to the clinical trial Animal models Small-scale human studies Treatment analysis, not intention-to- treat analysis "[This] points out the hazards of basing large-scale clinical trials on small populations of patients." Ferguson

23 Heartbeat – Nov 2001 Opening doors at AHA 2001 Understand the biology "To my way of thinking, it really reinforces our need, before we go jumping into mega-million dollar clinical trials, that we really need to understand a little bit about the biology of what is going on." Ferguson

24 Heartbeat – Nov 2001 Opening doors at AHA 2001 Coated stents If coated stents hold their promise, the issue of using an oral drug to treat a local problem may be moot Cannon

25 Heartbeat – Nov 2001 Opening doors at AHA 2001 HPS Heart Protection Study >20 000 patients with previous CV event or diabetes randomized to simvastatin (40 mg) or placebo 5-year follow-up Also looked at antioxidant vitamins Endpoints of vascular events and mortality

26 Heartbeat – Nov 2001 Opening doors at AHA 2001 Primary endpoint simvastatin (n=10 269) placebo (n=10 267)p value All-cause mortality events (%) 1328 (12.9%)1503 (14.6%)<0.001 Deaths from heart disease and related blood vessel disease (%) 791 (7.7%)943 (9.2%)<0.002 Collins R et al. AHA 2001 Primary endpoints in HPS

27 Heartbeat – Nov 2001 Opening doors at AHA 2001 Events by LDL level Baseline LDL (mg/dL) simvastatin (n=10 269) placebo (n=10 267) <100285360 100-129670881 130+10871365 Collins R et al. HPS trial website Data from www.hpsinfo.org

28 Heartbeat – Nov 2001 Opening doors at AHA 2001 Events vitamin (n=10 269) placebo (n=10 267)p value All-cause mortality (%) 1443 (14.1%)1388 (13.5%)NS All vascular mortality (%) 895 (8.7%)839 (8.2%)NS All nonvascular mortality (%) 548 (5.3%)549 (5.3%)NS Collins R et al. AHA 2001 Vitamins in HPS

29 Heartbeat – Nov 2001 Opening doors at AHA 2001 Secondary endpoint simvastatin (n=10 269) placebo (n=10 267)p value relative reduction vs placebo Effect on stroke 456 (4.4%) 613 (6.0%) <0.0000127% Major cardiovascular events 2042 (19.9%) 2606 (25.4%) <0.0000124% Deaths not related to heart disease 537 (5.2%) 560 (5.5%) n/sno difference Secondary endpoints in HPS Collins R et al. AHA 2001

30 Heartbeat – Nov 2001 Opening doors at AHA 2001 A confirmatory study What was really new here? It confirmed suspicions and assumptions we already had due to earlier studies Secondary prevention patients benefit from statin Patients with other risk factors benefit Weber

31 Heartbeat – Nov 2001 Opening doors at AHA 2001 simvastatin (n=2006) placebo (n=1976)p value relative reduction (adjusted) 279 (13.9%)369 (18.7%)<0.000128% Incidence of MI and stroke in diabetic patients without prior disease Collins R et al. AHA 2001

32 Heartbeat – Nov 2001 Opening doors at AHA 2001 Importance of low LDL results The low-LDL data is impressive. Even if you are at target levels, it is worth taking a statin Should we even test for cholesterol? Statin effects other than LDL lowering are becoming more important Ferguson

33 Heartbeat – Nov 2001 Opening doors at AHA 2001 Impact on care HPS will impact on care A statin other than pravachol Offers new hope for market after the removal of Baycol Raises possible application in a broader population not focused on lipid status Ferguson

34 Heartbeat – Nov 2001 Opening doors at AHA 2001 Not enough statin use The paradox is we don't use statins enough now, and we keep expanding the population it is useful for Fuster But all the doctors take statins, so there may be hope for the future Weber

35 Heartbeat – Nov 2001 Opening doors at AHA 2001 Clinical use of statins ATP III guidelines suggest 36 million patients receiving statins in the US, but estimates put it at 12 million A lot of the gap is in primary prevention "Hopefully this huge trial will make a big impact on the clinical use of this class of drugs." Cannon

36 Heartbeat – Nov 2001 Opening doors at AHA 2001 The vitamin problem A perception problem, people don't want to take a medicine all their life. But they will take ineffective vitamins "The bottom line for me is, hopefully people will throw away their vitamins and talk to their doctor about taking a statin." Cannon

37 Heartbeat – Nov 2001 Opening doors at AHA 2001 Price Insurance means price should not be a problem Perception of having to take a medicine People don't want the implication they are ill People don't realize taking statin would have a huge real effect Cannon

38 Heartbeat – Nov 2001 Opening doors at AHA 2001 Simvastatin use in HPS Year of follow-up % of simvastatin use simvastatin armplacebo arm Year 582%32% Year 681%38% Study average85%18% Collins R et al. AHA 2001

39 Heartbeat – Nov 2001 Opening doors at AHA 2001 Which drug to use We now have compelling evidence for a number of drugs Aspirin ACE inhibitors Statins "Now maybe you can get people to take one medicine, and maybe, if you're lucky, you can get them to take two. But you're not going to get them to take three, it's just not going to happen." Ferguson

40 Heartbeat – Nov 2001 Opening doors at AHA 2001 PENTUA PENtasaccharide in Unstable Angina A dose study of fondaparinux in 929 patients with unstable angina Indirect blocker of Factor Xa Outperformed heparin in preventing venous thrombosis following orthopedic surgery in earlier studies

41 Heartbeat – Nov 2001 Opening doors at AHA 2001 PENTUA: events at 9 and 30 days Treatment death, MI and recurrent ischemia (day 9) death, MI and recurrent ischemia (day 30) Fondaparinux 2.5 mg30.0%*3.9% Fondaparinux 4 mg43.5%5.4% Fondaparinux 8 mg41.0%5.4% Fondaparinux 12 mg34.8%4.6% Enoxaparin 1 mg/kg bid40.2%4.8% *p<0.05 for comparison with 4-mg, 8-mg doses of fondaparinux and versus enoxaparin Simoons ML et al. AHA 2001

42 Heartbeat – Nov 2001 Opening doors at AHA 2001 Upstream in the cascade The further upstream in both the anticoagulant and antiplatelet cascade you go, the more effective the approach Enoxaparin was earlier in the cascade than unfractionated heparin Clopidogrel higher in the cascade than oral IIb/IIIa inhibitors Pentasaccharide higher than enoxaparin Cannon

43 Heartbeat – Nov 2001 Opening doors at AHA 2001 PENTUA: bleeding Treatment major bleeding (day 9) major and minor bleeding (day 30) Fondaparinux 2.5 mg0.0%3.9% Fondaparinux 4 mg1.4%5.4% Fondaparinux 8 mg1.8%5.4% Fondaparinux 12 mg0.4%4.6% Enoxaparin 1 mg/kg bid0.0%4.8% Simoons ML et al. AHA 2001

44 Heartbeat – Nov 2001 Opening doors at AHA 2001 Questions about PENTUA The reverse dose-effect is troubling We never saw the ST-segment monitoring data "We still need to have some sort of ability to block thrombin if it is generated." Ferguson

45 Heartbeat – Nov 2001 Opening doors at AHA 2001 More caution on PENTUA Other questions on PENTUA Data based on a small number of patients Why is there no dose-response effect? A phase III trial may require a huge number of patients Weber

46 Heartbeat – Nov 2001 Opening doors at AHA 2001 Dose response No dose response shouldn't be a worry, no anticoagulant has a dose response for efficacy With heparin, lowest levels of PTT beneficial No difference found in enoxaprin Aspirin showed no difference by INR once you get above 1.5 INR Cannon

47 Heartbeat – Nov 2001 Opening doors at AHA 2001 Feedback mechanisms Dose effects are unclear in the anticoagulant field "The clotting systems works with an incredible number of feedback mechanisms." Fuster

48 Heartbeat – Nov 2001 Opening doors at AHA 2001 IONA Impact of Nicorandil in Angina 5126 patients with stable angina randomized to nicorandil or placebo Endpoints death, MI, hospitalization for angina 1.6 years average follow-up

49 Heartbeat – Nov 2001 Opening doors at AHA 2001 Endpoint placebo (n=2561) nicorandil (n=2565) hazard ratio 95% CI p value CHD death, nonfatal MI, and unplanned hospitalization for angina 15.5%13.1%0.830.72, 0.96 0.014 CHD death and nonfatal MI 5.2%4.2%0.790.61, 1.02 0.068 All CV events17.0%14.7%0.850.74, 0.98 0.025 IONA: outcomes Dargie H et al. AHA 2001

50 Heartbeat – Nov 2001 Opening doors at AHA 2001 Interpreting IONA UK has very low revascularization rate, which may affect interpretation Antianginal therapy is beneficial, especially for those who cannot be revascularized "It's a tool in your antianginal armementarium. We just don't happen to have it available in the United States right now." Ferguson

51 Heartbeat – Nov 2001 Opening doors at AHA 2001 Clinical importance In the future, we will face more and more patients who cannot be revascularized Elderly Previous revascularizations Cannon

52 Heartbeat – Nov 2001 Opening doors at AHA 2001 Summary A number of opening doors to new therapies New devices (REMATCH) Gene therapy (PREVENT) Expanding statin use (HPS) Moving higher in the coagulation cascade (PENTUA) Fuster

53 Heartbeat – Nov 2001 Opening doors at AHA 2001 Cannon's last word Several new approaches that are encouraging "We've heard evidence in the statin field saying that we really need to move on utilizing the data to change clinical practice." Cannon

54 Heartbeat – Nov 2001 Opening doors at AHA 2001 Ferguson's last word The most likely impact on clinical care will be from HPS and statins for people with normal LDL "This was a meeting that, for me, generated a lot of excitement about things we can potentially do in the future." Ferguson

55 Heartbeat – Nov 2001 Opening doors at AHA 2001 Weber's last word It is more and more difficult to add life to the seriously ill, but we may affect quality of life "Prevention is something that has become very exciting, and more importantly prevention at an earlier stage than previously was the case." Weber

56 Heartbeat – Nov 2001 Opening doors at AHA 2001 Fuster's last word In the last 20 years, we have only prolonged life by 7 years in the cardiovascular field We have to attack the problem earlier "In prolongation of life, when you look, really, at the last 2 decades, one becomes a little bit humble." Fuster


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