RITA 3: Aggressive intervention for Non-ST elevation MI

1. RITA 3: Aggressive intervention for Non-ST elevation MI 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. Trial design Randomized Intervention Trial of Unstable Angina (RITA-3) PI: Keith AA Fox 1810 patients with non-ST-elevation Ml or unstable angina. Randomized to conservative or interventional approach. Primary end points: death, MI, or refractory angina at 4 months and death or MI at 1 year. Eligible patients were men or women aged 55?80 years with previously treated or untreated hypertension and electrocardiographically documented LVH. Patients had trough sitting diastolic blood pressure mean readings of 95 to 115 mmHg or sitting systolic blood pressure mean readings of 160 to 200 mmHg at weeks 1 and 2 of the placebo run-in period. LVH was diagnosed by standard 12-lead ECG, and was defined according to criteria based on the product of Cornell voltage (RaVL + SV3) x QRS duration product criteria: >2440 mm x msec in men product of QRS duration x Cornell voltage + 6 mm exceeding the same value in women. Alternatively, the Sokolow-Lyon voltage combination (Sv1 + RV5 or V6) >38 mm was accepted as an alternative criterion for LVH in men and women. The exclusion criteria included certain cardiac and non-cardiac conditions that may limit the long-term survival of patients or increase nonadherence to study medication. Eligible patients were men or women aged 55?80 years with previously treated or untreated hypertension and electrocardiographically documented LVH. Patients had trough sitting diastolic blood pressure mean readings of 95 to 115 mmHg or sitting systolic blood pressure mean readings of 160 to 200 mmHg at weeks 1 and 2 of the placebo run-in period. LVH was diagnosed by standard 12-lead ECG, and was defined according to criteria based on the product of Cornell voltage (RaVL + SV3) x QRS duration product criteria: >2440 mm x msec in men product of QRS duration x Cornell voltage + 6 mm exceeding the same value in women. Alternatively, the Sokolow-Lyon voltage combination (Sv1 + RV5 or V6) >38 mm was accepted as an alternative criterion for LVH in men and women. The exclusion criteria included certain cardiac and non-cardiac conditions that may limit the long-term survival of patients or increase nonadherence to study medication.

3. RITA-3: Event rate

4. RITA-3: MI using standard definition

5. RITA-3: Angina

6. End of conservative management Patients entered into RITA-3 were less sick than TACTICS or FRISC II "I do think, indeed, that this strongly supports invasive strategy toward non ST- segment elevation."

7. How invasive? None of these trials were invasive by the aggressive US standard "Would an even more aggressive strategy be better than this kind of gentlemanlike invasive alternative?"

8. Trial comparison

9. FRISC II: Mortality and inflammation

10. Inflammation hypotheses Two hypotheses: Does the invasive procedure help provide a beneficial anti-inflammatory effect? Should we bring inflammation markers to as low a level possible before we revascularize?

11. Protein-guided therapy You could call it the dawn of the proteomic era in cardiovascular medicine "Dealing with the proteins makes us a whole lot smarter than just the traditional history, physical, and routine laboratory testing."

12. Prognostic proteins All proteins are not created equal in medicine "Just knowing that a protein has prognostic baggage doesn't necessarily mean that it's going to yield therapeutic value." We've learned there are some proteins that help with prognosis of patients and provide some treatment strategies

13. CD40 CD40 ligand is shed from platelets Involved in IIb/IIIa and clotting Drives the inflammatory cascade

14. Inflammation Inflammatory response Part of the way to heal a plaque fissure or erosion Subminimal cholesterol and transformation of foam cells causes a "hot segment"

15. Infarct centers Is it time to set up infarct centers? There are state-sanctioned trauma centers Trauma is a much smaller cause of death than heart disease Why not have state-recognized acute ischemic heart centers?

16. How many centers? How many centers should a major metropolitan area have? The case is so clear-cut favoring invasive centers, why don't we have them? "The only thing that's stopping us is financial and ego issues between hospitals and groups of doctors, isn't it?"

17. How do we get there? How do we implement this model? No easy answers, but we must articulate the case clearly. "It does seem that not doing this will doom a fair number of people to death or loss of heart function that wouldn't have occurred."

18. Mortality in PRAGUE-2 and DANAMI-2

19. Events in women

20. Women In PURSUIT it appeared women had a detrimental effect of IIb/IIIa inhibitor that depended on how intervention was used in different countries 15% to 20% of women have no obstructive disease even with ST-segment depression and other high-risk features

21. No good explanation If it had been seen in all 3 trials, I would get more worried It shouldn't be due to artery size, since stents and other techniques address that "I don't have a good explanation for this, if it is a true finding"

22. PCI results in women

23. Multivariate modeling We haven't seen the multivariate modeling from these trials When you pick out 1 thing like gender, you drag in all sorts of other variables "Whether it's specifically gender that's being called out here, that needs crisp analysis."

24. Defining risk The invasive approach should be standard of care in places that have the resources We have 9 to 10 low-risk patients for every high-risk patient "Where do we draw the line about where the invasive approach is really indicated?"

25. Risk stratification I think proteins combined with a good history is the way of the future Present high-risk indicators include dynamic ECG changes high-risk scores who already failed aspirin diabetes high CRP

26. What to look for Invasive strategy is recommended in patients with dynamic ST changes elevated troponin elevated CRP "It's going to be very interesting to see now what we do with the low-risk group because I think the course of the high-risk group is pretty clear."