Clinical trial commentary: HPS

1. Clinical trial commentary: HPS Eric J Topol MD Provost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, Ohio Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, North Carolina

2. HPS Heart Protection Study A study carried out on 20 536 patients in the UK evaluating use of a fixed dose of simvastatin in the prevention of CHD events

3. HPS Heart Protection Study Patients enrolled:40-80 years oldtotal cholesterol >135 mg/dL (>3.5 mmol/L)At risk of CHD due to prior disease Randomized to:simvastatin (40 mg) or placebovitamin cocktail (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene) or placebo2x2 factorial design

4. Simvastatin compliance in HPS

5. Vitamins

6. Primary endpoints in HPS

7. Simvastatin: major vascular events

8. Long-term treatment

9. Simvastatin effect by baseline LDL

10. Summary Simvastatin showed efficacy for a broad group of patients, including many who wouldn't meet current treatment guidelines Benefit was modest, but present in all subgroups divided by age, sex, and baseline LDL level  No appreciable downside Califf

11. Patient safety measures

12. Prior diseases as entry criteria Patients had to have an increased risk of CHD death due to prior disease to enter the trial MI or other CHD occlusive disease of noncoronary arteries diabetes mellitus or treated hypertension Statins or vitamins not clearly indicated or contraindicated according to patient's own doctors

13. Vitamins in HPS "vitamin" should be lower-cased, "nonvascular", not "non-vascular""vitamin" should be lower-cased, "nonvascular", not "non-vascular"

14. Communication with patients Delete extra space between "it" and "has"Delete extra space between "it" and "has"

15. Belief in vitamins persists Patients take these vitamins and think they are helping their cardiovascular health "So many trials have put the nails in the coffin for vitamins for cardiovascular benefit; I don't know why it persists." Topol

16. Report the negatives of vitamins

17. LDL levels and mortality

18. Challenging previous wisdom

19. Reserving judgment

20. Simvastatin effect by baseline LDL

21. Vascular events by LDL level

22. LDL as a surrogate LDL has held up well for many years as a surrogate, now it might be shot down "I think the combination of cerivastatin and HPS really gives the one-two punch to the concept that one can just develop a drug based on lowering LDL cholesterol and then really believe that you know what its total effects on human health are going to be."  Califf

23. Run-in period Patients were required to tolerate 40 mg of simvastatin daily for 30 days before being entered into the trial may have "cleansed" the data somewhat drop-out rate was not reported, but could influence interpretation of the trial more time could have been spent addressing some of the uncertainties

24. Choice of statin Which statin should be used at which dose? HPS group implied lovastatin comes off-patent and could be used cheaply Crestor (rosuvastatin) and the other "superstatins" offer even more LDL-lowering

25. Statin strategy Do we stay with our current strategy? we currently start with simvastatin or pravastatin because we have the data (and we should maybe use a higher dose of simvastatin) if LDL doesn't drop enough, we recommend atorvastatin – this is brought into question by HPS Califf

26. Practice in light of HPS Until we know more about HPS, patients should have be informed about their different statin choices we should use simvastatin 40 mg as reference standard the unproven statins shouldn't be the first choice until they have comparable data "Should the clinical world be held hostage to unproven theories and marketing strategies?"  Califf

27. How do statins work? Unanswered questions remain about statins does lowering LDL more with a given drug actually prevent more MIs and strokes? pleiotropic effects come into play what are the HDL effects? "That's the biggest wake-up call of HPS, we don't know how the darn statins work."  Topol Straightened curly quotes Lowercased first words in bulleted text Straightened curly quotes Lowercased first words in bulleted text

28. CRP levels and cardiovascular risk

29. Lovastatin by LDL/CRP level in AFCAPS/TexCAPS

30. Using CRP in the clinic

31. Practice in light of HPS

32. Effect of HPS on future trials

33. Ethics of using placebo

34. Use of surrogates in CV medicine

35. Cheap and independent trial

36. Outcome trial

37. Independence Independence does not mean industry has nothing to contribute; clinical trial is a shared responsibility "I would argue strongly that the interpretation of the data should be in the hands of people who don't work for the company that would stand to benefit from the treatment." Califf

38. National research infrastructure No national entity designed to support cooperative head-to-head clinical trials dominant costs subsidized by governments controls on industry's access to the data this model isn't used enough in the US, where we lose trials to industry interference  Topol

39. A different mechanism Once you have developed a scientific principle, the rest doesn't happen automatically "And I do think that there is increasing discussion and insight at the public policy level that we're going to have to have a different mechanism for outcome-based trials."  Califf

40. Topol: 2 thumbs up "It will be interesting to see in the months and years ahead if LDL measurements are abandoned, and what the clinical community decides to do regarding HPS's findings."  Topol "measurements" not "measurments""measurements" not "measurments"

41. Califf: 2 thumbs up "If we can just talk people who are currently taking vitamin E to stop and donate half of the money that they were spending to worthy causes, we would not only improve the health of the population but also contribute to lots of other worthwhile endeavors."  Califf