Clinical trial commentary: HPS

1. Clinical trial commentary: HPS Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine The Cleveland Clinic Foundation Cleveland, Ohio Robert M Califf MDProfessor 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 Collins R et al. HPS trial website

5. Vitamins "There was absolutely no effect of vitamins, proving once again that vitamins only enrich the urine and the people who make them in terms of coronary disease prevention." Califf

6. Primary endpoints in HPS Collins R et al. AHA 2001

7. Simvastatin: major vascular events Collins R et al. HPS website

8. Long-term treatment The event curves began together and gradually diverged over the course of the study "This is a treatment that should not be given for the short term, but should be given, probably, for life." Califf

9. Simvastatin effect by baseline LDL Collins R et al. HPS official site

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 Collins R et al. HPS official site

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 Collins R et al. HPS official site

14. Communication with patients We must report vitamins as neutral, but: "If you have stuff that costs money, and it has absolutely no benefit, why on earth would you take it in the first place?" "How do you convince people that, just because somebody writes in Parade magazine that vitamins are good for you, that they shouldn't be doing this?" Califf

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 "… this may push us over the top in terms of really wanting to convince people to not spend their money on this but spend it on things that work." Califf "We're into all this alternative, complementary, integrative medicine, and if we could find a vitamin that helps people, we'll sure recommend it. But if anything, it's sure going in the wrong direction." Topol

17. LDL levels and mortality They did not report on mortality alone for the low baseline LDL group "I sure would like to know if the survival benefit also showed no relationship to the baseline LDL." Topol

18. Challenging previous wisdom Fascinating results for the low LDL group • overturns CARE and others that implied a plateau of benefit for LDL-lowering • AFCAPS/TexCAPS showed benefit when patients had high CRP and low LDL Have we reached the point of not even measuring LDL and instead just giving a statin? Topol

19. Reserving judgment We do need to see more detailed data "As you know, there is nothing that would be more exciting to someone like me than being able to say, 'Don't worry about measuring LDL cholesterol, the whole concept was wrong to begin with.'" Califf

20. Simvastatin effect by baseline LDL Collins R et al. HPS official site

21. Vascular events by LDL level Collins R et al. HPS trial website

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

28. CRP levels and cardiovascular risk Jialal et al. Circulation 2001

29. Lovastatin by LDL/CRP level in AFCAPS/TexCAPS *Event rates over 5-year follow-up** LDL cutoff = 149.1 mg/dL *** CRP cutoff = 0.16 mg/dL; Ridker et al. N Engl J Med 2001

30. Using CRP in the clinic How often should you measure CRP? • needs prospective study • for now we measure as part of routine blood sample in a clinic visit • if patient is on a statin, CRP is measured when they come back for their liver function test • costs <$8 to run the assay Topol

31. Practice in light of HPS I don't believe potent LDL lowering means you have a better drug, but opinions differ • work with agents with the longest track record (simvastatin, pravastatin) • save atorvastatin for unmanageable LDL • in LDL <100, give a statin if the patient has elevated CRP Topol

32. Effect of HPS on future trials Are trials on statins in the acute phase unnecessary now? • MIRACL • A to Z "I think the window is closing rapidly, and the only issue is whether there is something different about an unstable plaque in the first couple of months." Califf

33. Ethics of using placebo Can we still justify placebo in cardiovascular trials? • SYMPHONY showed a trend toward detriment for low LDL patients • safety committees need to look at data of outstanding trials • trials like MIRACL seem to have been overshadowed by HPS results

34. Use of surrogates in CV medicine HPS argues for an end to using surrogates as sole criteria for drug development • still a role for surrogates as a way to winnow out therapies • there is a risk you will miss a treatment because it doesn't affect the surrogate of the day Califf

35. Cheap and independent trial Much was made of HPS as a cheap and independent trial • avoided industry interference • $30 million for a 20 000 patient trial • extended follow-up Is this a model for future trials? Topol

36. Outcome trial We need comparative, competitive study with clinical outcomes • surrogates won't tell us enough • so many beneficial treatments • beyond the age of placebo in many areas of CV medicine • we should not spend millions on queries about data that are irrelevant to the main outcomes Califf

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

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