HPS Clinical trial commentary HPS Eric J Topol

HPS 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 Thumbs up/Thumbs down – December 2001

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 Thumbs up/Thumbs down – December 2001

HPS Heart Protection Study Patients enrolled: 40 -80 years old total cholesterol >135 mg/d. L (>3. 5 mmol/L) At risk of CHD due to prior disease Randomized to: simvastatin (40 mg) or placebo vitamin cocktail (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene) or placebo 2 x 2 factorial design Thumbs up/Thumbs down – December 2001

HPS Simvastatin compliance in HPS % of simvastatin use Year of follow-up simvastatin arm placebo arm Year 5 82% 32% Year 6 81% 38% Study average 85% 18% Thumbs up/Thumbs down – December 2001 Collins R et al. HPS trial website

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Primary endpoints in HPS simvastatin (n=10 269) placebo (n=10 267) 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 Primary endpoint Thumbs up/Thumbs down – December 2001 p value Collins R et al. AHA 2001

HPS Simvastatin: major vascular events Vascular event statin (n=10 269) placebo (n=10 267) Total CHD 914 (8. 9%) 1234 (12. 0%) Total stroke 456 (4. 4%) 613 (6. 0%) Revascularization 926 (9. 0%) 1185 (11. 5%) 2042 (19. 9%) 2606 (25. 4%) ANY OF ABOVE Thumbs up/Thumbs down – December 2001 Collins R et al. HPS website

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Simvastatin effect by baseline LDL reduction (%) Baseline LDL (mmol/L) vascular events statin placebo (n=10 269) (n=10 267) statin (n=10 269) placebo (n=10 267) <3. 0 (116 mg/d. L) 1. 8 2. 7 602 761 3. 0 -<3. 5 2. 2 3. 2 483 655 3. 5 (135 mg/d. L) 2. 7 3. 7 957 1190 All patients 2. 3 3. 3 2042 2606 Thumbs up/Thumbs down – December 2001 Collins R et al. HPS official site

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Patient safety measures Bloo patients showing elevation simvastatin (n=10 269) placebo (n=10 267) Liver enzymes (ALT >3 x ULN) 77 (0. 8%) 65 (0. 6%) Muscle (CK >10 x ULN) 9 (0. 09%) 5 (0. 05%) d enzymes (x upper limit of normal) Thumbs up/Thumbs down – December 2001 Collins R et al. HPS official site

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Vitamins in HPS vitamin (n=10 269) placebo (n=10 267) p value 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 Events All-cause mortality (%) Thumbs up/Thumbs down – December 2001 Collins R et al. HPS official site

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Challenging previous wisdom Fascinating results for the low LDL group • overturns CARE and others that implied a plateau of benefit for LDL-lowering • AFCAPS/Tex. CAPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Simvastatin effect by baseline LDL reduction (%) Baseline LDL (mmol/L) vascular events statin placebo (n=10 269) (n=10 267) statin (n=10 269) placebo (n=10 267) <3. 0 (116 mg/d. L) 1. 8 2. 7 602 761 3. 0 -<3. 5 2. 2 3. 2 483 655 3. 5 (135 mg/d. L) 2. 7 3. 7 957 1190 All patients 2. 3 3. 3 2042 2606 Thumbs up/Thumbs down – December 2001 Collins R et al. HPS official site

HPS Vascular events by LDL level B simvastatin (n=10 269) placebo (n=10 267) <100 285 360 100 -129 670 881 1087 1365 aseline LDL (mg/d. L) 130+ Thumbs up/Thumbs down – December 2001 Collins R et al. HPS trial website

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS Choice of statin Which statin should be used at which dose? • HPS group implied lovastatin comes offpatent and could be used cheaply • Crestor (rosuvastatin) and the other "superstatins" offer even more LDLlowering Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS CRP levels and cardiovascular risk CRP levels (mg/d. L) Risk > 2. 0 High 1. 2 -1. 9 Moderate <1. 2 Low Thumbs up/Thumbs down – December 2001 Jialal et al. Circulation 2001

HPS Lovastatin by LDL/CRP level in AFCAPS/Tex. CAPS Treatment event rate: lovastatin (%) event rate placebo (%) RR (95% CI) p value All cases of LDL > median (n=2866) 2. 9 5. 3 0. 53 (0. 37 -0. 77) 0. 001 LDL < median CRP > median (n=1428) 2. 9 5. 1 0. 58 (0. 34 -0. 98) 0. 04 LDL < median CRP < median (n=1448) 2. 5 2. 2 1. 08 (0. 56 -02. 08) 0. 74 *Event rates over 5 -year follow-up ** LDL cutoff = 149. 1 mg/d. L *** CRP cutoff = 0. 16 mg/d. L; Thumbs up/Thumbs down – December 2001 Ridker et al. N Engl J Med 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 whethere is something different about an unstable plaque in the first couple of months. " Califf Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 a different mechanism for outcome-based trials. " Califf Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001

HPS 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 Thumbs up/Thumbs down – December 2001