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The Vioxx Debacle Implications for Clinical Trials Medical Grand Rounds March 3, 2005 Neil A Kurtzman, MD Grover Murray Professor University Distinguished Professor Texas Tech University Medical Center • Was there a valid medical reason for • • withdrawing Vioxx? What is the safety profile of the COX-2 inhibitors? What are the implications of this issue for clinical trials in general? • Why do we do clinical trials? • Safety and efficacy • Evidence based medicine • The law requires them • We must do them even when we know the result before the study is done • Consider ACE inhibitors and diabetic • • nephropathy We knew ACE inhibitors were safe and efficacious for hypertension before they were used to treat diabetic nephropathy So safety was not an issue, efficacy in treating diabetic nephropathy was • A 46 yo white type 1diabetic man was referred • • • • to me in 1990 by his ophthalmologist because of proteinuria – 1.5 g/day He was hypertensive Cr 1.2 He was blind He was treated with ACEI and furosemide • His blood pressure was perfectly controlled • His blood sugar was always out of control • His proteinuria gradually (over a few years) • • disappeared – it’s now about 100mg/day His Cr in 2005 is 1.2 A clinical trial is not necessary to prove that ACE inhibitors retard the progression of diabetic nephropathy because a scenario like the above was never seen before their use • Similar results have been seen in patients with • • Type 2 DM Yet because clinical trials proving their efficacy (in Type 2 DM) had not been done it was felt justified to conduct trial comparing ARBs vs non-ACEI drugs in patients with proteinuria Evidence Based Medicine was used to justify dubious studies • You don’t need a clinical trial to demonstrate • • • • the truly efficacious treatments Morphine for pain Diuretics for edema Penicillin for syphilis Insulin for DKA • What use are clinical trials? • They may detect small differences in treatments • Or no difference • The are necessary to detect effects that are far in • • • the future Prevention studies They are very hard to do The Vioxx debacle will make them even harder • A drug can be unsafe and non-efficacious X • It can be safe and non-efficacious X • Safe and efficacious X • Unsafe and efficacious * - thus a risk/benefit analysis is required • Clinical trials examining prevention are • • • • fraught with hazard Consider a drug designed to prevent Alzheimer’s Disease It would have to be given 15-20 years before the disease would be detectable Any such drug would have side effects The side effects would be observed before any therapeutic effect could be seen • The drug might well be withdrawn before its • • beneficial effects could be noted Suppose it caused a small but significant increase AMI, but totally prevented Alzheimer’s Disease That would be a price worth paying, but we’d never find out because the trial would have been halted • When we prescribe a drug the question is not • • how safe is it compared to a placebo It will always be less safe But how safe compared to other treatments or to no treatment at all The Purpose of Medicine • Prolong life • • • - prevent premature death Relieve pain and suffering What to do when treatment for one exacerbates the other? Typically physicians focus on the first purpose while downplaying the second • NSAIDS lead to hospital admissions for ulcer • • complications in 0.25 - 1.6% of users per year They cause at least 7000 deaths per year in the US Celecoxib does not prevent ulcer complications (CLASS JAMA 284:1247, 2000) VIGOR Study NEJM 343:1520,2000 • Mortality rates were the same for Vioxx and • • • • naproxen (0.5 and 0.4%) CV death rates were also identical (0.2%) Ischemic CVAs were the same (0.2%) AMI much less common in the naproxen group 0.1 vs 0.4% RR 0.2 (0.1 - 0.6) • Merck withdrew Vioxx because of an increased • • • • • • rate of AMI in a colon polyp prevention study The data from this study have just been published Vioxx was compared to a placebo Thus there could be no offsetting side effect that would mitigate any bad effect of Vioxx Sugar pills don’t cause GI bleeding Any positive therapeutic effect was years away The increased AMI rate was seen after 18 months CV Thrombotic Events in Controlled Clinical Trials of Rofecoxib Circulation 104:2280, 2001 Includes the VIGOR Trial COX-2 Selective NSAIDS and Risk of Serious CAD Lancet 360:1071, 2002 • Retrospective study of about 300,00 0 TennCare • • • • • • patients 50 – 84 yo Vioxx >25 mg/day more likely to have CAD All user RR 1.70 NS (0.98 – 2.95) New users 1.93 (1.09 – 3.42) <25 mg/day no increase in risk 1.03 (0.76 – 1.37) No cause and effect can be concluded Selective COX-2 Inhibition and CV Disease Am Heart J 146:591, 2003 • Concludes that there was not an excess of • thrombotic CV events among patients taking Vioxx Also concludes that naproxen likely has a cardioprotective effect Risk of CV Event and Rofecoxib: Cumulative meta-analysis Lancet 364:2021, 2004 • No mortality data – CV or otherwise • No risk/benefit analysis • Concludes that increased risk of AMI was • • • • evident from 2000 on That CV toxicity was not dose dependent That the VIGOR result were likely not due to a cardio-protective effect of naproxen That the drug should have been removed from the market in 2000 And that it’s all Merck’s fault • Pages of critical mail appeared in the Lancet’s • letters section Meta-analysis is to analysis as metaphysics is to physics Patients Exposed to Rofecoxib and Celecoxib Have Different Odds of Nonfatal MI Ann Int Med 142:157, 2005 Rofecoxib vs celecoxib OR 2.72 (CI, 1.24 – 5.95 Rofecoxib vs naproxen 3.39 (1.37 – 8.40) Selective COX-2 Inhibition and CV Effects Arch Int Med 165:181, 2005 Retrospective study Largely African-American High risk for CV disease The Risk of MI with COX-2 Inhibitors: A Population Study of Elderly Patients Ann Int Med: In press Also retrospective From Quebec Pfizer Says Study Shows Heart Risk From Celebrex FDA Is Reviewing Information; Shares Tumble 11% on News By SCOTT HENSLEY Staff Reporter of THE WALL STREET JOURNAL December 19, 2004 6:34 p.m. Pfizer Inc. said a government-sponsored study of its arthritis drug Celebrex in cancer prevention found a significant risk of cardiovascular problems, an unanticipated result that raises new questions about the safety of the popular drug. CV Risk Associated with celecoxib in a Clinical Trial for Colorectal Prevention NEJM 2/23/05 CV Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention trial NEJM 2/23/05 NEJM Feb 23, 2005 Risk of AMI and sudden cardiac death in patients treated with COX 2 selective and non-selective NSAIDs: nested control study Lancet 365:475, 2005 Despite the title, no mortality data in the paper • Complications of the COX-2 Inhibitors • • Parecoxib and Valdecoxib after Cardiac Surgery – NEJM 2/23/05 Increased CV events with these drugs after CABG That the NEJM published this is a measure of the hysteria that surrounds this topic • The data show that: • Vioxx increases AMI • Vioxx doesn’t increase AMI • Celebrex does not increase the rate of AMI • Celebrex decreases AMI • Celebrex increases AMI • Naproxen protects against AMI • Naproxen does not protect against AMI • Naproxen is worse than Celebrex • If a drug that increases the rate of AMI is bad • • • then a drug that reduces it must be good Final Report of Aspirin Component of the Ongoing Physicians Health Study: NEJM 321:129, 1989 Double blind, randomized, placebo-controlled Test the hypothesis that ASA in low doses reduces mortality from CV disease in healthy males • No effect on CV death rate • No effect on non CV death rate • No effect on total deaths • Marked decrease in both fatal and non fatal MI • Thus this study provides no evidence supporting ASA as primary prevention for CV mortality in healthy males Warning Label for Adriamycin Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3 to 5% at a dose of 400 mg/m², 5 to 8% at 450 mg/m² and 6 to 20% at 500 mg/m².* The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg/m². This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy or with preexisting heart disease Myocardial toxicity manifested in its most severe form by potentially fatal congestive heart failure may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m² of doxorubicin, 3 to 5% at a dose of 400 mg/m², 5 to 8% at 450 mg/m² and 6 to 20% at 500 mg/m² The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg/m². This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy or with preexisting heart disease • Nobody has called for the removal of • • • Adriamycin from the market Cancer is obviously felt to be more important than pain But is it? I would ague that in many cases the reverse is true • Most people over 65 have DJD • Many of these patients have chronic pain that • • is disabling These are the same patients that are at high risk for CV disease Not treating this pain is not an option • What are the options? • Acetaminophen – effective in many patients, • • • but not all Must be given 3– 4 time/day Breakthrough pain, especially at night is common Some studies show it to be less effective than NSAIDs • Nonselective COX inhibitors • Effective • Serious GI complications common and • sometimes fatal Probably not a good drug to take every day for 20 years • COX-2 inhibitors • They are effective • Only Vioxx among these drugs available in the • US has been shown to decrease adverse GI events It’s off the market • Narcotics • Effective • But CNS effect makes their use problematic in elderly patients • Surgery and other invasive intervention • • • common on a pain service Often effective Have their own risk profiles Not every joint can be replaced or manipulated Lancet 364:665, 2004 • Lumiracoxib appears to have a better safety • profile than the other COX-2 inhibitors But is the FDA in a mood to approve another COX-2 inhibitor in the wake of the negative publicity generated by the Vioxx withdrawal? The Purpose of Medicine • Prevent premature death • Relieve pain and suffering • What to do when these two goals conflict? • How much pain and suffering is worth how • • • much of a reduction in life? How much pain relief and reduced likelihood of GI bleeding is worth how many MIs in an elderly population? No formula or set of practice guidelines will satisfactorily answer the question Good judgment is the only answer • In my view the data thus far available doesn’t • justify the removal of Vioxx Merck made the decision based on liability consideration rather than on strict medical reasons • Implications for clinical trials • Many long term clinical trials are apt to be • • considered too risky by the drug companies A drug that may prevent a disease that will not occur until far in the future may prove to have side effects before any therapeutic effect can be seen This is particularly true if it is being compared to a placebo • The placebo will not have its own side effect • • • profile that might offset those untoward effects of the study drug Even if there are off setting effects the study drug may still be in trouble Heart attacks seem to worry both the public and the profession more than GI bleeding Hysterical reactions to side effects are more likely to be the rule rather than the exception • One of the country’s leading cardiologist’s said • • that “Any drug that causes heart attacks shouldn’t be on the market.” Suppose it caused one AMI for every 100 cases of lung cancer that it cured Any treatment requires a risk/benefit analysis Merck May Return Vioxx to Market Move Depends on Whether FDA Panel Decides Risks Exist in Similar Medicines By ANNA WILDE MATHEWS and SCOTT HENSLEY Staff Reporters of THE WALL STREET JOURNAL February 18, 2005 1:30 p.m. FDA Advisers Recommend Return of Vioxx to U.S. Market Shares of Merck Surge 13% on News By ANNA WILDE MATHEWS Staff Reporter of THE WALL STREET JOURNAL February 18, 2005 9:12 p.m. Nothing is easier than to imagine that one has taken all relevant factors into account, when in reality there may be other factors which have influence, even if no data have been collected on them or they are not quantifiable. Where there are very significant differences in known factors between one group and another, it would be reckless to assume that all remaining unknown factors are the same. Thomas Sowell • Think carefully before you prescribe • Evaluate clinical trials critically 30 Celebrex Studies Pfizer's announcement Friday stemmed from a trial conducted by the National Cancer Institute. The study, called the Adenoma Prevention with Celecoxib trial, involved patients taking high doses of Celebrex--400mg and 800mg daily -- to see if the drug could prevent colon cancer. The National Cancer Institute, which sponsored the study, stopped giving patients Celebrex after learning of the increased risk to patients during a review of the data. Recommended doses of Celebrex are 100mg to 200mg a day for osteoarthritis pain and swelling and 200mg to 400mg for rheumatoid arthritis symptoms, Pfizer said. Pfizer also said this about a separate study: "In a separate longterm study, the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo. These findings are based on an identical analysis used to assess cardiovascular risk in the APC trial and conducted by the same independent safety review board. The information from this Pfizer sponsored trial was also received by Pfizer last night and, as with the APC information, was immediately shared by the company with the U.S. Food and Drug Administration."