Evidence-based Diagnosis: A Workshop on Evaluating and Using Medical Tests Small Group 3: Friday, June 10, 11:00 12:30 A B C D E Objectives: RCT Checklist RRR vs. ARR NNT = 1/ARR NNH = 1/ARI NNT Treatment Cost Problems Without Answers Problem Topic Difficulty 1 Oseltamivir for Post Exposure Prophylaxis Beginner X X 2 Marcolide Antibiotics for Pertussis TO BE WRITTEN 3 Warfarin for VTE TO BE WRITTEN 4 Early Goal-Directed Therapy for Sepsis Beginner X X 5 Aspirin and t-pa for Acute MI (Same as EBD Problem 9.5) Beginner X X 6 Clopidogrel (Plavix) for TIA Beginner X X X 7 t-pa for Acute Ischemic Stroke Beginner X X 8 Coiling vs. Clipping for Aneurysmal Bleeding Beginner X X RCT Checklist RRR vs. ARR NNT = 1/ARR NNH = 1/ARI NNT Treatment Cost Page 1 of 8 1
1. Oseltamivir for Post Exposure Prophylaxis Case: The patient is a 6-year-old girl with fever, myalgias, cough and sore throat for 1 day. A rapid antigen test for influenza is positive. (See SG-1, Problem 1.) Her mother is 12 weeks pregnant and does not have any flu symptoms at this time. Setting aside the question of whether to treat the patient herself with oseltamivir, we will focus on the question of whether to treat her mother with prophylactic oseltamivir. Welliver et al(1) did a randomized trial of prophylactic oseltamivir to prevent influenza in household contacts of patients with clinical influenza. The table below summarized their results in the subgroup where the index case was (like the 6-year-old in this question) positive for influenza. Household Contacts of Flu+ Index Cases Flu No Flu Risk Oseltamivir 3 206 209 3/209 = 1.4% Placebo 26 180 206 26/206 = 12.6% 29 386 415 a) Calculate the NNT and explain how to interpret it. Prophylactic oseltamivir dosing is 75 mg daily for 5 days. This drug cost is about $50. b) In household contacts such as the mother in this problem, how much to you have to spend in oseltamivir to prevent one case of the flu. Now consider the question of whether it was worth doing a rapid antigen test on the 6-yearold girl for flu purely to guide prophylaxis in the mother. Things get complicated here, because Welliver et al used the PCR (gold standard) to determine whether the index case had the flu. The rapid flu test can be assumed to be 100% specific relative to the PCR but only 50% sensitive. Assumptions: Prophylactic oseltamivir is of no benefit if the index case is gold-standard (PCR) negative for the flu. It is worth $250 in oseltamivir costs to reduce the mother s risk of flu by the amount shown in the table above. Since the actual treatment cost is only $50, net gain of prophylactic treatment is $250 - $50 = $200. Page 2 of 8 2
You could also look at this as the cost B of failing to treat the mother if the index patient is gold-standard (PCR) positive. The rapid influenza test costs $10. Ignore the side effects of oseltamivir (which are minimal) and the issue of increasing oseltamivir resistance. c) At what range of flu probabilities does it make sense to test the index case in order to guide prophylactic treatment of the household contact? (You may use this link.) d) This is a good opportunity to play with the spreadsheet. What happens if the rapid test is free? 2. Marcolide Antibiotics for Pertussis 3. Warfarin for VTE 4. Early Goal-Directed Therapy for Sepsis Rivers et al (2) performed a noteworthy and somewhat controversial clinical trial of Early Goal Directed Therapy (EGDT) to reduce 28-day mortality in patients with severe sepsis and septic shock. The main results are shown in the following table. Dead within 28 days Mortalit y Yes No Total EGDT 40 90 130 0.31 Standard 61 72 133 0.46 263 a) How many patients with severe sepsis do you have to treat with EGDT instead of standard care to save one from dying within 28 days? Early Goal Directed Therapy was a bundle of interventions performed according to a protocol in a special ED unit by a trained team consisting of an attending emergency physician, 2 emergency medicine residents, and 3 nurses. Here is the paper s description of the protocol: The protocol was as follows. A 500-ml bolus of crystalloid was given every 30 minutes to achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given to maintain a mean arterial pressure of at least 65 mm Hg. If the mean arterial pressure was greater than 90 mm Hg, vasodilators were given until it was 90 mm Hg or below. If the central venous oxygen saturation was less than 70 percent, red cells Page 3 of 8 3
were transfused to achieve a hematocrit of at least 30 percent. After the central venous pressure, mean arterial pressure, and hematocrit were thus optimized, if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 μg per kilogram of body weight per minute, a dose that was increased by 2.5 μg per kilogram per minute every 30 minutes until the central venous oxygen saturation was 70 percent or higher or until a maximal dose of 20 μg per kilogram per minute was given. Dobutamine was decreased in dose or discontinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was above 120 beats per minute. To decrease oxygen consumption, patients in whom hemodynamic optimization could not be achieved received mechanical ventilation and sedatives. Standard Therapy was also performed in the same unit by the same team. Both EGDT and standard therapy involved placing a central venous line, but once the line was placed the standard therapy patients were admitted to the ICU, while the EGDT patients were kept in the ED unit for 6+ hours. The physicians who ultimately assumed care in the ICU were blinded to initial treatment group. One of the main enrollment criteria for this study was a serum lactate >= 4.0 mmol/l. At many community hospitals, including Mills-Peninsula Hospital in Burlingame, this study has resulted in an imperative to place a central line in all patients with a significant infection and a lactate >= 4.0. b) Is this imperative to place a central line in all patients with severe sepsis consistent with the results to this study? Explain your answer. 5. Aspirin and t-pa for Acute MI (Same as EBD Problem 9.5) In the chapter, we learned from the ISIS-2 Study (3) that aspirin therapy (one month of 160 mg/day) in patients with acute myocardial infarction (AMI) reduced 30-day cardiovascular mortality from 11.8% in the placebo group to 9.4% in the aspirin group (P < 0.00001). a) What is the absolute risk reduction (ARR)? b) How many AMI patients need to be treated with aspirin for 30 days to prevent one death? c) A 120-pill bottle of 81 mg aspirin tablets costs about $5.00. Considering only the cost of the treatment drug, use this to calculate the cost effectiveness ratio ($/Cardiovascular death prevented) for aspirin therapy of AMI. (Be careful, you only need 60 aspirin pills to treat one patient for 30 days.) ISIS-2 and other studies also showed that, when added to aspirin, thrombolysis with streptokinase reduced mortality even further. The GUSTO Study (4) compared thrombolysis using tissue plasminogen activator (tpa) with thrombolysis using streptokinase (SK) in reducing the 30-day mortality of patients with acute myocardial infarction (AMI) receiving aspirin. This study showed a 14% relative risk reduction in the tpa-treated patients. Controversy exists because other large studies found no difference in 30-day mortality. Also, only the subgroup of US (not European) patients showed a benefit, and it was not a blinded study. However, for this problem assume that the 14% relative risk reduction is real. The 30-day mortality risk in the SK group was 7.3%. Page 4 of 8 4
d) What was the 30-day mortality risk in the tpa group? e) What was the absolute risk reduction associated with tpa (vs. SK)? f) How many patients need to be treated with tpa instead of SK to prevent one death? g) The cost of tpa is about $3400 per course of treatment, and the cost of SK is about $560 1. (5) What is the approximate treatment drug cost per death prevented by using tpa instead of SK? 6. Clopidogrel (Plavix) for TIA The Fast Assessment of Stroke and TIA to prevent Early Recurrence (FASTER) Trial was a randomized controlled trial of clopidogrel (Plavix ) vs. placebo to prevent stroke at 90 days in patients within 24 hours of TIA.(6) All patients in the trial received aspirin. Here are the results: TOTAL Stroke No Stroke Clopidogrel 14 184 198 Placebo 21 173 194 A protocol referring to this study stated clopidogrel combined with aspirin reduced the 90-day risk of stroke by 36% compared to aspirin alone in a pilot trial of 392 patients treated acutely after minor stroke or TIA, and it was well tolerated. a) To what measure of treatment effect (e.g. RR, OR, RRR, ARR, etc.) does the 36% refer? 1 Current prices are SK $563 and tpa (alteplase) $3405, so the extra cost of tpa is now $2842. (See Peacock et al, 2007) Page 5 of 8 5
b) Based on this study result, how many TIA patients do we have to treat with colpidogrel plus aspirin instead of aspirin alone to prevent 1 from having a stroke in the subsequent 90 days? Currently clopidogrel is available only as Plavix manufactured by Bristol-Myers Squibb in conjunction with Sanofi-Aventis Pharmaceuticals. (It is expected to go off patent in 2011.) A quick look at drugstore.com (11/7/2010) shows that 1 pill costs about $5. A 90 day course of clopidogrel requires 97 pills (each 75 mg). This is because the first dose is 8 pills, then 1 pill per day afterwards. At the price of $5 per pill, how much does it cost in Plavix alone to prevent 1 stroke at 90 days in a TIA patient (whom you can treat within 24 hours of symptoms onset). 7. t-pa for Acute Ischemic Stroke A New York Times article (5/28/2007) summarized the results of the NINDS randomized blinded trial of t-pa (tissue plasminogen activator) within 3 hours of symptom onset in acute ischemic stroke.(7) In 1995, after 40 years of trying to find something to break up blood clots in the brain, the cause of most strokes, researchers announced that tpa worked. A large federal study showed that, without it, about one patient in five escaped serious injury. With it, one in three escaped. The drug had a serious side effect it could cause potentially life-threatening bleeding in the brain in about 6 percent of patients. This is an accurate summary of the study s results, although we emphasize that the study was limited to patients within 3 hours of symptom onset. a) What was the risk of serious injury in the placebo group? b) What was the risk of serious injury in the t-pa group? c) What is the absolute risk reduction (ARR) and number needed to treat (NNT) with tpa to prevent one ischemic stroke patient from suffering serious injury? d) What is tpa s absolute risk increase (ARI) for serious intracranial bleed ( bleeding in the brain )? What is the number needed to harm? Page 6 of 8 6
e) How many serious injuries are prevented for each serious intracranial bleed caused? (Warning: the serious intracranial bleeds were also counted as serious injuries the primary study outcome.) 8. Coiling versus Clipping for Bleeding Cerebral Aneurysms Case: A previously health 62 year old man presents to the ED with 24-hours of headache. (See SG-1, Problem 8.) A CT of the brain shows subarachnoid hemorrhage and magnetic resonance angiography shows a leaking cerebral artery aneurysm. (For those who want more detail, it is an 8 x 7 x 7 mm leaking anterior communicating artery aneurysm with localized adjacent subarachnoid hemorrhage in the interhemispheric fissure and medial margin of the right sylvian fissure. ) Clinical Information: The question arises as to whether to treat this problem with clipping or coiling. Clipping is an operating room procedure that involves a craniotomy (opening the skull) and placing a metal clip at the base of the aneurysm. Coiling is a transvascular procedure done in the interventional radiology suite and involves passing an arterial catheter through the neck and into the brain, then occluding the aneurysm by feeding a thrombogenic wire into it. Clipping has higher operative risk but a lower chance of re-bleeding. The International Subarachnoid Aneurysm Treatment (ISAT) Trial(8) was a randomized trial of the effect of coiling vs. clipping on the outcome of death or dependency in patients with bleeding cerebral aneurysms who could be treated with either modality. Here are the results. Dead or Dependent at 12 months: Coil: 250/1063 = 24% (10 lost to f/u) Clip: 326/1055 = 31% (15 lost to f/u) a) What is the NNT? Explain it in a sentence that might be comprehensible to someone unfamiliar with NNT. b) It was impossible to blind the patients or their treating physicians to treatment group (coiling vs. clipping). The assessment of outcome (death or disability) was done by examiners/interviewers blinded to treatment group. How would these facts affect the trial results? Page 7 of 8 7
REFERENCES 1. Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. Jama. 2001 Feb 14;285(6):748-54. 2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. 3. ISIS-2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988 Aug 13;2(8607):349-60. 4. GUSTO. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med. 1993 Sep 2;329(10):673-82. 5. Peacock WF, Hollander JE, Smalling RW, Bresler MJ. Reperfusion strategies in the emergency treatment of ST-segment elevation myocardial infarction. Am J Emerg Med. 2007 Mar;25(3):353-66. 6. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007 Nov;6(11):961-9. 7. NINDS. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med. 1995 Dec 14;333(24):1581-7. 8. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet. 2005 Sep 3-9;366(9488):809-17. Page 8 of 8 8