Selecting the Right Primary Outcome Measures for Cardiac Arrest Research: We Can Pay Now, or We Can Pay Later
Disclosure: Dr. Bobrow discloses that the University of Arizona receives funding from the Medtronic Foundation for the Heart Rescue Program. The grant is to establish a statewide cardiac arrest system of care.
Pub Date: Monday, Oct. 3, 2011
Author: Bentley J. Bobrow, MD FACEP
Affiliation: Maricopa Medical Center, Emergency Medicine Department
University of Arizona College of Medicine – Phoenix
Arizona Department of Health Services, Phoenix, Arizona
Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, Nadkarni VM, Abella BS, Adrie C, Berg RA, Merchant RM, O’Connor RE, Meltzer DO, Holm MB, Longstreth WT, Halperin HR; on behalf of the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation. 2011, published online before print October 3, 2011, 10.1161/CIR.0b013e3182340239.
Becker and colleagues’ paper highlights the need for selecting the best outcome measures (i.e. what and when parameters) for cardiac arrest studies. The statement also points out that the absence of a simple validated neurologic functional outcome is a major drawback to the field and creation of a new tool should be a priority for future resuscitation research. Notably, this statement includes a crucial discussion of the seldom talked about but fundamental financial realities associated with choosing cardiac arrest study outcomes.
Cardiac arrest continues to be a major public health problem in the United States and exacts a massive monetary price tag, including direct morbidity and mortality expenses, medical personal time, and societal burden.1 Despite nearly five decades of resuscitation research efforts aimed at improving outcomes from out-of-hospital cardiac arrest (OHCA), the overall survival rate has remained stagnant at around 7.6% nationwide.2 One potential explanation for this is that funding allocated for resuscitation research is orders of magnitude less than funding allocated to other emergency medical conditions such as myocardial infarction, stroke and heart failure.3 In fact, Ornato found that there were 490 published randomized controlled trials per 10,000 deaths/yr for myocardial infarction, while at the same time there were a paltry 6 randomized cardiac arrest trials per 10,000 deaths/yr for cardiac arrest.3 That’s not a typo, the number is 6. This huge disparity in funding directly limits both the quantity and quality of cardiac arrest studies and therefore significantly impedes the progress of life-saving research. Ironically, when investigators are limited by what they can “afford” to have as study end points, it leads to an often overlooked but even larger societal health cost.3 In other words, ‘we can pay now, or we can pay later.’
The reason that primary outcome selection is so vital to a study is that the evidence based guidelines for CPR and ACLS which determine what actually happens during resuscitations are based largely upon these studies. Current cardiac arrest studies have a wide range of primary outcomes defined differently and frequently measured at varying time intervals along the resuscitation continuum. The most glaring example of this is the great heterogeneity in assessing survival. Survival seems like an easily measured, straightforward and evident outcome, right? Upon further examination, some investigators have chosen to assess survival to hospital admission, some survival to hospital discharge, and others have gauged neurologic function at hospital discharge and at dissimilar time points (3, 6, and 12 months after hospital discharge). To complicate the issue even further, our most commonly utilized neurologic scoring tool, the Cerebral Performance Category (CPC) scale has never been subjected to validity or reliability studies and correlates poorly with standardized neuropsychological measures.4 Each of these definitions of survival is very different and the selection of one survival definition over the other for a particular investigation can drastically alter study conclusions. This potentially leads to Type I and Type II experimental errors and risks of either missing potentially beneficial therapies or even worse--identifying therapies which ultimately result in survival with poor neurological status. We need only to look back at the example of high-dose epinephrine, and perhaps vasopressin, to be reminded of this.5-7
Ideally clinical cardiac arrest trials would be robust enough to assess not just survival to hospital discharge but what we really care most about as healthcare providers and policy makers – that is: survival with functional quality-of-life after cardiopulmonary arrest.
Clearly the particulars of study end points (when, what, and the how much – cost) is at the core of improving resuscitation science and hastening our collective goal of universally increasing meaningful survival from cardiac arrest. The unfortunate truth is that too few cardiac arrest studies have enough resources to answer vital questions that will fill the gaps in our knowledge of resuscitation therapies. Thus we are continuously “patching” studies together like a quilt in an effort to know for sure if specific therapies actually are beneficial or not. By bringing to light the fundamental issues surrounding selection of primary outcome measures, this consensus statement addresses the areas in clear need of research attention and additional resources. This paper is an important step toward improving cardiac arrest study design and will advance efforts to decrease the morbidity and mortality associated with cardiopulmonary arrest.
- Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209.
- Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010;3(1):63-81.
- Ornato JP, Becker LB, Weisfeldt ML, Wright BA. Cardiac arrest and resuscitation: an opportunity to align research prioritization and public health need. Circulation. 2010;122(18):1876-1879.
- Tiainen M, Poutiainen E, Kovala T, Takkunen O, Happola O, Roine RO. Cognitive and neurophysiological outcome of cardiac arrest survivors treated with therapeutic hypothermia. Stroke. 2007;38(8):2303-2308.
- Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton TJ, Feingold M, Cryer PE, Wortsman J, Nowak RM. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA. 1991;265(9):1139-1144.
- Brown CG, Martin DR, Pepe PE, Stueven H, Cummins RO, Gonzalez E, Jastremski M. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med. 1992;327(15):1051-1055.
- Perondi MB, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350(17):1722-1730.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association