Art and Science in Registry Studies of Anemia and Myocardial Infarction

HomeCirculation: Cardiovascular InterventionsVol. 11, No. 12Art and Science in Registry Studies of Anemia and Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBArt and Science in Registry Studies of Anemia and Myocardial Infarction Harold L. Dauerman, MD and Deepak L. Bhatt, MD, MPH Harold L. DauermanHarold L. Dauerman Harold L. Dauerman, MD, Division of Cardiology, McClure 1, University of Vermont Medical Center, 111 Colchester Ave, Burlington, Vermont 05401. Email E-mail Address: [email protected] University of Vermont Larner College of Medicine (H.L.D.). and Deepak L. BhattDeepak L. Bhatt Brigham and Women's Hospital Heart and Vascular Center, and Harvard Medical School, Boston, MA (D.L.B.). Originally published14 Dec 2018https://doi.org/10.1161/CIRCINTERVENTIONS.118.007571Circulation: Cardiovascular Interventions. 2018;11:e007571This article is a commentary on the followingAssociation of Anemia With Outcomes Among ST-Segment–Elevation Myocardial Infarction Patients Receiving Primary Percutaneous Coronary InterventionSee Article by Moghaddam et alIn this issue of Circulation: Cardiovascular Interventions, Moghaddam et al1 analyze 10 years of data from the Vancouver Coastal Health Authority Primary PCI program and demonstrate that anemic patients are at no increased risk of hospital mortality after primary percutaneous coronary intervention (pPCI) compared with patients without anemia (odds ratio, 0.99; 95% CI, 0.57–1.73). While there was no clear association between pPCI and reperfusion times, an anemic ST-elevation myocardial infarction (STEMI) patient requiring transfer for pPCI had a 15 minutes increased reperfusion delay compared with transfer STEMI patients without anemia (P=0.048). Notably, anemic pPCI patients had a 78% increased risk of major bleeding compared with nonanemic patients undergoing primary PCI (odds ratio, 1.78: 95% CI, 1.25–2.56). The authors conclude that anemic STEMI patients may safely receive timely pPCI, but with particular consideration for bleeding avoidance strategies.While the multivariable-adjusted mortality analysis demonstrated no independent increased risk of death attributed to anemia for pPCI patients, what does that actually mean to a physician or a patient: is the safety of pPCI actually the same for both anemic and nonanemic patients? Is the bleeding risk associated with anemia modifiable?Science, Anemia, and MIMulticenter registries play a critical role in examining risk factors among populations with acute MI. In the Vancouver pPCI registry data, anemia is identified in 16.8% of the patients referred for pPCI, making it a more frequent risk factor than peripheral artery disease but less common than diabetes mellitus. The authors are to be congratulated for enrolling nonselected patients at 2 centers over 10 years, including patients at the highest risk of adverse events (ie, STEMI patients with cardiogenic shock). Despite these broad inclusion criteria, the study design underestimates the prevalence of anemia in the MI community: if a STEMI patient presented from an assisted living facility, had a do not resuscitate order, significant emphysema and dementia, he or she would not have been transferred for pPCI. The true prevalence of anemia among unselected patients with acute MI requires a population-based study, including all patients with acute MI presenting to all hospitals in a defined area regardless of treatment strategy. Using such an approach in the Worcester Heart Attack Study, the incidence of anemia among patients with MI is far higher (nearly 1 in 3 patients)2 and suggests that the interaction of anemia, MI, and death is of even greater concern than almost any other risk factor associated with postinfarction outcomes.The authors identify not only the incidence of anemia but the significant hospital mortality risk associated with pPCI in anemic versus nonanemic populations (8.1 versus 3.8%, P<0.001; Figure). In broader population-based registries, this heightened risk of early death is again seen (16.2 versus 8.9%, P<0.001) in association with anemia and MI2; this mortality risk was also confirmed in clinical trial populations.3 Objective numbers such as these represent the science of anemia and MI: we can quote a patient their risk of death during the acute hospitalization based crudely on the presence or absence of anemia. Or, we can incorporate anemia into a more complicated risk score, as was done in the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) primary PCI trial,4 to incorporate multiple elements of risk about pPCI. It is not clear that we can say pPCI is safe in the anemic population; scientifically, we can only say what we observe. Namely, patients with anemia referred for pPCI have a much higher rate of death and bleeding than nonanemic patients. Similarly, we can tell our anemic pPCI patients that they have nearly a 1 in 5 chance of major bleeding, and that we will try to minimize the risk of bleeding using strategies proven to reduce bleeding in other patient groups.5,6 However, we can not really know that the radial artery approach, bivalirudin, or ultrasound-guided femoral access will reduce bleeding complications to the level of a nonanemic patient because we have not established the mechanism which confers bleeding risk in anemic patients with MI.Download figureDownload PowerPointFigure. Two registry designs define the 2-fold increased risk of mortality associated with anemia and myocardial infarction. The differences in inclusion criteria for these 2 registry designs lead to variations in absolute mortality rates, but the risk associated with anemia is persistent.Art, Anemia, and MIThe science inherent to registry studies of anemia and MI is the observed risk of adverse events; the art of any registry design is implying causal associations between risk factors and outcomes. Multivariable analysis in the Vancouver pPCI registry asks whether anemia is the cause of death or simply a bystander of associated comorbidities. If one looks at the baseline clinical characteristics of Vancouver pPCI patients with anemia versus no anemia, the characteristics point in one direction: anemia is associated with high-risk comorbid presentations that guarantee the scientific observation of a 2-fold increased STEMI mortality risk (Figure).Does anemia confer an inherent risk of death independent of comorbidities such as older age and renal failure? If a registry demonstrates such an independent risk, one could leap to a hypothesis: correction of anemia (transfusion, erythropoietin, iron supplementation) could reduce the risk of death among anemic patients undergoing pPCI. Such a hypothesis about aggressive transfusion in anemic pPCI patients is not clearly supported by current observations and recommendations.7 In the Vancouver analysis, the authors controlled for a set of a priori variables (eg, age, sex, diabetes mellitus) and found that anemia per se was not associated with death after controlling for these conditions. Thus, one might conclude that correction of anemia would be unlikely to change the death rate.7 But other analyses have found opposite conclusions about the independent prognostic significance of anemia2,3; each analysis used different methods and different patient populations to create an interpretation of the intrinsic risk of death associated with anemia, and thus, artistic variations in interpretation are guaranteed.This limitation of all registry analyses is well known and certainly applies to patients with anemia and MI. One of the original analyses of anemia and MI emphasized the limitations of determining causal relationships from registry or retrospective designs: "however, we would underscore that all nonrandomized comparisons must be viewed with caution because, despite multivariable analyses, there can be residual confounding by indication…only randomized trials can definitely resolve the benefit of transfusions in ACS."3Primary PCI, Anemia, and Clinical ImplicationsIs pPCI safe in patients with anemia? Unfortunately, this question cannot be answered in the context of the current registry design. We have no comparator group (ie, no reperfusion strategy) in this study. Furthermore, the association between anemia and delay in reperfusion does not preclude a benefit; there are multiple potential causes of reperfusion delay and whether anemia is a more powerful predictor than older age, rural location, or transport time is not established.8 To the physician and the patient, the science is informative in terms of general risk estimates for hospital mortality; an anemia based risk aversion for patients or interventional cardiologists related to pPCI is neither more nor less warranted than for other higher risk patient subgroups (eg, cardiogenic shock, chronic kidney disease).The Vancouver anemic pPCI patients have an absolute higher rate of bleeding (18.2% versus 9.4%, P<0.001) compared with nonanemic patients. They also have an independent 78% increased relative risk of major bleeding after controlling for key comorbidities. This provides the physician with an estimate for bleeding risk after pPCI; it also provides support for a hypothesis: the key to improving outcomes is not correcting anemia itself but correction of bleeding risk. The cause of this bleeding risk—a fragile access site, enhanced gastrointestinal mucosal irritation, inherent platelet or coagulation factor disorders—is unknown in the population of patients with anemia and MI.But one could imagine a clinical trial examining methods to decrease access site bleeding (radial versus femoral), gastrointestinal bleeding (proton pump inhibitors versus placebo9) or antiplatelet therapy intensity (ticagrelor versus clopidogrel) focusing on this particular high-risk group, similar to prior trials comparing radial versus femoral approach specifically in women.10 At this point, we have only our clinical judgment in approaching pPCI, with potential tools to minimize the bleeding in this high-risk group (use a radial approach, avoid glycoprotein inhibitors, and consider proton pump inhibition). While no registry is artistically able to give us causality and clear treatment plans, good registries give us the simple science to define more precisely the risk for the patient; as demonstrated by Moghaddam et al,1 caution is warranted for anemic patients undergoing pPCI. A future randomized trial focusing on strategies to prevent bleeding among anemic patients undergoing pPCI is the only clear way to recommend best practices in this challenging subgroup.DisclosuresDr Dauerman is a consultant for Medtronic, Edwards and Boston Scientific, and he has received research grants from Boston Scientific, Edwards and Medtronic. Dr Bhatt is a member of the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences, and he is on the board of directors at Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft. He is chair of the American Heart Association Quality Oversight Committee. Dr Bhatt is also on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial [Edoxaban Compared to Standar Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation], funded by Daiichi Sankyo), and the Population Health Research Institute. He received honoraria from theAmerican College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees). Dr Bhatt is also associated with Clinical Cardiology (Deputy Editor), NCDR-ACTION (National Cardiovascular Data Registry--Acute Coronary Treatment and Intervention Outcomes Network) Registry Steering Committee (Chair), VA CART (Veterans Administration Cardiovascular Assessment, Reporting and Tracking System) Research and Publications Committee (Chair). Dr Bhatt receives research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company. He receives royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease). Dr Bhatt is a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte, and he is a trustee at the American College of Cardiology. Dr Bhatt performs unfunded research for FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circinterventionsHarold L. Dauerman, MD, Division of Cardiology, McClure 1, University of Vermont Medical Center, 111 Colchester Ave, Burlington, Vermont 05401. Email harold.[email protected]orgReferences1. Moghaddam N, Wong GC, Cairns JA, Goodman SG, Perry-Arnesen M, Tocher W, Mackay M, Singer J, Lee T, Rao SV, Fordyce CB. Association of anemia with outcomes among ST-elevation myocardial infarction patients receiving primary percutaneous coronary intervention.Circ Interventions. 2018; 11:e007175. doi: 10.1161/CIRCINTERVENTIONS.118.007175LinkGoogle Scholar2. Dauerman HL, Lessard D, Yarzebski J, Gore JM, Goldberg RJ. Bleeding complications in patients with anemia and acute myocardial infarction.Am J Cardiol. 2005; 96:1379–1383. doi: 10.1016/j.amjcard.2005.06.088CrossrefMedlineGoogle Scholar3. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, Gibson CM, Braunwald E. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes.Circulation. 2005; 111:2042–2049. doi: 10.1161/01.CIR.0000162477.70955.5FLinkGoogle Scholar4. Halkin A, Singh M, Nikolsky E, Grines CL, Tcheng JE, Garcia E, Cox DA, Turco M, Stuckey TD, Na Y, Lansky AJ, Gersh BJ, O'Neill WW, Mehran R, Stone GW. Prediction of mortality after primary percutaneous coronary intervention for acute myocardial infarction: the CADILLAC risk score.J Am Coll Cardiol. 2005; 45:1397–1405. doi: 10.1016/j.jacc.2005.01.041CrossrefMedlineGoogle Scholar5. Dauerman HL, Rao SV, Resnic FS, Applegate RJ. Bleeding avoidance strategies. Consensus and controversy.J Am Coll Cardiol. 2011; 58:1–10. doi: 10.1016/j.jacc.2011.02.039CrossrefMedlineGoogle Scholar6. Vora AN, Peterson ED, McCoy LA, Garratt KN, Kutcher MA, Marso SP, Roe MT, Messenger JC, Rao SV. The impact of bleeding avoidance strategies on hospital-level variation in bleeding rates following percutaneous coronary intervention: insights from the National Cardiovascular Data Registry CathPCI Registry.JACC Cardiovasc Interv. 2016; 9:771–779. doi: 10.1016/j.jcin.2016.01.033CrossrefMedlineGoogle Scholar7. Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, Gernsheimer T, Holcomb JB, Kaplan LJ, Katz LM, Peterson N, Ramsey G, Rao SV, Roback JD, Shander A, Tobian AA. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage.JAMA. 2016; 316:2025–2035. doi: 10.1001/jama.2016.9185CrossrefMedlineGoogle Scholar8. Dauerman HL, Bates ER, Kontos MC, Li S, Garvey JL, Henry TD, Manoukian SV, Roe MT. Nationwide analysis of patients with ST-segment-elevation myocardial infarction transferred for primary percutaneous intervention: findings from the American Heart Association Mission: lifeline program.Circ Cardiovasc Interv. 2015; 8:e002450. doi: 10.1161/CIRCINTERVENTIONS.114.002450LinkGoogle Scholar9. Vaduganathan M, Cannon CP, Cryer BL, Liu Y, Hsieh WH, Doros G, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Bhatt DL; COGENT Investigators. Efficacy and safety of proton-pump inhibitors in high-risk cardiovascular subsets of the COGENT trial.Am J Med. 2016; 129:1002–1005. doi: 10.1016/j.amjmed.2016.03.042CrossrefMedlineGoogle Scholar10. Rao SV, Hess CN, Barham B, Aberle LH, Anstrom KJ, Patel TB, Jorgensen JP, Mazzaferri EL, Jolly SS, Jacobs A, Newby LK, Gibson CM, Kong DF, Mehran R, Waksman R, Gilchrist IC, McCourt BJ, Messenger JC, Peterson ED, Harrington RA, Krucoff MW. A registry-based randomized trial comparing radial and femoral approaches in women undergoing percutaneous coronary intervention: the SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) trial.JACC Cardiovasc Interv. 2014; 7:857–867. doi: doi.org/10.1016/j.jcin.2014.04.007CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesAssociation of Anemia With Outcomes Among ST-Segment–Elevation Myocardial Infarction Patients Receiving Primary Percutaneous Coronary InterventionNima Moghaddam, et al. Circulation: Cardiovascular Interventions. 2018;11 December 2018Vol 11, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.118.007571PMID: 30562087 Originally publishedDecember 14, 2018 KeywordsdeathriskEditorialsmyocardial infarctionpercutaneous coronary interventionanemiaPDF download Advertisement SubjectsMyocardial InfarctionPercutaneous Coronary Intervention

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