Impact of Anemia on the Risk of Bleeding Following Percutaneous Coronary Interventions in Patients ≥75 Years of Age
David Mart´ı, MD, PhD*, Damaris Carballeira, MD, Mar´ıa Jos´e Morales, MD, Ricardo Concepci´on, MD, Hugo del Castillo, MD, Alexander Marschall, MD, Freddy Andr´es Delgado-Calva, MD, Carmen Deju´an-Bitri´a, MD, Joaqu´ın P´erez-Guzm´an, MD, Edurne L´opez-Sober´on, MD, Jorge Palazuelos, MD, PhD, and Salvador A´lvarez-Ant´on, MD
Abstract
Bleeding risk stratification is an unresolved issue in older adults. Anemia may reflect sub- clinical blood losses that can be exacerbated after percutaneous coronary intervention . We sought to prospectively determine the contribution of anemia to the risk of bleeding in 448 consecutive patients aged 75 or more years, treated by percutaneous coronary inter- ventions without concomitant indication for oral anticoagulation. We evaluated the effect of WHO-defined anemia on the incidence of 1-year nonaccess site-related major bleeding. The prevalence of anemia was 39%, and 13.1% of anemic and 5.2% of nonanemic patients suffered a bleeding event (hazard ratio 2.75, 95% confidence interval 1.37 to 5.54, p = 0.004). Neither PRECISE-DAPT nor CRUSADE scores were superior to hemoglobin for the prediction of bleeding. In conclusion, anemia is a powerful predictor of bleeding with potential utility for simplifying tailoring therapies.
Introduction
The accurate balance of thrombotic and bleeding risks is an essential step of percutaneous coronary interventions (PCI). Older adults are a growing and particularly challeng- ing group since they combine amyloid angiopathy, platelet hyperreactivity, and complex anatomies that make them prone to adverse events.1−5 Despite the increased risk, they benefit from intervention, so risk stratification is particu- larly important.6−8 Clinical scales are laborious and of lim- ited utility.9 Thus, any factor that allows rapid and easy classification of patients will be remarkably useful. Anemia is a frequent finding in patients undergoing PCI, and is asso- ciated with significant increases in postprocedural mortal- ity, reinfarction, and bleeding.10 In older adults, anemia often reflects chronic blood losses or hemorrhagic diathesis that can be exacerbated after PCI.11 We hypothesized that anemia is a potent predictor of bleeding in such patients. Our objectives were to determine the independent contribu- tion of anemia to the risk of major bleeding, as well as to assess its predictive capacity compared with established bleeding risk scores.
Methods
We conducted a prospective observational study that enrolled all consecutive patients aged ≥75 years treated by urgent or elective PCI in a university hospital during the years 2012 to 2017. Patients with an indication for oral anti- coagulants were excluded for the final analysis.
Follow-up at 12 months was confirmed by hospital records, office visits, or phone calls. Patients in whom the information on the events was incomplete were considered lost to follow-up. Adverse events were adjudicated by a senior investigator unaware of baseline characteristics in consensus with the attending physician. Variables were included in a dedicated database by trained cardiologists. The study protocol was approved by the Ethics Committee of the Central Defense Hospital, Alcal´a University, Madrid, Spain.
All patients underwent blood sampling within 24 hours before the procedure. Definitions of anemia met WHO crite- ria based on hemoglobin (Hb) levels.12 CRUSADE and PRECISE-DAPT bleeding risk scores were calculated in both acute and chronic patients, using the variables collected prospectively and using specific electronic applications.13,14 Technical aspects and parenteral anticoagulation (biva- lirudin or unfractionated heparin-based regimens) were at the choice of the interventional cardiologist. Glycoprotein IIb/IIIa inhibitors were used only in bailout situations. Standard duration of double antiplatelet therapy was 1 month for bare-metal stents, 6 months for drug-eluting stents, and 12 months for acute coronary syndromes.
The primary end point was 1-year nonaccess site-related major bleeding according to Bleeding Academic Research Consortium (BARC) criteria types 3 or 5,15 including both in-hospital and out-of-hospital events. A restrictive transfu- sion threshold was applied, being performed only in patients with Hb <8 g/dl, or with clinical compromise. Other measured outcomes were death, myocardial infarc- tion, and stroke. Death cause was classified as specified by the Academic Research Consortium criteria.16 Myocardial infarction was defined in accordance with the universal definition.17
Differences in baseline characteristics were analyzed using independent sample t test for continuous variables and Pearson’s chi-square test for categorical variables. One-year survival curves were calculated with the Kaplan-Meier method, and differences between groups of patients (anemic and nonanemic) were evaluated with the log-rank statistic. We assessed the relation between baseline variables and bleeding using a Cox proportional hazards survival model. Hazard ratios (HRs) with 95% confidence intervals (CI) are patients aged ≥75 years. The final population consisted of 448 patients who had no indication of oral anticoagulation.
Anemia was identified in 174 patients (39%; 95% CI 34% to 43%). Despite no differences in age or gender, ane- mic patients depicted a greater burden of co-morbidities and more complex clinical presentation, as well as a trend to more frequent acute coronary syndrome without ST-ele- vation compared to ST-elevation myocardial infarction. Bleeding risk scores showed high values in the presence of anemia, but interestingly also in nonanemic patients (Table 1).
Although anemic patients required more frequent femoral access, probably due to their particular baseline characteris- tics, most procedures were performed by radial approach and with bivalirudin-based anticoagulation (Table 2). A high proportion of the patients showed complex lesions and required treatment of long coronary segments, receiving mostly drug-eluting stents. Nonanemic patients trended toward a greater use of potent P2Y12 inhibitors.
One-year follow-up was complete in 432 patients (96.4%), and primary end point occurred in 33 patients (cumulative incidence 8.2%; 95% CI, 5.4% to 11.0%). Most common locations of bleeding were digestive (n = 22), intra- cranial (n = 5), or urological (n = 4). There were 2 cases of type 5 (fatal bleeding) BARC bleeding, both in anemic patients; and in 5 patients (15.2% of bleeding events), death occurred within 30 days after bleeding. Baseline anemia was an independent predictor of 1-year primary end point (HR 2.75, CI 95% 1.37 to 5.54, p = 0.004; Table 3).
Discussion
In this prospective study of consecutive patients aged ≥75 years receiving contemporary PCI, we reached 3 main findings: (1) Anemia is a powerful independent predictor of spontaneous bleeding, with 2.7-fold increases in the incidence of 1-year nonaccess site-related major bleeding; (2) the risk of bleeding is notably high in patients with Hb lev- els <11 g/dl; and (3) despite the limited predictive capacity of any of them, Hb represents an attractive alternative to MACE is a composite of cardiovascular death, myocardial infarction, or stroke. BARC 3 or 5 refers to nonaccess site-related bleeding. the more laborious scores, allowing a simpler and faster patient classification.
Several studies have analyzed the prognostic value of anemia in the general population.10 The original contribu- tions of our study are the focus on the older population and bleeding as the main outcome. As in recent publications, we have excluded anticoagulated patients as they have per se a high bleeding risk, since the main interest is stratifica- tion for clinical decision-making in nonanticoagulated patients who present an uncertain risk of bleeding.14
The prevalence of anemia increases with age, from 7% to 8% in patients aged 65 to 74, to figures above 20% to 25% in patients over 85 years.19,20 However, in the popula- tion that is admitted for PCI, even higher frequencies are expected in relation to the prevalence of vascular diseases, antithrombotic treatments, and chronic pathologies. Fag- gioni et al and Ali et al reported prevalence of 40% and 16% in 2 large PCI cohorts with average ages of around 70 and 65 years.21,22 In our series, we found a prevalence of 39% in population ≥75 years, which is consistent with pre- vious estimates. Half of these were mild anemia and did not associate a higher incidence of bleeding. It is plausible that these cases corresponded more frequently to nutritional def- icits. Moderate grades (Hb <11 g/dl in both men and women) were strongly related to the incidence of bleeding, possibly due to a higher prevalence of subclinical bleeding, blood dyscrasia, or chronic inflammation.20 For instance, patients with moderate-to-severe anemia had higher non- statistically significant frequencies of chronic kidney dis- ease (33.8% vs 22.0%), previous heart failure (24.6% vs 18.3 %) or malignancy (10.8% vs 7.3%) versus mildly ane- mic patients.
With respect to the outcomes measures, most of the pre- vious studies have focused on mortality and major adverse cardiovascular events (MACE).10 However, higher rates of these events do not assist in important decisions regarding the intensity or duration of antiplatelet treatment. We evalu- ated bleeding as it influences more in such aspects, and in fact, we appreciate from our results that although there are numerically more thrombosis in the anemic group, the greater impact is in bleeding and nonthrombotic mortality. These results are coherent with recent observations showing that although anemia (or co-morbidities promoting anemia) increases platelet reactivity, the most intense association is with bleeding and all-cause mortality rather than MACE.23
Clinical practice guidelines recommend the use of risk scores for the selection of dual antiplatelet therapy (DAPT) duration.24 Thus, in patients with PRECISE-DAPT ≥25, they consider shortening DAPT to 3 or 6 months according to clinical indication. Unfortunately, older adults in whom stratification is more important, are those in whom bleeding scores have more limitations.9 Some groups have shown that a PRECISE-DAPT cutoff ≥25 may not be generaliz- able in a contemporary aged population.25,26 In addition, CRUSADE score depends largely on renal function, which we know greatly impacts ischemic events, so its ability to discriminate ischemia or bleeding is also limited.27 In our series none of these scores, which require 5 and 8 variables respectively, were superior to baseline hemoglobin for the prediction of bleeding. In fact, the usual cut-off points of all 3 showed good negative predictive value, but hemoglobin
doubled the positive predictive value with respect to the others. Hemoglobin <11 g/dl preferentially identifies hem- orrhagic versus ischemic risk, and the absence of anemia would identify a low-risk group, despite age and high PRE- CISE-DAPT values, in which shortening duration of DAPT would not be justified. Predictive capacity is modest in all cases (AUCs <0.7), and there is still a wide room for improvement through the identification of new variables, biomarkers, or diagnostic techniques.
Our work has some limitations that must be considered. Unidentified confounders or more exhaustive monitoring could contribute to a higher incidence of bleeding or trans- fusions in the anemic group. We do not have data on the effect of antiplatelet de-escalation after hospital discharge. Although there are some losses of follow-up, we judge that they are acceptable in this limited-resource population. Finally, we do not have corpuscular values or specific hematological information that could further corroborate our etiological hypothesis of the severity of anemia.
In conclusion, baseline anemia is a readily available, easily interpretable, and potent risk factor for major bleed- ing following PCI in the older adults. Its identification must be an imperative step, before the selection of the optimal treatment for the patient.
References
1. Dauerman HL, Bhatt DL, Gretler DD, French PA, Smyth SS, Becker RC. Bridging the gap between clinical trials of antiplatelet therapies and applications among older adults patients. Am Heart J 2010;159: 508–517.
2. Schoenenberger AW, Radovanovic D, Windecker S, Iglesias JF, Pedrazzini G, Stuck AE, Erne P, AMIS Plus Investigators. Temporal trends in the treatment and outcomes of older adults patients with acute coronary syndrome. Eur Heart J 2016;37:1304–1311.
3. Franchini M. Hemostasis and aging. Crit Rev Oncol Hematol 2006;60: 144–151.
4. Shanmugam VB, Harper R, Meredith I, Malaiapan Y, Psaltis PJ. An overview of PCI in the very older adults. J Geriatr Cardiol 2015;12: 174–184.
5. Matteau A, Yeh RW, Camenzind E, Steg PG, Wijns W, Mills J, Gersh- lick A, de Belder M, Ducrocq G, Mauri L. Balancing long-term risks of ischemic and bleeding complications after percutaneous coronary intervention with drug-eluting stents. Am J Cardiol 2015;116:686– 693.
6. Pfisterer M, Buser P, Osswald S, Allemann U, Amann W, Angehrn W, Eeckhout E, Erne P, Estlinbaum W, Kuster G, Moccetti T, Naegeli B, Rickenbacher P, Trial of Invasive versus Medical therapy in Older adults SR-25990C patients (TIME) Investigators. Trial of invasive versus medical therapy in older adults patients (TIME) investigators. outcome of older adults patients with chronic symptomatic coronary artery disease with an invasive vs optimized medical treatment strategy: one-year results of the randomized TIME trial. JAMA 2003;289:1117–1123.
7. Damman P, Clayton T, Wallentin L, Lagerqvist B, Fox KA, Hirsch A, Windhausen F, Swahn E, Pocock SJ, Tijssen JG, de Winter RJ. Effects of age on long-term outcomes after a routine invasive or selective inva- sive strategy in patients presenting with non-ST segment elevation acute coronary syndromes: a collaborative analysis of individual data from the FRISC II – ICTUS – RITA-3 (FIR) trials. Heart 2012;98:207–213.
8. Tegn N, Abdelnoor M, Aaberge L, Endresen K, Smith P, Aakhus S, Gjertsen E, Dahl-Hofseth O, Ranhoff AH, Gullestad L, Bendz B, After Eighty study investigators. Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study): an open- label randomised controlled trial. Lancet 2016;387:1057–1065.
9. Ariza-Sol´e A, Formiga F, Lorente V, S´anchez-Salado JC, S´anchez- Elvira G, Roura G, S´anchez-Prieto R, Vila M, Moliner P, Cequier A. Efficacy of bleeding risk scores in older adults patients with acute cor- onary syndromes. Rev Esp Cardiol (Engl Ed) 2014;67:463–470.
10. Kwok CS, Tiong D, Pradhan A, Andreou AY, Nolan J, Bertrand OF, Curzen N, Urban P, Myint PK, Zaman AG, Loke YK, Mamas MA. Meta-analysis of the prognostic impact of anemia in patients undergo- ing percutaneous coronary intervention. Am J Cardiol 2016;118:610– 620.
11. Goodnough LT, Schrier SL. Evaluation and management of anemia in the older adults. Am J Hematol 2014;89:88–96.
12. WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization; 2011. (WHO/NMH/ NHD/MNM/11.1). http://www.who.int/vmnis/indicators/haemoglo- bin.pdf.
13. Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, Wang TY, Gibler WB, Ohman EM, Roe MT, Pollack CV Jr, Peterson ED, Alexander KP. Baseline risk of major bleeding in non-ST-seg- ment-elevation myocardial infarction: the CRUSADE (can rapid risk stratification of unstable angina patients Suppress ADverse outcomes with early implementation of the ACC/AHA Guidelines) bleeding Score. Circulation 2009;119:1873–1882.
14. Costa F, van Klaveren D, James S, Heg D, R€aber L, Feres F, Pilgrim T, Hong MK, Kim HS, Colombo A, Steg PG, Zanchin T, Palmerini T, Wallentin L, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Val- gimigli M, PRECISE-DAPT Study Investigators. Derivation and vali- dation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRE- CISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389:1025–1034.
15. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardio- vascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation 2011;123:2736–2747.
16. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A,Hamon M, Krucoff MW, Serruys PW, Academic Research Consor- tium. Clinical end points in coronary stent trials: a case for standard- ized definitions. Circulation 2007;115:2344–2351.
17. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR. White HD; Joint ESC/ACCF/AHA/WHF task force for the universal defini- tion of myocardial infarction. third universal definition of myocardial infarction. Circulation 2012;126:2020–2035.
18. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–845.
19. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortal- ity, cognition, and function in community-dwelling older adults. Am J Med 2006;119:327–334.
20. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:2263–2268.
21. Faggioni M, Baber U, Sartori S, Chandrasekhar J, Cohen DJ, Henry TD, Claessen BE, Dangas GD, Gibson CM, Krucoff MW, Vogel B, Moliterno DJ, Sorrentino S, Colombo A, Chieffo A, Kini A, Farhan S, Ariti C, Witzenbichler B, Weisz G, Steg PG, Pocock S, Mehran R. Influence of baseline anemia on dual antiplatelet therapy cessation and risk of adverse events after percutaneous coronary intervention. Circ Cardiovasc Interv 2019;12:e007133.
22. Ali ZA, Poludasu S, Qureshi YH, Krishnan P, Ali AA, Tatonetti N, Downey P, Zalewski A, Nazif T, George I, Mandava A, Baber U, Dan- gas G, Mehran R, Kini AS, Sharma SK. Impact of major bleeding on long-term mortality in anemic versus nonanemic patients undergoing percutaneous coronary intervention using bivalirudin. Am J Cardiol 2014;113:1481–1486.
23. Giustino G, Kirtane AJ, Baber U, G´en´ereux P, Witzenbichler B, Neu- mann FJ, Weisz G, Maehara A, Rinaldi MJ, Metzger C, Henry TD, Cox DA, Duffy PL, Mazzaferri EL, Brodie BR, Stuckey TD, Gurbel PA, Dangas GD, Francese DP, Ozan O, Mehran R, Stone GW. Impact of anemia on platelet reactivity and ischemic and bleeding risk: from the assessment of dual antiplatelet therapy with drug-eluting stents study. Am J Cardiol 2016;117:1877–1883.
24. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Ben- edetto U, Byrne RA, Collet JP, Falk V, Head SJ, J€uni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, Sib- bing D, Stefanini GG, Windecker S, Yadav R, Zembala MO. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165.
25. Montalto C, Crimi G, Morici N, Savonitto S, De Servi S. Use of clini- cal risk score in an older adults population: need for Ad Hoc validation and calibration. J Am Coll Cardiol 2019;74:161–162.
26. Guerrero C, Ariza-Sol´e A, Formiga F, Mart´ınez-Sell´es M, Vid´an MT, Aboal J. Applicability of the PRECISE-DAPT score in older adults patients with myocardial infarction. J Geriatr Cardiol 2018;15:713– 717.
27. Baber U, Li SX, Pinnelas R, Pocock SJ, Krucoff MW, Ariti C, Gibson CM, Steg PG, Weisz G, Witzenbichler B, Henry TD, Kini AS, Stuckey T, Cohen DJ, Iakovou I, Dangas G, Aquino MB, Sartori S, Chieffo A, Moliterno DJ, Colombo A, Mehran R. Incidence, patterns, and impact of dual antiplatelet therapy cessation among patients with and without chronic kidney disease undergoing percutaneous coronary interven- tion: results from the PARIS registry (patterns of non-adherence to anti-platelet regimens in stented patients). Circ Cardiovasc Interv 2018;11:e006144.