The impact of platelet count on mortality in unstable angina/non ST-segment elevation myocardial infarction

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1 The impact of platelet count on mortality in unstable angina/non ST-segment elevation myocardial infarction Christian Mueller, MD, a,b Franz-Josef Neumann, MD, a Willibald Hochholzer, MD, a,b Dietmar Trenk, PhD, a Thomas Zeller, MD, a André P. Perruchoud, MD, b and Heinz J. Buettner, MD a Bad Krozingen, Germany; and Basel, Switzerland Background Expanding the knowledge of pathogenesis of arteriosclerosis points at a central role of platelets in the development of acute coronary syndromes. Therefore, we sought to determine the impact of platelet count on long-term outcome in unstable angina/non ST-segment elevation myocardial infarction (UA/NSTEMI) receiving contemporary treatment. Methods This prospective cohort study included 1616 consecutive patients with UA/NSTEMI. All patients underwent coronary angiography and, if appropriate, subsequent catheter-based revascularization within 24 hours of admission. Patients were divided in quintiles according to platelet count. The primary end point was all-cause mortality during long-term follow-up of up to 60 months. Results During follow-up (median 17 months, interquartile range 6-31 months), 89 deaths and 74 nonfatal myocardial infarctions occurred. Patients with higher platelet counts were younger, more often female, and had lower height and weight as compared with patients with lower platelet counts. Mortality was significantly lower among patients in the second quintile of platelet count ( /L) as compared with the other quintiles (hazard ratio 0.39, 95% CI 0.19 to 0.81, P =.011). Kaplan-Meier survival analysis showed cumulative 4-year mortality rates of 12.5%, 3.8%, 10.4%, 9.8%, and 11.4% for patients in the first, second, third, fourth, and fifth quintiles. This association persisted after multivariate adjustment. No association of platelet count and nonfatal myocardial infarctions was observed. Conclusions We found a nonlinear association between platelet count and long-term mortality. The lowest mortality was observed in patients with a platelet count between 181 and /L. (Am Heart J 2006;151:1214.e e7.) Approximately 2.5 million patients worldwide are hospitalized for unstable angina/non ST-segment elevation myocardial infarction (UA/NSTEMI) each year. 1,2 Expanding knowledge of the pathogenesis of arteriosclerosis points at a central role of platelets in development of acute coronary syndromes. 3-5 Considering these insights, it is not surprising that antiplatelet therapy with aspirin has been the cornerstone of the medical management in patients with UA/NSTEMI for 2 decades. 1,6,7 Further refinements in the inhibition of platelet aggregation including intravenous glycoprotein IIb/IIIa From the a Herz-Zentrum, Bad Krozingen, Germany, and b Department of Internal Medicine, University Hospital Basel, Basel, Switzerland. Submitted November 9, 2005; accepted March 20, Reprint requests: Christian Mueller, MD, Department of Medicine, University Hospital Basel Petersgraben 4, CH Basel, Switzerland. chmueller@uhbs.ch /$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi: /j.ahj receptor antagonists and oral dual antiplatelet therapy with aspirin and thienopyridines have allowed the emergence of early coronary stenting as the pivotal management strategy of patients with UA/NSTEMI Over the past years, further insights in the pathophysiology of arteriosclerosis demonstrated that platelets not only promote thrombus formation, but may also trigger acute coronary events through other mechanisms, such as stimulation of inflammatory processes. 3-5,14 Platelets can both release markers of inflammation (eg, soluble CD40 ligand, h-thromboglobulin) 5,15 and directly activate other cells (eg, leukocytes), which can lead to further release of inflammatory markers. 5,16,17 Several of these markers have demonstrated to be associated with poor outcome in patients with UA/NSTEMI In addition, recent studies point to a possible correlation of platelet count and blood levels of certain inflammatory markers These associations and the important role of platelets in the pathophysiology of UA/NSTEMI make platelet count a potential

2 1214.e2 Mueller et al American Heart Journal June 2006 prognostic marker, which is determined inexpensively in clinical routine. The purpose of this study was to evaluate the impact of platelet count on long-term outcomes after UA/NSTEMI in a large cohort of consecutive unselected patients treated with an early invasive strategy. Methods Study population Consecutive patients admitted to our center with UA/ NSTEMI from January 1996 to December 1999 were included in this analysis. The study protocol required typical chest pain at rest and early coronary angiography. We excluded patients with de novo angina pectoris on exertion or worsening angina during exertion only, patients with persistent ST elevation, patients in whom angiography was not performed because of patient refusal (n = 6) or extremely severe concomitant disease (n = 9 with severe dementia or advanced malignancy), and patients without platelet count on admission (n = 51). The study was carried out according to the principles of the Declaration of Helsinki and approved by the institutional review board. Informed consent was obtained from all participating patients. At hospital discharge, all patients were counseled to consume a low-cholesterol diet, and statins were recommended to achieve an low-density lipoprotein cholesterol b100 mg/dl during follow-up. The decision to divide the platelet count into quintiles was not developed before the initiation of the study in Patient management Patients with persistent chest pain underwent immediate coronary angiography. In patients asymptomatic while on medical therapy, coronary angiography was performed within 24 hours of admission. Whenever possible, coronary stenting of the culprit lesion was performed immediately after angiography. Stenting was not restricted to patients with 1- and 2-vessel disease, but also favored in patients with 3-vessel disease with suitable lesions. All patients underwent electrocardiographic recordings immediately after percutaneous coronary intervention (PCI) or coronary artery bypass grafting and on the following morning. In addition, cardiac markers (creatine kinase [CK] MB and CK-MB) were determined at 8 to 24 hours after the intervention and, additionally, whenever ischemic symptoms developed. Dual antiplatelet therapy with aspirin and ticlopidine was restricted to patients receiving coronary stents and did not exceed a duration of 4 weeks. If revascularization was indicated, but PCI was not considered the optimal treatment option (unprotected left main disease, diffuse 3-vessel disease), patients were scheduled for urgent coronary artery bypass grafting. Follow-up All patients were scheduled for outpatient visits at 6 months. In addition, patients were contacted by questionnaire. For patients reporting cardiac symptoms, at least one clinical and electrocardiographic examination was performed at the outpatient clinic or by the referring physician. All information derived from contingent hospital readmission records or provided by the referring physician or by the outpatient clinic was reviewed and entered into the computer database. Figure 1 Distribution of platelet counts on admission in 1616 patients with UA/NSTEMI. Study end points and statistical analysis The primary end point was defined as death from all causes. As secondary end points, we assessed nonfatal myocardial infarction and the composite of death and nonfatal myocardial infarction. Myocardial infarction was defined as typical chest pain at rest followed by an increase in creatine phosphokinase (CK and CK-MB beyond 2 times the upper limit of normal, and 5 times the upper limit of normal after coronary artery bypass grafting), or new Q waves in the electrocardiogram. To meet this end point criterion, patients who had initially presented with myocardial infarction had to have new ST-segment changes and an increase in CK of 50% or above the previous trough level in at least 2 samples reaching a minimum 3 times the upper limit of normal. The statistical analyses were performed using the SPSS/PC (version 13.0, SPSS Inc, Chicago, IL) software package. A statistical significance level of.05 was used. Comparisons were made using analysis of variance for independent samples and m 2 tests as appropriate. All hypothesis testing was 2-tailed. Cox proportional hazards regression analysis was used as the appropriate method throughout. Multivariate Cox regression analysis was performed to identify independent predictors of death. Together with platelet count, all baseline demographic, clinical, and angiographic variables as well as medication at discharge were entered in a univariate Cox regression analysis. All variables associated with long-term mortality in univariate analysis ( P b.05) were entered into the multivariate model. As a measure of overall kidney function, the glomerular filtration

3 American Heart Journal Volume 151, Number 6 Mueller et al 1214.e3 Table I. Baseline patient, angiographic, and procedural characteristics according to platelet count (in 10 9 /L) on admission First quintile Second quintile Third quintile Fourth quintile Fifth quintile < >_>_ 280 n = 322 n = 320 n = 320 n = 331 n = 323 P* Age (y) 67 F F F F F 12 b.001 Female sex 57 (18) 83 (26) 98 (31) 106 (32) 121 (38) b.001 Height (cm) 171 F F F F F 8 b.001 Weight (kg) 79 F F F F F 13 b.001 Prior myocardial infarction 130 (40) 128 (40) 113 (35) 107 (32) 105 (33).072 Prior coronary bypass grafting 64 (20) 45 (14) 43 (13) 23 (7) 27 (8) b.001 Prior coronary angioplasty 81 (25) 68 (21) 66 (21) 53 (16) 53 (16).020 Risk factors Smoker 66 (21) 63 (20) 82 (26) 82 (25) 84 (26).169 Hypercholesterolemia 216 (67) 217 (68) 212 (66) 216 (65) 198 (61).445 Hypertension 206 (64) 206 (64) 193 (60) 199 (60) 193 (60).591 Diabetes mellitus 66 (21) 57 (18) 65 (20) 55 (17) 62 (19).673 Obesity (BMI N30) 58 (18) 67 (21) 48 (15) 57 (17) 54 (17).380 GFR (ml d min 1 d 1.73 m 2 ) 91 F F F F F White blood cell count (106/L) 7,579 F 2,395 8,034 F 2,343 8,326 F 2,252 9,904 F 1,403 10,030 F 3,657 b.001 C-reactive protein (mg/l) 1.59 F F F F F Current cardiac disease.143 Angina at rest N48 h 36 (11) 41 (13) 51 (16) 50 (15) 44 (14) Angina at rest b48 h 206 (64) 178 (56) 181 (57) 193 (58) 182 (56) Non Q-wave 41 (13) 50 (16) 42 (13) 32 (10) 35 (11) myocardial infarction Angina at rest N48 h to 8 wk 39 (12) 51 (16) 46 (14) 56 (17) 62 (19) post myocardial infarction Cardiopulmonary resuscitation 1 (0.3) 4 (1.3) 7 (2.2) 5 (1.5) 7 (2.2).261 Defibrillation (only) 4 (1.2) 2 (0.6) 7 (2.2) 6 (1.8) 8 (2.5).363 Cardiogenic shock 3 (0.9) 2 (0.6) 3 (0.9) 1 (0.3) 4 (1.2).722 ST depression N0.1 mv 23 (7) 40 (13) 45 (14) 22 (7) 30 (9).004 T-wave inversion 88 (27) 103 (32) 91 (28) 98 (30) 87 (27).593 Troponin T z0.01 Ag/L 136 (20) 155 (23) 127 (19) 135 (20) 133 (19).238 No. of coronary vessels.044 with 50% stenosis 0 28 (9) 43 (13) 43 (13) 49 (15) 52 (16) 1 66 (21) 62 (19) 73 (23) 89 (27) 77 (24) 2 76 (24) 82 (26) 83 (26) 74 (22) 79 (25) (47) 133 (42) 121 (38) 119 (36) 115 (36) Definite treatment PCI 182 (57) 192 (60) 183 (57) 193 (58) 188 (58).922 Coronary artery bypass grafting 53 (17) 50 (16) 38 (12) 48 (15) 46 (14).540 Medical therapy 87 (27) 78 (24) 99 (31) 90 (27) 89 (28).475 Number of stents 0.9 F F F F F Glycoprotein IIb/IIIa antagonist use 18 (11) 26 (15) 13 (8) 25 (14) 19 (12).345 Discharge medication Aspirin 280 (91) 259 (84) 271 (88) 286 (89) 272 (87).076 Thienopyridine 153 (50) 169 (55) 155 (50) 168 (53) 161 (51).735 Oral anticoagulation 20 (7) 19 (6) 18 (6) 8 (3) 13 (4).111 h-blocker 253 (82) 242 (79) 242 (7) 258 (81) 242 (77).509 Nitrate 194 (63) 186 (60) 181 (59) 193 (60) 185 (59).804 Calcium antagonist 31 (10) 41 (13) 44 (14) 26 (8) 45 (14).055 ACE inhibitor or 191 (62) 184 (60) 164 (53) 167 (52) 172 (55).050 angiotesin blocker Diuretic 78 (25) 72 (23) 63 (21) 62 (19) 55 (18).115 Digoxin 16 (5) 13 (4) 12 (4) 14 (4) 12 (4).921 Statin 186 (61) 197 (64) 206 (67) 205 (64) 200 (64).617 Insulin 17 (6) 16 (5) 18 (6) 11 (3) 18 (6).637 Oral antidiabetic medication 22 (7) 24 (8) 27 (9) 27 (8) 25 (8).959 Data are expressed as mean F SD or number (percentage) if not denoted otherwise. BMI, Body mass index; GFR, glomerular filtration rate; ACE, angiotensin-converting enzyme. *For the comparison between groups.

4 1214.e4 Mueller et al American Heart Journal June 2006 Table II. Association between platelet count and outcome within total follow-up First quintile Second quintile Third quintile Fourth quintile Fifth quintile < >280 Hazard ratio (95% CI)* P Death 20 (6.2) 8 (2.5) 21 (6.6) 18 (5.4) 22 (6.8) 0.39 ( ).011 Cardiovascular 18 (5.6) 8 (2.5) 19 (5.9) 16 (4.8) 21 (6.5) 0.43 ( ).023 death Nonfatal MI 15 (4.7) 18 (5.6) 15 (4.7) 14 (4.2) 12 (3.7) 1.28 ( ).370 TVR 39 (12) 45 (14) 38 (12) 48 (15) 51 (16) 0.94 ( ).745 Data are expressed as number (percentage). MI, Myocardial infarction; TVR, target vessel revascularization. *For patients in the second quintile of platelet count relative to the other quintiles. rate was entered. We calculated the glomerular filtration rate with the use of the abbreviated Modification of Diet in Renal Disease Study equation 25 : Glomerular filtration rate (in ml d min 1 d 1.73 m 2 of body surface area) = 186 (serum creatinine in mg/dl) (age in years) in female subjects in black subjects. The cumulative survival curves were constructed with the use of the Kaplan- Meier method. Figure 2 Results Baseline characteristics A total of 1616 unselected consecutive patients with symptoms of myocardial ischemia at rest without persistent ST-segment elevation were enrolled in the study. The median platelet count was /L (minimum 39, maximum 992, interquartile range /L) (Figure 1). The quintiles of platelet count were b181, 181 to 210, 211 to 241, 242 to 279, and z /L. Table I describes the baseline, demographic, clinical, angiographic and procedural characteristics of the cohort divided into quintiles of platelet count on admission. Interestingly, patients with higher platelet counts were younger, more often female, and had both lower height and weight as compared with patients with lower platelet counts. Moreover, patients with higher platelet counts had less often undergone prior coronary artery bypass grafting or PCI. Coronary angiography revealed that patients with higher platelet counts had less extensive coronary artery disease. Treatment Despite these important differences in baseline characteristics, treatment was remarkably similar in all quintiles of platelet count. About 70% of patients underwent revascularization. Percutaneous coronary intervention was the predominant revascularization strategy and was performed very early at a median of 5.3 hours from admission. Percutaneous coronary intervention was not restricted to patients with 1- or 2-vessel disease, but was also performed in patients with 3-vessel disease and suitable lesions. Coronary stents Cumulative rates of death in relation to platelet count. were implanted in about 80% of the patients. Percutaneous coronary intervention was performed almost 4 times more often than coronary artery bypass grafting. Patients undergoing surgical treatment received 3.2 F 0.9 distal bypass graft anastomoses including left internal mammary artery grafts in 89%. Outcome Eighty-nine deaths and 74 nonfatal myocardial infarctions occurred during a median follow-up of 17 months

5 American Heart Journal Volume 151, Number 6 Mueller et al 1214.e5 Table III. Independent predictors of long-term mortality in multivariate analysis Hazard ratio (95% CI) Age (continuous) 1.06 ( ).001 Platelet count 0.34 ( ).022 (second quintile vs others) Use of aspirin 0.37 ( ).003 Use of h-blocker 0.44 ( ).005 Coronaries with z50% stenosis 1.89 ( ) b.001 (interquartile range 6-31) (Table II). Overall, 82 (92%) of 89 deaths were adjudicated to be of cardiovascular origin. Inhospital rates for mortality (0.9%-2.2%) and nonfatal myocardial infarction (2.2%- 3.8%) were low and similar in all groups. During total follow-up, overall mortality was significantly lower among patients in the second quintile of platelet count ( /L) as compared with the other quintiles. Patients with a platelet count in the second quintile had b40% the long-term mortality as compared with patients in the other groups (hazard ratio 0.39, 95% CI 0.19 to 0.81, P =.011). Kaplan- Meier survival analysis showed cumulative 4-year mortality rates of 12.5%, 3.8%, 10.4, 9.8%, and 11.4% for patients in the first, second, third, fourth, and fifth quintiles (Figure 2). Among secondary end points, the rate for nonfatal myocardial infarction and target vessel revascularization was not different between the quintiles of platelet count (Table II). Multivariate analysis In a multivariate Cox regression analysis adjusted for all baseline demographic, clinical, and angiographic variables shown in Table I, platelet count remained a significant independent predictor of mortality during long-term follow-up (second quintile vs the other quintiles: hazard ratio 0.34, 95% CI , P =.022) (Table III). Discussion This large prospective study in consecutive unselected patients with UA/NSTEMI receiving contemporary treatment with early revascularization evaluated the impact of platelet count on long-term mortality. Our major finding was a nonlinear association between platelet count and long-term mortality with the lowest mortality observed in patients with a platelet count between 181 and /L. The reduction in mortality rates persisted after multivariate adjustment. By its low cost and universal availability, platelet count may become a preferred prognostic marker in UA/ NSTEMI, particularly for the identification of low-risk patients, if these data are confirmed by further trials. It is P important to note that overall mortality was low and similar to other studies applying contemporary early revascularization strategy. 12,13 Our analysis has 4 particular strengths. First, it is derived from a prospective study of consecutive unselected patients rather than a randomized trial. This eliminates selection bias and eases the extrapolation of findings into clinical practice. Second, it includes long-term follow-up. Third, a uniform revascularization strategy was applied in all patients. Fourth, the extent of coronary artery disease was quantified in all patients and included in the multivariate analysis as a potential confounder. The J-shaped relation between platelet count and mortality might be explained by mainly 3 mechanisms: platelet-induced inflammation, extent of coronary artery disease, and comorbidity. First, lower platelet count may be associated with lower levels of inflammatory cytokines, which are associated with poor outcome in UA/NSTEMI Recent studies point to a possible correlation of platelet count and blood levels of certain inflammatory markers This could be well demonstrated for soluble CD40 ligand, an independent predictor of adverse outcome in UA/NSTEMI, 19 in 2 studies evaluating patients with inflammatory disorders, essential thrombocytopenia, and different types of thrombocytosis as well as in healthy controls. 21,24 The increase in mortality from the second to the fifth quintile could be well explained by this association. However, the seemingly paradoxically elevated mortality in patients with very low platelet count needs to be attributed to additional factors. More extensive coronary artery disease may be an important mediator responsible for the higher mortality in patients with very low platelet count. Patients in the first platelet count quintile were older and had more often prior coronary artery bypass grafting, prior angioplasty, and 3-vessel disease. Third, low platelet count in the first platelet count quintile can be caused by comorbidity with a hidden prothrombotic state including malignancy and heparin-induced thrombocytopenia, which can be associated with increased risk of death. 26 A significant association of low platelet count (b /L) and adverse clinical outcome in patients with high-risk PCI and UA/NSTEMI has also been demonstrated in 2 analyses of large trials (EPIC and PURSUIT). 27,28 In contrast to our findings in patients with UA/ NSTEMI, no clear association between platelet count and outcome could be demonstrated in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing fibrinolytic therapy. 29,30 Although the HERO-1 trial indicated a correlation of higher platelet count with an increased rate of TIMI-3 flow at 90 minutes after fibrinolytic therapy, no association between platelet count and mortality at 35 days was found. 29 However, an analysis of 3787 patients from

6 1214.e6 Mueller et al American Heart Journal June clinical trials of intravenous fibrinolytic therapy for acute STEMI could not verify this association between platelet count and TIMI-3 flow. 30 Furthermore, no association between platelet count and mortality at 30 days was found. These findings of missing association between platelet count and outcome in STEMI might be explained by the different treatment of study patients. Although our patients underwent early PCI or bypass grafting, the described patients with STEMI received fibrinolytic therapy, which is associated with a wide impact on the coagulation system One recent study has demonstrated the suspected association of inflammatory markers, platelet count, and outcome. 34 Johansen et al analyzed blood samples from the aortic root and coronary sinus drawn simultaneously before and after completed coronary angioplasty in 26 patients. Plasma levels of platelet-derived growth factor and h-thromboglobulin, as well as platelet counts, were measured. Restenosis was evaluated by quantitative coronary angiography after 6 months. Significant increases both in platelet-derived growth factor and h-thromboglobulin were encountered in the aortic root after coronary angioplasty in patients who developed restenosis as compared with patients without restenosis. Patients who developed restenosis also had significantly higher platelet counts compared to those without. This finding may strengthen the hypothesis that platelets contribute to the process of restenosis and, potentially, cardiac mortality after UA/NSTEMI. Although the findings of this study complement and extend our knowledge regarding the impact of platelet count on cardiovascular disease and may be the key to a better understanding of different outcomes in various subgroups of patients with acute coronary syndromes, they have received little notice until now. Outcome in patients with a platelet count between 181 and /L and receiving a short period of dual antiplatelet therapy was excellent in our trial. If these data are confirmed by further trials, the clinical impact of this observation may be that the initial platelet count can be used as a prognostic marker. After validation, it might be a useful adjunct for identifying those patients who may benefit from a more intensified therapy (eg, higher dosed or prolonged dual antiplatelet therapy). 13,35 Limitations Several study limitations should be acknowledged. First and foremost, given the observational nature of this study, timing and treatment of patients were left to the discretion of the attending physician. Although definite treatment and inhospital outcome did not differ between quintiles, a possible bias cannot be completely excluded. In addition, the decision to divide the platelet count into quintiles was not developed before the initiation of the study in We observed some differences in demographic characteristics between quintiles of platelet count. Patients with higher platelet counts were younger, more often female, and had both lower height and weight as compared with patients with lower platelet counts. This observation may be at least partly explained by the lower distribution volume of platelets in small and light persons, and is fully supported by the pooled thrombolysis data analysis. 30 Furthermore, this study does not elucidate the causes of the reduced mortality in patients with a low normal platelet count. Further studies are mandatory to confirm our observation and to define the optimal therapeutic range regarding platelet count. Conclusions In conclusion, we found a nonlinear association between platelet count and long-term mortality. Patients with a platelet count between 181 and /AL had less than half the mortality as compared with patients with lower or higher platelet counts. This observation persisted after multivariate adjustment. If confirmed by other studies, its low cost and universal availability would make platelet count a preferred prognostic marker in UA/NSTEMI, particularly for the identification of low-risk patients. We thank Peter Betz, MD, and Anita Abels for help in data acquisition. References 1. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non ST-segment elevation myocardial infarction 2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002;106: Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Engl J Med 2000;342: Hansson GK. 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Activation of the contact system and inflammation after thrombolytic therapy in patients with acute myocardial infarction. Am J Cardiol 2004;93: Salvioni A, Perego GB, Marenzi G, et al. Late activation of the fibrinolytic system in myocardial infarction treated with thrombolytic therapy. Influence of the coronary anatomical substrate. Eur Heart J 1996;17: Johansen O, Brekke M, Seljeflot I, et al. Blood platelet count and reactivity are associated with restenosis 6 months after coronary angioplasty. Scand Cardiovasc J 2004;38: Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345: Appendix A The following cardiologists contributed to patient management: Wolfgang Perach, M.D.; Klaus Werner, M.D.; Michael Gick, M.D.; Hans-Peter Bestehorn, M.D.; Thomas Comberg, M.D.; and Valerio Bassignana, M.D.