Intensive Care Med (2015) 41:806–813 DOI 10.1007/s00134-015-3760-y

Min-Juei Tsai Shuo-Ming Ou Chia-Jen Shih Pei-wen Chao Lan-Fu Wang Yu-Ning Shih Szu-Yuan Li Shu-Chen Kuo Yen-Tao Hsu Yung-Tai Chen

Received: 9 December 2014 Accepted: 16 March 2015 Published online: 1 April 2015 Ó Springer-Verlag Berlin Heidelberg and ESICM 2015

ORIGINAL

Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study

L.-F. Wang Insurance database. ParMiaoli General Hospital, Ministry of Health ticipants: All patients (age and Welfare Chest Department, Miaoli City, C18 years) who were hospitalized for Taiwan

sepsis between January 2000 and December 2010. Measurements: Conditional logistic Take-home message: Prior use of antiplatelet agents was associated with a regression was used to adjust for survival benefit in sepsis patients. confounding. Adjusted odd ratios (ORs) were used to compare the Electronic supplementary material mortality rate due to sepsis in anThe online version of this article S.-C. Kuo (doi:10.1007/s00134-015-3760-y) contains tiplatelet drug users and nonusers. supplementary material, which is available National Institute of Infectious Diseases and Results: Of 683,421 included paVaccinology, National Health Research to authorized users. tients, 229,792 (33.6 %) patients died Institutes, Miaoli City, Miaoli County, during hospitalization for sepsis, and Taiwan the rest (64.4 %) survived to disS.-C. Kuo charge. Use of antiplatelet agents M.-J. Tsai Division of Infectious Diseases, Taipei before admission was associated with Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan a lower risk of mortality in sepsis Veterans General Hospital, Suao Branch, patients (aOR 0.82, 95 % confidence Yilan, Taiwan Y.-T. Chen ()) interval [CI] 0.81–0.83, P \ 0.001). Department of Nephrology, Taipei City M.-J. Tsai  S.-M. Ou  C.-J. Shih  Hospital Heping Fuyou Branch, Taipei 112, By using another case–control study S.-Y. Li  S.-C. Kuo  Y.-T. Chen Taiwan design, the beneficial effect was more National Yang-Ming University School of e-mail: [email protected] significant in current users (aOR 0.78, Medicine, Taipei, Taiwan Tel.: 886-2-2388-9595 95 % CI 0.76–0.79) than in recent users (aOR 0.88, 95 % CI 0.85–0.91), S.-M. Ou  S.-Y. Li but was not significant in past users Division of Nephrology, Department of Abstract Background: AnMedicine, Taipei Veterans General tiplatelet agents are widely used for (aOR 1.00, 95 % CI 0.98–1.02). Hospital, Taipei, Taiwan Limitations: Observational study. cardiovascular diseases, but their Conclusions: Prior use of anpleiotropic effects in sepsis are conC.-J. Shih troversial. Objective: To investigate tiplatelet agents was associated with a Department of Medicine, Taipei Veterans survival benefit in sepsis patients. General Hospital, Yuanshan Branch, Yilan, the association between antiplatelet agents and the survival benefit for Taiwan Keywords Sepsis  Antiplatelet  sepsis patients. Design: A nationP. Chao Mortality wide population-based cohort and Department of Anesthesiology, Wan Fang nested case–control study. SetHospital, Taipei Medical University, Taipei, ting: Taiwan National Health Taiwan Y.-N. Shih  Y.-T. Hsu ()) Department of Chest, Taipei City Hospital Heping Fuyou Branch, Taipei 112, Taiwan e-mail: [email protected] Tel.: 886-2-2388-9595

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Introduction Sepsis is a prevalent syndrome that causes substantial morbidity and mortality. In the USA, over 750,000 cases of sepsis are treated in hospitals each year [1], corresponding to an estimated economic burden of nearly 17 billion US dollars [2]. Approximately 20–24 % of patients who are diagnosed with sepsis will progress to shock or acute organ dysfunction. Such cases of severe sepsis represent 10 % of all admissions to intensive care units (ICUs). Depending on the stage, severe sepsis can be associated with a mortality rate of 26–61 % [3, 4]. Several factors were identified to be associated with the development of multiple organ failure and death in sepsis, such as reactive oxygen species (ROS), inflammatory mediators, macro- and microcirculatory alterations [5]. Among these factors, platelet activation plays one of the most important roles which may induce microvascular thrombosis and release of inflammatory mediators via platelet–endothelial interaction [6]. It also plays an important role in the activation of the innate immune response through the expression of cell surface receptors and recognition of pathogens by toll-like receptors (TLRs) [7]. In animal studies, antiplatelet agents reduced platelet activation and further suppressed endotoxin-induced ischemic organ damage and leukocyte activation [8, 9]. For these reasons, attenuation of platelet activation was hypothesized to be of benefit for septic patients. Although several retrospective cohort studies have evaluated the potential benefit of antiplatelet agents in sepsis or septic shock patients, the results are inconsistent across studies. Eisen et al. [10] reported that aspirin administration was associated with a lower mortality in sepsis patients. Sossdorf et al. [11] also reported a similar survival benefit of aspirin but not clopidogrel. In contrast, Valerio-Rojas et al. [12] investigated ICU patients with severe sepsis or septic shock, but found no association between the use of antiplatelet agents and survival benefit. However, these studies may be limited as a result of the small samples, only consideration of aspirin as co-medications, de novo instead of prior use of aspirin, and lack of consideration for drug exposure timing (such as current, recent, and past use). Therefore, we conducted this nationwide, large-scale, population-based cohort and nested case–control study by using the Taiwan National Health Insurance (NHI) Research Database (NHIRD) to determine whether the prior use of antiplatelet drugs (e.g., aspirin and ADP inhibitors) is associated with a survival benefit in sepsis patients and the influence of exposure timing (current, recent, and past use) of antiplatelet drugs. We interpreted the actual treatment course of antiplatelet agents for each individual, to determine the difference between recent and current users. To our knowledge, the current study is the largest and most comprehensive investigation of the association between antiplatelet agents and survival benefit in sepsis patients.

Materials and methods Data sources Taiwan’s NHI program was established in 1995. Owing to the use of mandatory, universal enrollment, 98 % of the population is included in Taiwan’s NHI program. For all patients enrolled in the NHI program, the NHIRD maintained by the National Health Research Institute stores all of their demographic information, diagnoses [according to the ninth revision of the International Classification of Diseases, clinical modification (ICD-9-CM)], procedures, and medications. The data set used in this study consists of de-identified secondary data released to the public for research purposes. Because the NHIRD consisted of deidentified secondary data, this study was exempt from full review by the Institutional Review Board of Taipei City Hospital (TCHIRB-1030603-W). Settings and participants This current cohort study was designed to determine the association between the use of antiplatelet agents and subsequent mortality in patients with sepsis. The study cohort comprised all patients with a first-time discharge diagnosis of sepsis (ICD-9 CM code 038x) and received antibiotic treatments between January 2000 and December 2010. The accuracy of diagnosis of sepsis was validated in our previous study according to The American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference [13]. The accuracy was 92.3 % in our 340 randomly selected inpatients (j = 0.806; 95 % confidence interval, 0.799–0.813) [14]. We excluded patients younger than 20 years or those without a 5-year follow-up period before hospitalization for sepsis. The index date was the first day of hospitalization for sepsis. All patients were followed until death, loss to follow-up or 31 December 2011, whichever came first. We also performed another analysis by using a nested-control study design for the same patient groups to provide more detail on the timing effect of antiplatelet drugs. Exposure assessment We identified all oral antiplatelet agents, including aspirin, clopidogrel, and ticlopidine, prescribed within 1 year before the index date. We categorized the use of antiplatelet drugs as past, recent, or current use, according to the time of the prescription termination date (date of dispensation plus number of days of supply). Current antiplatelet drug users were defined as those who were hospitalized for sepsis during the use of antiplatelet drugs. Recent antiplatelet drug users were those who were

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hospitalized for sepsis 1–30 days after the prescription Table 1 Demographic and clinical characteristics of patients termination date. Past users were those who were hospiAntiplatelet talized for sepsis 31–365 days after the prescription Characteristic termination date. Usera Nonuser P value Definition of cases and controls

No. of patients Male Age (years)

In the cohort study design, antiplatelet users were idenlevelb tified as patients who received antiplatelet drugs currently Urbanization 1 or within 30 days before admission for sepsis. Those who 2 did not receive antiplatelet drug within 30 days before 3 4 admission were defined as nonusers. In the nested-control study design, cases were identi- Site of infection fied as patients who died during hospitalization for sepsis. Respiratory tract Controls were selected by a density-based sampling ap- Bacteremia proach, which allows for a close approximation of the GU tract odds ratio (OR) to the rate ratio. For each case, we created Intra-abdomen Wound a pool of potential eligible controls who survived from Device-related sepsis. From these eligible controls, one patient was se- CNS lected at random and matched to a case with the same Endocarditis year of admission for sepsis by age (±2 years), gender, Others urbanization level, the Charlson comorbidity index (CCI) CCI scorec score (±1), and infection site. Cases and controls had 1 year of prescription drug data, which allowed us to Mean ± SD 0 assess prescription drug use. Statistical analysis Demographic data for patients and controls were compared by Chi-squared tests for categorical variables and by the independent t test or Mann–Whitney U test for continuous variables. ORs were used to compare the mortality rate due to sepsis in antiplatelet drug users and nonusers. Conditional logistic regression was used to adjust for covariates listed in Table 1. In the nested-control study design, those identical matching variables were not adjusted, including sex, age, urbanization level, site of infection, and CCI score. We also tested whether the association between antiplatelet drug use and mortality due to sepsis significantly interacted with age, gender, CCI, hypertension, myocardial infarction, cerebrovascular disease, infection site, or the number of organ failures by the likelihood ratio test of nested models and stratified subgroup analyses. Microsoft SQL Server 2012 (Microsoft Corp., Redmond, WA, USA) was used for data linkage, processing, and sampling. All analyses were performed with SAS version 9.2 (SAS Institute Inc.), using two-sided significance tests at a P value level of less than 5 %.

117,447 565,974 64,193 (54.7) 312,419 (55.2) \0.001 74.4 (11.1) 66.1 (17.5) \0.001 \0.001 58,857 45,641 10,851 2098

(50.1) 283,690 (50.1) (38.9) 219,674 (38.8) (9.2) 52,616 (9.3) (1.8) 9994 (1.8)

63,146 1092 38,421 13,124 4428 1736 440 571 6394

(53.8) 281,263 (49.7) (0.9) 5071 (0.9) (32.7) 160,436 (28.3) (11.2) 73,143 (12.9) (3.8) 24,444 (4.3) (1.5) 8327 (1.5) (0.4) 3137 (0.6) (0.5) 3108 (0.5) (5.4) 33,742 (6.0)

1108 (0.9) 46,836 (8.3) 1 4449 (3.8) 57,910 (10.2) 2 8624 (7.3) 62,807 (11.1) 3 12,080 (10.3) 65,544 (11.6) 4 14,716 (12.5) 63,780 (11.3) 5 15,106 (12.9) 54,695 (9.7) C6 61,364 (52.2) 214,402 (37.9) Hypertension 108,276 (92.2) 359,914 (63.6) Dyslipidemia 58,968 (50.2) 172,174 (30.4) Heart failure 52,671 (44.8) 133,048 (23.5) Myocardial infarction 23,529 (20.0) 32,079 (5.7) Cerebrovascular disease 84,201 (71.7) 221,192 (39.1)

\0.001 0.265 \0.001 \0.001 \0.001 0.859 \0.001 0.007 \0.001 \0.001

\0.001 \0.001 \0.001 \0.001 \0.001

No. number, GU genitourinary, CNS central nervous system, SD standard deviation, CCI Charlson comorbidity index a Prescription termination date (date of dispensation ? day supply) overlaps with the index date or prescription termination date of 1–30 days before the index date b Urbanization levels in Taiwan are divided into four strata according to the Taiwan National Health Research Institute publications. Level 1 designates the most urbanized areas, and level 4 designates the least urbanized areas c CCI score is used to determine overall systemic health. With each increased level of CCI score, there are stepwise increases in the cumulative mortality

during hospitalization. Among these patients, 117,447 antiplatelet users and 565,974 nonusers were enrolled. Characteristics of these subjects are shown in Table 1. The mean age of patients was 71.3 years (SD 14.4 years), and most were male (60.8 %). The most common infection sites were the respiratory and genitourinary tracts. In Results this analysis, antiplatelet users were older and had higher This study comprised 683,421 subjects who were hospi- comorbidity index score and incidence of comorbidity talized for sepsis, and 229,792 patients (33.6 %) died (including hypertension, dyslipidemia, heart failure,

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Table 2 Crude and adjusted odds ratio for the risk of mortality from sepsis with oral antiplatelet drug use Odds ratio (95 % CI)

Antiplatelet nonuser Antiplatelet useb

No. of events

No. of patients

Crude

P value

Adjusteda

P value

190,997 (33.7) 38,795 (33.0)

565,974 117,447

1 (reference) 0.97 (0.96–0.98)

\0.001

1 (reference) 0.82 (0.81–0.83)

\0.001

a

Adjusted for age, gender, infection site, urbanization level, Charlson comorbidity index score, hypertension, dyslipidemia, heart failure, myocardial infarction, and cerebrovascular disease Using any antiplatelet within 30 days before the index date

b

sepsis. These different results may be related to the small sample size or difficulty in data interpretation in these studies. The current study uses the largest sample size to date. The results demonstrate an association between the use of antiplatelet agents and survival benefit in sepsis patients (aOR 0.82), especially for patients who are using antiplatelet drugs when sepsis is diagnosed (aOR 0.78). Although antiplatelet users were older and had more comorbidity than control group, this survival benefit was still significant even before adjustment. The survival benefit was accentuated after adjusting these confounding factors. There is very limited evidence of the association between antiplatelet usage and the incidence of sepsis. O’Neal et al. [15] had reported that prehospital use of statins may be protective in sepsis and acute lung injury. In that study of 575 patients, prehospital aspirin usage potentiated this beneficial effect. Eisen et al. [10] also performed a retrospective study of 5523 sepsis patients, including 2082 patients who received low-dose aspirin within 24 h of sepsis detection. Compared to patients who did not receive aspirin, patients who received aspirin showed significantly lower rates of mortality (20.0 vs. 9.4 %) and progression into severe sepsis (19.4 vs. 6.1 %). Sossdorf et al. [11] found a survival benefit with aspirin use (OR 0.57, P = 0.008), but not clopidogrel use (P = 0.208), among 979 sepsis patients. However, the number of clopidogrel users was limited (n = 60) compared to the number of aspirin users (n = 274). Thus, the result may not have had sufficient power to be assessed. Our research, which included more ADP inhibitor users than the previous study, not only confirmed the survival benefit of aspirin use, but also showed a benefit of ADP inhibitor use (i.e., clopidogrel and ticlopidine) in sepsis patients. Previous studies have only focused on the current use of antiplatelet agents when sepsis is diagnosed. However, the inhibitory effect of aspirin and ADP inhibitors on platelet activation lasts much longer than the half-life of these drugs [16]. Both drugs irreversibly inhibit platelets through different key enzymes. Aspirin inhibits thromDiscussion boxane A2, and platelet function is recovered about Previous investigations have differing conclusions with 7–10 days after drug withdrawal [16]. ADP inhibitors respect to the survival benefits of antiplatelet agents in block the P2Y12 component of the ADP receptor, and

myocardial infarction, and cerebrovascular disease) than nonusers. The use of antiplatelet agents within 30 days before admission was associated with a lower risk of mortality in sepsis patients, with an adjusted OR (aOR) of 0.82 (95 % CI 0.81–0.83, P \ 0.001) as listed in Table 2. To clarify the timing effect of this survival benefit, we performed another analysis by using nested-control study design. After the matching process, 186,374 cases and 186,374 matched controls were enrolled. A total of 43,418 patients (18.9 %) were excluded because no matching control was available (Supplemental Table 1). Use of antiplatelet agents before admission was associated with a lower risk of mortality in sepsis patients, with an adjusted OR (aOR) of 0.88 (95 % CI 0.87–0.90, P \ 0.001). Current or recent use of antiplatelet agents, but not past use, was associated with a significantly lower risk of mortality, with aORs of 0.78 (95 % CI 0.76–0.79), 0.88 (95 % CI 0.85–0.91), and 1.00 (95 % CI 0.98–1.02), respectively (Table 3). Subgroup analysis stratified by the type of antiplatelet drug revealed a similar effect on mortality in sepsis patients, with aORs of 0.89 (95 % CI 0.88–0.90) and 0.92 (95 % CI 0.90–0.94) for aspirin and ADP inhibitors, respectively. Recent aspirin users still had a survival benefit (aOR 0.90, 95 % CI 0.87–0.94, P \ 0.001), but recent ADP inhibitor users did not (P = 0.264) (Table 3). We performed another subgroup analysis to explore the association between the use of antiplatelet drugs and the risk of mortality in sepsis patients according to age, gender, comorbidities, infection site, shock status (use of inotropes and/or vasopressors following sepsis), mechanical ventilation status, and number of organ failures (Fig. 1). The survival benefit effects of the prior use of antiplatelet drugs in sepsis patients were generally consistent across all examined subgroups. However, this survival benefit effect of antiplatelet drugs was not observed in patients who had two or more organ failures.

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Table 3 Crude and adjusted odds ratio for the risk of mortality from sepsis with oral antiplatelet drug use by using nested-control study design Number

Odds ratio (95 % CI) Control (n = 186,374)

129,193

121,667

Antiplatelet use Anyc Currentd Recente 1–7 days 8–30 days Pastf Aspirin nonuserb

57,181 20,997 10,139 3183 6956 26,045 135,025

64,707 26,850 11,473 3756 7717 26,384 128,324

0.82 0.72 0.82 0.79 0.83 0.92 1

(0.81–0.83) (0.71–0.74) (0.80–0.84) (0.75–0.83) (0.81–0.86) (0.90–0.93) (reference)

\0.001 \0.001 \0.001 \0.001 \0.001 \0.001

0.88 (0.87–0.90) 0.78 (0.76–0.79) 0.88 (0.85–0.91) 0.84 (0.80–0.89) 0.90 (0.87–0.93) 1.00 (0.98–1.02) 1 (reference)

\0.001 \0.001 \0.001 \0.001 \0.001 0.733

Aspirin use Anyc Currentd Recente 1–7 days 8–30 days Pastf ADP inhibitor nonuserb,g

51,349 17,087 8691 2731 5960 25,571 173,006

58,050 21,948 9862 3218 6644 26,240 171,224

0.83 0.73 0.83 0.80 0.84 0.93 1

(0.82–0.84) (0.71–0.75) (0.80–0.85) (0.76–0.84) (0.81–0.87) (0.91–0.95) (reference)

\0.001 \0.001 \0.001 \0.001 \0.001 \0.001

0.89 (0.88–0.90) 0.78 (0.76–0.80) 0.89 (0.86–0.91) 0.85 (0.81–0.90) 0.90 (0.87–0.94) 0.99 (0.97–1.01) 1 (reference)

\0.001 \0.001 \0.001 \0.001 \0.001 0.349

13,368 5177 2277 687 1590 5914

15,150 6180 2528 800 1728 6442

0.87 0.83 0.89 0.85 0.91 0.91

(0.85–0.89) (0.79–0.86) (0.84–0.94) (0.76–0.94) (0.76–0.94) (0.88–0.95)

\0.001 \0.001 \0.001 \0.001 \0.001 \0.001

Antiplatelet nonuser

ADP inhibitor use Anyc Currentd Recente 1–7 days 8–30 days Pastf

b

Crude

P value

Adjusteda

Case (n = 186,374)

1 (reference)

P value

1 (reference)

0.92 0.86 0.94 0.90 0.96 0.97

(0.90–0.94) \0.001 (0.83–0.90) \0.001 (0.89–1.00) 0.040 (0.81–0.99) 0.039 (0.90–1.03) 0.264 (0.94–1.01) 0.167

a

Adjusted for hypertension, dyslipidemia, heart failure, myocar- e Prescription termination date of 1–30 days before the index date f dial infarction, and cerebrovascular disease Prescription termination date of 31–365 days before the index b During the year prior to the index date date c g Use of one prescription at any time before the index date ADP inhibitor include clopidogrel and ticlopidine d Prescription termination date (date of dispensation ? day supply) overlaps with the index date

platelet function is recovered 5 days after discontinuing the drug [17]. Thus, recent users of these drugs should also be considered. Our study is the first to confirm that recent users of antiplatelet agents before hospitalization for sepsis also have a potential survival benefit. Compared to patients who are currently receiving antiplatelet agents, those who recently received or discontinued antiplatelet agents had a significant, but lower, survival benefit (aOR 0.88 vs. 0.78). The survival benefit was inversely proportional to the interval between drug discontinuation and sepsis onset, with the disappearance of benefits when drugs were discontinued more than 30 days before sepsis onset. Subgroup analyses showed that the survival benefit lasted longer in aspirin users (8–30 days after discontinuation) than in ADP inhibitor users. There are several potential mechanisms for the beneficial effect of antiplatelet therapy in sepsis patients. Platelet activation may contribute to microvascular thrombosis and lead to organ ischemia and tissue injury. Antiplatelet agents can impede platelet activation and

inhibit the surface expression of adhesion molecules (e.g., the glycoprotein IIb/IIIa receptor), a key step in microvascular thrombus formation [18]. This hypothesis is supported by an animal study published by Winning et al. [19], in which antiplatelet agents abolished endotoxininduced thrombocytopenia and reduced fibrin deposition within the pulmonary microcirculation. However, previous clinical investigations focused on the therapeutic benefit of antithrombotic or anticoagulant agent demonstrated controversial results in sepsis [20]. A randomized clinical trial (the HETRASE study) suggested that unfractionated heparin was not able to demonstrate a survival benefit in terms of the 28-day mortality [21]. Two other randomized controlled trials also revealed no survival benefit of anti-thrombin III therapy [22] and tissue factor pathway inhibitor in adult patients with severe sepsis [23]. The effect of anti-thrombosis was not seen to be the only possible mechanism of the benefit of antiplatelet agent usage in sepsis. Other than inhibition of microcirculation thrombosis, antiplatelet agents also play an important role in the inflammatory response within the

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Fig. 1 Forest plot of the effect of prior antiplatelet use on mortality in patients with sepsis by subgroup

vessel wall via influencing platelet–endothelium interaction. Endothelial damage and platelet activation mediate the adaptive immune response to microorganisms. Platelet activation influences pathogen recognition by TLRs and the release of several different active compounds that affect the innate immune response [6]. Antiplatelet activation therapy can decrease the secretion of inflammatory mediators [24] and attenuate interactions between immune cell subsets [9, 25, 26]. In an animal model of sepsis, a survival benefit was found when animals were

treated with anti-inflammatory agents, including aspirin [27]. However, three randomized studies failed to show a survival benefit of COX inhibitor therapy for patients with clinically defined sepsis [28–30]. Antiplatelet agents still can influence prognosis of sepsis via other mechanisms, for example, endothelial damage [31], platelet adhesion, fibrin deposition [32], regulation of neutrophils infiltration [33], and precipitation of bacteria trapping [34]. Further research is needed to clarify whether the survival benefit of antiplatelet agents in sepsis is mediated via their anti-

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inflammatory effects and/or microcirculatory improvement. The major strengths of our study are the large sample size and nationwide population-based design. The study relied on a comprehensive medical claims database and included all patients diagnosed with sepsis from January 2000 to December 2010. Matching with age, sex, CCI, and the primary site of infection made the results more convincing. However, this study still has several limitations. The first major limitation is the retrospective and observational design. As a result of the non-randomized observation design of the present study, it is not possible to establish the direction or the eventual causality of this correlation. The benefit observed with antiplatelet administration in this study was exclusively limited to a prophylactic administration. Nothing can be inferred about the potential use of antiplatelet agents as a therapy for sepsis. Further prospective randomized controlled studies are needed to confirm our results. Second, some patient data, such as tobacco use, treatment adherence, premorbid activity level, and laboratory results, were not available in the claims database. Thus, associations between sepsis-related outcomes and laboratory tests (e.g., white blood cell count, C-reactive protein level, pro-calcitonin, and other infection profiles) cannot be extrapolated. Besides, the severity of illness, premorbid activity level, tobacco use, and treatment adherence could not be interpreted by using the administrative database. Third, because of the nature of the administrative database, information about over-the-counter drugs (e.g., aspirin), self-pay prescriptions, or adherence to prescribed medication were not available in our research. Consequently, some antiplatelet users may have been misclassified as nonusers, contributing to an

underestimation of the protective effect of antiplatelet agents in sepsis. Fourth, the case–control design led to the exclusion of 18.9 % of the cases, which may contribute to some bias. Thus, we used a cohort study design as the main analysis to prevent the loss of patient numbers. Finally, the diagnosis of sepsis in our study was derived from administrative claims data. Although the accuracy of the NHIRD in recording sepsis diagnoses had been validated [14, 35], it may not be as accurate as diagnoses using a standardized protocol. No specific or reliable intervention for sepsis has been developed for at least two generations [36]. Finding a cost-effective and safe agent, even if the effect were small or adjuvant, would represent a great advance in treating this deadly and costly condition. We report that prior use of antiplatelet agents, including aspirin and ADP inhibitors, was associated with a significant survival benefit for sepsis patients. The potential survival benefit was present for both current and recent users (drug withdrawal within 30 days before sepsis onset). It may be worthwhile to conduct further randomized control studies to confirm the casual relationship between the use of antiplatelet agents and the survival benefit in sepsis. Acknowledgments This study was based in part on data from the Taiwan National Health Insurance (NHI) Research Database provided by the Bureau of NHI, Department of Health and managed by National Health Research Institutes. The interpretations and conclusions contained herein do not represent those of Bureau of NHI, Department of Health, and National Health Research Institutes. Conflicts of interest We declare that we have no conflicts of interest.

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Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study.

Antiplatelet agents are widely used for cardiovascular disea ses, but their pleiotropic effects in sepsis are controversial...
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