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Table of Contents
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 19  |  Issue : 4  |  Page : 626-637
Effect of antiplatelet therapy on mortality and acute lung injury in critically ill patients: A systematic review and meta-analysis


1 Department of Internal Medicine, John H Stroger, Jr. Hospital of Cook County, Chicago, IL 60612, USA
2 Division of Cardiovascular Diseases, Albert Einstein College of Medicine, Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA
3 Division of Cardiovascular Medicine, Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA
4 Department of Cardiovascular Medicine, St. Lukes University Health Network, Bethlehem, PA 18015, USA
5 Department of Internal Medicine, University of Louisville, Louisville, KY 40292, USA
6 Division of Cardiovascular Diseases, 13400 East Mayo Boulevard, Mayo Clinic, Scottsdale, AZ 85259, USA
7 Department of Anesthesiology, Hospital of the University of Pennsylvania, 6 Dulles, Philadelphia, PA 19104, USA
8 Department of Anesthesiology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ, USA

Click here for correspondence address and email

Date of Submission11-May-2016
Date of Acceptance21-Jul-2016
Date of Web Publication7-Oct-2016
 

   Abstract 


Aim: Platelet function is intricately linked to the pathophysiology of critical Illness, and some studies have shown that antiplatelet therapy (APT) may decrease mortality and incidence of acute respiratory distress syndrome (ARDS) in these patients. Our objective was to understand the efficacy of APT by conducting a meta-analysis. Materials and Methods: We conducted a meta-analysis using PubMed, Central, Embase, The Cochrane Central Register, the ClinicalTrials.gov Website, and Google Scholar. Studies were included if they investigated critically ill patients receiving antiplatelet therapy and mentioned the outcomes being studied (mortality, duration of hospitalization, ARDS, and need for mechanical ventilation). Results: We found that there was a significant reduction in all-cause mortality in patients on APT compared to control (odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.70–0.97). Both the incidence of acute lung injury/ARDS (OR: 0.67; 95% CI: 0.57–0.78) and need for mechanical ventilation (OR: 0.74; 95% CI: 0.60–0.91) were lower in the antiplatelet group. No significant difference in duration of hospitalization was observed between the two groups (standardized mean difference: −0.02; 95% CI: −0.11–0.07). Conclusion: Our meta-analysis suggests that critically ill patients who are on APT have an improved survival, decreased incidence of ARDS, and decreased need for mechanical ventilation.

Keywords: Acute respiratory distress syndrome; Antiplatelet therapy; Critical illness; Meta-analysis; Sepsis

How to cite this article:
Mohananey D, Sethi J, Villablanca PA, Ali MS, Kumar R, Baruah A, Bhatia N, Agrawal S, Hussain Z, Shamoun FE, Augoustides JT, Ramakrishna H. Effect of antiplatelet therapy on mortality and acute lung injury in critically ill patients: A systematic review and meta-analysis. Ann Card Anaesth 2016;19:626-37

How to cite this URL:
Mohananey D, Sethi J, Villablanca PA, Ali MS, Kumar R, Baruah A, Bhatia N, Agrawal S, Hussain Z, Shamoun FE, Augoustides JT, Ramakrishna H. Effect of antiplatelet therapy on mortality and acute lung injury in critically ill patients: A systematic review and meta-analysis. Ann Card Anaesth [serial online] 2016 [cited 2017 Oct 24];19:626-37. Available from: http://www.annals.in/text.asp?2016/19/4/626/191576





   Introduction Top


Despite recent advances in the treatment, the burden of sepsis and septic shock remains high, with an incidence between 11 and 240 per 100,000 population, hospital costs of more than $20 billion annually in the United States, and a mortality as high as 80%.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Among patients admitted to the Intensive Care Unit (ICU), acute respiratory distress syndrome (ARDS) is a leading cause of increased mortality and long-term reduction in quality of life.[16],[17],[18] Despite the great burden of sepsis and ARDS, very few effective strategies are available for treatment.[16],[17],[18],[19]

Platelets are a vital component of normal hemostasis as well as pathological thrombosis. Antiplatelet therapy (APT) works by interfering with one of the several steps of platelet activation including adhesion, release, and/or aggregation.[20] While the benefit of APT is well established for primary and secondary prevention of cardiovascular and cerebrovascular diseases,[21] recent studies have revealed that these agents may also benefit patients with serious infections, sepsis, and those who are admitted to the ICU.[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35]

Platelets play an important role in the inflammatory cascade that results in the development of ARDS.[36],[37],[38] Observational studies suggest that prehospital use of APT may be protective against the development of ARDS. In addition, data also suggests that these agents may be of benefit in patients with existing ARDS.[22]

In light of this data, potential use of APT in reducing length of stay and mortality in these patients carries significant weight and has global health and economic ramifications. Given the possible benefit of antiplatelet agents as described in observational data, we aimed to perform a systematic review of literature and meta-analysis to further study the efficacy of these agents in critically ill patients.


   Materials and Methods Top


Search strategy

A computerized literature search of all publications in the PubMed, Central, Embase, the Cochrane database, ClinicalTrials.gov website, and Google Scholar databases was performed. We also utilized manual searches for article reference lists and conference proceedings. This was last assessed as up-to-date on March 1, 2016.

Search terms included varying combinations of the following: “ICU,” “critical illness,” “sepsis,” “septic shock,” “ARDS,” “pneumonia,” “infection,” “mechanical ventilation,” “antiplatelet drugs,” “aspirin,” “clopidogrel,” “prasugrel,” “ticlopidine,” “cilostazol,” “dipyridamole,” “tirofiban,” eptifibatide,” “abciximab,” “anagrelide,” “ticagrelor,” “vorapaxar,” “atopaxar,” and “Pentoxifylline.”

Inclusion criteria

The PRISMA statement of reporting systematic reviews and meta-analysis was applied to the methods for this study [Supplementary Table 1].[40]



The following inclusion criteria were used:

  • Studies on critically ill patients including: Studies with adult patients admitted to the ICU or postoperative patients or patients admitted to the hospital with serious infections/sepsis/systemic inflammatory response syndrome (SIRS)/septic shock
  • Studies where one or more antiplatelet agents were used: Irreversible COX inhibitor (aspirin); adenosine diphosphate inhibitors (clopidogrel, prasugrel, ticlopidine, and ticagrelor); phosphodiesterase inhibitors (cilostazol, anagrelide, Pentoxifylline); adenosine reuptake inhibitors (dipyridamole); glycoprotein IIb/IIIa inhibitors (tirofiban, eptifibatide, and abciximab); and protease activated receptor-1 antagonist (atopaxar, vorapaxar).


The following exclusion criteria were applied to the search:

  • Studies with nonhuman participants
  • Studies which did not have a direct comparison between antiplatelet users and nonantiplatelet users
  • Studies which did not report one or more of the end-points for this meta-analysis (mortality, ARDS, length of hospital stay, and need for mechanical ventilation)
  • Studies where the drug being studied was not an antiplatelet agent; for example, studies on only nonsteroidal anti-inflammatory drugs (NSAID), antithrombotic agents, and statins. Two reviewers (DM and JS) independently extracted the data from identified studies.


Disagreements were resolved by consensus, or if necessary, by a third party (MA). An attempt was made to obtain data from authors of all ongoing studies which met the search criteria.

Study end-points

The primary outcome of this analysis was all-cause mortality. Secondary outcomes included incidence of acute lung injury (ALI) or ARDS, length of hospital stay, and need for mechanical ventilation. Individual study definitions for ALI, ARDS, and sepsis were used for this meta-analysis [Table 1].
Table 1: Description of included studies

Click here to view


In studies where multiple follow-up periods were available, the longest follow-up was included in the analysis.

Study analysis

Data were summarized across treatment arms using the Mantel-Haenszel odds ratio (OR) or standardized mean difference (SMD). We evaluated heterogeneity of effects using the Higgins' I2 statistic. Fixed effects model was used except in cases where heterogeneity was significant (defined as I2 >40%). In these cases, random effects models were used.[42]

To address publication bias, we used four methods: Funnel plots,[43] Begg and Mazumdar test,[44] Egger test,[45] and Duval and Tweedie's test.[46] Sensitivity analyses were performed using the one-study out method, addressing the influence of each study by testing whether deleting each individually would significantly change the pooled results of the meta-analysis on the final effect and its precision. We also carried out a sensitivity analysis by comparing studies on aspirin with studies where patients were on APT other than aspirin, either alone or in combination with aspirin. Finally, chronological cumulative analyses were used to test if the effect size and precision shifts based on technical advancement in critical care medicine. The statistical analysis was performed by the Comprehensive Meta-Analysis version 2.0 software (Biostat, Inc., New Jersey, USA).

Individual study quality appraisal

Two authors (DM, JS) independently assessed the risk of bias of included studies using the standardized Newcastle-Ottawa scale.[47] This validated instrument for appraising observational studies measures the risk of bias in eight categories: Representativeness of the exposed cohort (S1); selection of the nonexposed cohort (S2); ascertainment of exposure (S3); demonstration that the outcome of interest was not present at the start of the study (S4); comparability (C1 and C2); assessment of outcome (E1); was follow-up long enough for outcomes to occur (E2); and adequacy of follow-up of cohorts (E3) [Supplementary Table 2]. Discrepancies were resolved by discussion or adjudication by a third author (MA).




   Results Top


Our search yielded 1862 articles which were narrowed down to 15 individual full-text articles and 1 conference abstract,[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[48] and included three different studies, out of which two were included in our analysis. This process gave us 17 individual studies with a total of 721,763 patients to include in our analysis [Supplementary Figure 1].[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[48]



All the studies reported event rate, except for 3[22],[23],[31] that reported the overall effect using confidence interval (CI) overall effect rather than event rate. This effect was incorporated in the analysis. Among the 17 studies, 16 used aspirin,[22],[23],[24],[25],[26],[28],[29],[30],[31],[32],[33],[34],[35],[48] 10 used clopidogrel,[23],[25],[26],[27],[29],[31],[32],[33],[34],[35] 5 used ticlopidine,[25],[28],[29],[32],[33] 2 used dipyridamole,[25],[33] and only 1 used anagrelide, cilostazol, and persantine [Table 1].[25] Most of our studies included patients on prehospitalization APT except the study by Boyle et al.[22] and Al Harbi et al.[48] which included some patients with de novo initiation of APT during hospitalization.

In an effort to stratify or compare patients on APT, 7 studies used the Acute Physiology and Chronic Health Evaluation (APACHE) II score,[22],[24],[25],[26],[29],[34],[48] 2 studies used the APACHE III score,[25],[33] 2 studies used the Sequential Organ Failure Assessment Score [29],[35] while the rest did not use any of these risk scores [Table 1].

All-cause mortality

We found that all-cause mortality was significantly lower in patients on APT (OR: 0.83; 95% CI: 0.70–0.97). There was high heterogeneity in the results; I2 of 71% [Figure 1].
Figure 1: All-cause mortality

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Duration of hospitalization

We also found that while the length of hospital stay was shorter in patients on APT, this effect did not reach statistical significance (SMD, −0.02; 95% CI: −0.11–0.07). There was high heterogeneity in the results; I2 of 68% [Figure 2].
Figure 2: Duration of hospitalization

Click here to view


Incidence of acute lung injury/acute respiratory distress

The incidence of ALI and ARDS was reduced in patients on APT (OR: 0.67; 95% CI: 0.57–0.78) [Figure 3]. There was low heterogeneity in these studies; I2 of 25% [Figure 3].
Figure 3: Incidence of acute lung injury/acute respiratory distress

Click here to view


Need for mechanical ventilation

The need for mechanical ventilation was less in patients on APT (OR: 0.74; 95% CI: 0.60–0.91). There was low heterogeneity in these studies; I2 of 21% [Figure 4].
Figure 4: Need for mechanical ventilation

Click here to view


Sensitivity analysis and cumulative analysis

Sensitivity analysis whereby each study was removed individually did not demonstrate significant difference or change in the overall outcomes, except in the analyses of need for mechanical ventilation. When the study by Valerio-Rojas et al.[33] was removed for the outcome, the effect becomes nonsignificant (OR: 0.83; 95% CI: 0.64–1.08). We also carried out a sensitivity analysis by comparing studies on aspirin with studies where patients were on APT other than aspirin, either alone or in combination with aspirin. Comparison of these two groups showed consistent results across all outcomes. Chronological cumulative analysis for each outcome did not find any significant change in the final effect outcomes [Supplementary Figure 2] and [Supplementary Figure 3].[33]



Publication bias

Funnel plot analysis did not show bias for all outcomes. Similar results were observed after quantifying with others' methods (Begg and Mazumdar, Egger, and Duval and Tweedie's tests)[43],[44],[45],[46] [Supplementary Figure 4] and [Supplementary Figure 5]. The individual study quality appraisal and the risk of bias are summarized in Supplementary [Table 2].




   Discussion Top


Our meta-analysis of 17 observational cohort studies with over 720,000 patients revealed that critically ill patients on APT have improved survival when compared to those who do not receive APT. To the best of our knowledge, this is the largest meta-analysis on this topic. A recent meta-analysis by Wang et al. aimed to summarize similar evidence but includes only 9 studies as compared to the 17 in this meta-analysis.[39] This is partly due to a different search strategy as well as our inclusion of conference abstracts and literature published after their cutoff date of November 2015. In our study, the use of APT was also found to be associated with a reduced incidence of ALI/ARDS. Sensitivity analysis revealed that this beneficial effect is not limited to aspirin but rather is consistent across the different antiplatelet drugs used in the included studies. Of note, while bleeding risk or need for transfusion was not assessed using meta-analysis techniques given the small number of studies, an increased risk of these outcomes was not seen in studies that did report these results.[24],[33],[34] In fact, a large single-center study reported a decreased risk of bleeding [24] while another study reported a decreased need for transfusion in patients on APT.[33]

Previously performed animal studies have shown results similar to our meta-analysis. A study on the effects of clopidogrel on experimentally-induced endotoxemia in mice revealed a trend toward improved survival beyond 48 h.[35] A study of clopidogrel in polymicrobial sepsis in mice reported decreased thrombocytopenia and end-organ damage.[50] Blockade of the glycoprotein IIb/IIIa receptor has shown to decrease mortality in rabbits with  Escherichia More Details coli endotoxin-induced shock.[51] Another study investigating E. coli sepsis in baboon models revealed decreased incidence of microangiopathic hemolysis and renal insufficiency.[52]

Platelet function is intricately linked to the pathophysiology of sepsis and its complications. Sepsis decreases the hemostatic function of platelets while the capabilities of platelets for molecular expression and cytokine production remain unimpaired and growth factor production is upregulated.[53] The antimicrobial peptides produced by platelets (known as defensins) are bactericidal and essential to the host immune response; however, the resultant inflammatory response may contribute significantly to the microvascular dysfunction characteristic of sepsis.[54] In addition, during sepsis, there is an increase in phagocytic neutrophil-platelet complexes. These complexes, while aiding in pathogen elimination, also lead to an overwhelming inflammatory response that damages the host. In fact, a study focusing on platelet function in patients with sepsis revealed that while platelet-leukocyte adhesion increased in sepsis, there was a decrease in circulating platelet-neutrophil complexes in patients who died and also in those who had multi-organ dysfunction.[55] This suggests that there may be peripheral sequestration of these complexes in sepsis, which, in turn, may lead to end-organ damage. Platelet activation also results in hypercoagulation and disseminated intravascular coagulation.[56]

ARDS is a devastating complication in critically ill patients. The pathophysiology of ARDS is characterized by damage to the alveolar-capillary barrier resulting in increased vascular permeability and influx of protein-rich fluid into interstitial and alveolar membranes.[57] Platelet activation plays a critical role in this process. Bronchoalveolar lavage fluid from patients with ARDS has excessive quantities of platelet-specific alpha granules, thereby demonstrating the increased platelet activity in these patients.[58] Activation of platelets leads to adhesion of platelets to the endothelium and release of inflammatory and thrombotic agents along with leukocyte recruitment, edema, and production of neutrophil extracellular traps (NET).[59] In ARDS, a high concentration of proinflammatory factors in the alveoli can lead to overproduction of NET, which causes direct-tissue injury. They also further activate platelets to promote fibrin deposition and perpetuate the ongoing inflammatory cascade.[60],[61] Our meta-analysis demonstrates a decreased incidence of ALI/ARDS in patients on antiplatelet medications. This is in line with animal studies done previously. Treatment with aspirin reduced transfusion-associated lung injury in mice.[37] Another study revealed that in rabbit lungs with ALI, blockade of thromboxane A2 (a mediator inhibited by aspirin) eliminated pulmonary hypertension and improved oxygenation.[62]

There are currently several randomized controlled trials in progress that aim to evaluate the role of APT in sepsis and ARDS. One phase II study aims to randomly assign patients with sepsis/septic shock to aspirin use versus placebo. The primary outcome for this study is a reduction of organ dysfunction. Another study aims to study the effect of aspirin in reducing the severity of ARDS as determined by the oxygenation index. In a similar phase II study, researchers are studying the efficacy of aspirin in preventing ARDS in patients who are at increased risk for ALI.[63],[64],[65]

Limitations

There are several limitations to our meta-analysis. First, all the included studies were observational (reflecting the paucity of randomized trials on this topic) and, therefore, prone to bias. Second, this is a meta-analysis performed on study-level data. Third, the definitions and reporting of adverse outcomes and risk of enrolled patients differed across studies. Fourth, most of our studies included patients with prehospital antiplatelet use and as such inferences cannot be extended to new initiation of APT in patients admitted with critical illness. Furthermore, one of the included studies had coexisting NSAID use in both the aspirin group and the control,[24] which could possibly have influenced the effect on mortality and duration of hospitalization. Previous data are controversial on the use of NSAIDs in sepsis and we cannot be sure of how the inclusion of this study would change the effect size.[66] Another limitation of our analysis is that the new definition of sepsis (2016) and ARDS (2012) could not be taken into account as it would lead to the removal of a large number of studies still using the older definitions.[41],[49],[67] These limitations may explain some of the heterogeneity seen in this meta-analysis for various outcomes. On the other hand, despite these limitations, the consistency of the magnitude, direction of the overall effect, and stability of the results after the sensitivity analyses, in conjunction with the large number of patients studied (the largest patient population studied to-date for a meta-analysis on this topic), support the strength of the conclusions.


   Conclusion Top


Our meta-analysis shows that critically ill patients receiving APT have a moderately improved survival, decreased incidence of ARDS, and decreased need for mechanical ventilation. These data need to be validated by large randomized controlled trials, which are lacking in this area.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Harish Ramakrishna
Department of Anesthesiology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9784.191576

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