
==== Front
Res Pract Thromb Haemost
Res Pract Thromb Haemost
Research and Practice in Thrombosis and Haemostasis
2475-0379
Elsevier

S2475-0379(24)00221-8
10.1016/j.rpth.2024.102526
102526
Original Article
The association of antiplatelet agents with mortality among patients with non–COVID-19 community-acquired pneumonia: a systematic review and meta-analysis
Lother Sylvain A. Sylvain.Lother@umanitoba.ca
@sylvainlother
12∗
Tennenhouse Lana 3
Rabbani Rasheda 4
Abou-Setta Ahmed M. @Dr_AbouSetta
45
Askin Nicole 6
Turgeon Alexis F. @AlexisTurgeon_
78
Murthy Srinivas @srinmurthy99
9
Houston Brett L. 1011
Houston Donald S. 1011
Mendelson Asher A. @AsherMendelson
2
Paul Jonathan D. @Jonathan_PaulMD
12
Farkouh Michael E. @drmikefarkouh
13
Hasmatali Jovan 2
Rush Barret @barretrushMD
2
Nkosi Joel 3
Goligher Ewan C. @ecgoligher
14
Rimmer Emily 1011
Marshall John C. @DrJohnCMarshall
15
Shaw Souradet Y. @SouradetS
5
Lawler Patrick R. 1617
Keynan Yoav @YoavKeynan
1518
Zarychanski Ryan @RZarychanski
21011
1 Section of Infectious Diseases, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
2 Section of Critical Care, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
3 Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
4 George & Fay Yee Centre for Healthcare Innovation, Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
5 Department of Community Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
6 Neil John Maclean Health Sciences Library, University of Manitoba, Winnipeg, Manitoba, Canada
7 Department of Anesthesiology and Critical Care, Université Laval, Quebec City, Quebec, Canada
8 Population Health and Optimal Health Practices Research Unit, Departments of Traumatology, Emergency Medicine, and Critical Care Medicine, Université Laval Research Center, Centre Hospitalier Universitaire de Quebec-Université Laval, Quebec City, Quebec, Canada
9 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
10 Department of Medical Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada
11 Section of Hematology and Medical Oncology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
12 Section of Cardiology, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois, USA
13 Department of Cardiology, Cedars-Sinai Health System, Los Angeles, California, USA
14 Interdepartmental Division of Critical Care Medicine, and the Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada
15 Departments of Surgery and Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
16 Divison of Cardiology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
17 Department of Medicine, McGill University Health Centre and McGill University, Montreal, Quebec, Canada
18 Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
∗ Correspondence Sylvain A. Lother, University of Manitoba, Health Sciences Center, GC 436, 820 Sherbrook St, Winnipeg, MB R3A1R9, Canada. Sylvain.Lother@umanitoba.ca@sylvainlother
22 7 2024
7 2024
22 7 2024
8 5 10252619 4 2024
16 7 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Community-acquired pneumonia (CAP) triggers inflammatory and thrombotic host responses driving morbidity and mortality. Antiplatelet agents may favorably modulate these pathways; however, their role in non–COVID-19 CAP remains uncertain.

Objectives

To evaluate the association of antiplatelet agents with mortality in hospitalized patients with non–COVID-19 CAP.

Methods

We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) of adult patients hospitalized for non–COVID-19 CAP exposed to antiplatelet agents (acetylsalicylic acid or P2Y12 inhibitors). We searched MEDLINE, Embase, and CENTRAL from inception to August 2023. Our primary outcome was all-cause mortality: meta-analyzed (random-effects models) separately for observational studies and RCTs. For observational studies, we used adjusted mortality estimates.

Results

We included 13 observational studies (123,012 patients; 6 reported adjusted mortality estimates) and 2 RCTs (225 patients; both high risk of bias). In observational studies reporting hazard ratio, antiplatelet agents were associated with lower mortality (hazard ratio, 0.65; 95% CI, 0.46-0.91; I2 = 85%; 4 studies, 91,430 patients). In studies reporting adjusted odds ratio, antiplatelet agent exposure was associated with reduced odds of mortality (odds ratio, 0.67; 95% CI, 0.45-1.00; I2 = 0%; 2 studies, 24,889 patients). Among RCTs, there was a nonsignificant association with mortality (risk ratio, 0.66; 95% CI, 0.20-2.25; I2 = 54%; 2 studies, 225 patients). By the Grading of Recommendations, Assessment, Development, and Evaluation criteria, the certainty of the evidence was low, primarily due to risk of bias.

Conclusion

In hospitalized patients with non–COVID-19 CAP, antiplatelet agents may be associated with reduced mortality compared with usual care or placebo, but the certainty of evidence is low.

Essentials

• Pneumonia is a lung infection that increases inflammation and clotting.

• We analyzed studies of antiplatelet drugs in hospitalized patients with non-COVID pneumonia.

• Antiplatelet agents may be associated with reduced mortality in patients with pneumonia.

• Included studies were at high risk of bias, and the certainty of the findings was low.

Keywords

aspirin
clopidogrel
infection
mortality
pneumonia
==== Body
pmc1 Introduction

Community-acquired pneumonia (CAP) is a leading cause of hospitalization and mortality globally [[1], [2], [3]]. Inflammatory and thrombotic host responses contribute to end-organ dysfunction through micro- and macro-vascular thrombosis [4,5]. Cardiovascular events complicate CAP in up to a third of hospitalizations [[6], [7], [8]], and vascular thrombosis occurs in up to 11% of patients [6,9,10].

Antiplatelet agents including acetylsalicylic acid (ASA) and P2Y12 inhibitors such as clopidogrel, prasugrel, and ticagrelor are widely accessible medications that have pleiotropic effects, including antithrombotic and antiinflammatory activities [[11], [12], [13]]. These mechanisms may blunt maladaptive host responses to infection [14].

ASA demonstrated no clinical benefits in trials of hospitalized patients with COVID-19 pneumonia at short durations of follow-up (<30 days) [[15], [16], [17]], although there was a suggestion of a mortality benefit at longer follow-up duration (180 days) [14]. In non–COVID-19 CAP, a small randomized controlled trial (RCT) showed reduced acute coronary syndromes and cardiovascular deaths in patients treated with ASA after hospitalization for CAP [18]. Several other retrospective and prospective cohort studies have suggested a potential benefit for antiplatelet agent exposure; however, because of disease and study heterogeneity, their overall effect on hospitalized patients with CAP remains uncertain [[19], [20], [21]].

This systematic review and meta-analysis evaluated the association of antiplatelet agents with mortality, the need for organ support, and cardiovascular events in patients hospitalized with non–COVID-19 CAP.

2 Methods

Using an a priori published protocol [22], we conducted a systematic review using methodological approaches outlined in the Cochrane Handbook for Systematic Reviewers [23]. Our review was reported following the Preferred Reporting items for Systematic Reviews and Meta-Analyses (PRISMA) [24]. The review question and methods were informed by experts in various specialties of medicine, knowledge synthesis, and research methodology. Screening, full-text review, data extraction, and quality assessment/risk of bias evaluation were performed in duplicate by independent reviewers (S.A.L., L.T.) who were blinded to each other’s assessments. The roles of each team member are summarized in Author Contributions. The protocol was registered with Open Science Framework on January 30, 2024 (https://doi.org/10.17605/OSF.IO/H2G7C).

2.1 Populations, interventions, comparators, and outcome measures

We included studies of hospitalized adults admitted for non–COVID-19 CAP that compared patients who did and did not receive an antiplatelet agent; we excluded studies of hospital-acquired pneumonia or ventilator-associated pneumonia. Study designs included observational studies (retrospective and/or prospective) and RCTs; we excluded quasi-randomized trials and case–control studies. Antiplatelet exposure was defined as receipt of ASA or a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) at any dose or frequency after study enrollment. Studies that included patients with antiplatelet exposure prior to study enrollment were included, regardless of the indication. Complete inclusion and exclusion criteria are listed in the Supplementary Table.

Our primary outcome was all-cause mortality at longest follow-up. The primary safety outcome was author-defined major bleeding. Secondary outcomes measured at longest follow-up were intensive care unit admission, hospital length of stay, use of invasive mechanical ventilation (IMV), cardiovascular organ support, organ support (composite including use of high flow nasal oxygen, noninvasive positive pressure ventilation, IMV, vasopressors, inotropes, or extracorporeal life support), and the incidence of arterial thrombosis or incidence of venous thromboembolism.

2.2 Search strategy and identification of studies

Our search strategy (Supplementary Methods) was peer-reviewed using the Peer Review of Electronic Search Strategies (PRESS) checklist [25]. Using the Offshore Vessel Inspection Database (OVID) platform, we systematically searched MEDLINE (including Epub ahead of print and in-process, in-data-review, and other non-indexed citations), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to August 2023; we also searched clinical trial registries (clinicaltrials.gov, World Health Organization International Clinical Trials Registry Platform). We applied a modified version of the SIGN RCT and observational study filters [26]. Reference lists of relevant reviews and included studies were searched for additional citations. Reference management was performed in EndNote (Version 20.5, Thomson Reuters).

2.3 Study selection, data extraction, and risk of bias assessment

We screened citations applying eligibility criteria and recorded decisions using the Rayyan platform [27]. Data were extracted from included studies using standardized forms in Microsoft Excel for Mac (version 16.69). From each study, we extracted study characteristics, intervention characteristics (including the type of antiplatelet agent, total daily dose, and the proportion exposed to the antiplatelet agent before enrollment), duration of participant follow-up, and outcome data. We assessed the internal validity of included RCTs using the Cochrane Risk of Bias (RoB) tool (version 2) [28]. For observational studies, study quality was assessed using the Newcastle-Ottawa Scale [29]. Information regarding RoB was used to guide sensitivity analyses and explore heterogeneity.

2.4 Data analysis

Meta-analyses were conducted using random effect inverse variance models. In the meta-analysis of the primary outcome, study-level adjusted mortality estimates from observational studies were pooled and presented separately as adjusted hazard ratio (HR) and adjusted odds ratio (OR) with 95% CIs. Unadjusted study-level summary effect comparisons from RCTs were presented as risk ratios (RRs) with 95% CI. Unadjusted summary effect estimates for secondary outcomes were expressed as RR with 95% CI for dichotomous data. Statistical heterogeneity was quantified using the I2 statistic [30]. All analyses were conducted using the general meta and metafor package in RStudio version 2023.09.1+494, R version, 4.3.2 (R Project for Statistical computing) [31]. We used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework to evaluate the strength of the evidence [32].

2.5 Subgroup analyses

Subgroup and sensitivity analyses were planned a priori for the primary mortality outcome. We performed subgroup analyses based on methodological factors (risk of bias), clinical factors (etiology of CAP and illness severity), intervention factors (type and dose of antiplatelet, prehospital exposure to antiplatelet, and duration of antiplatelet intervention), and duration of study follow-up.

3 Results

3.1 Trial characteristics and included study populations

Of the 7696 citations identified, we included 15 unique studies: 13 observational studies (n = 123,012) [19,[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44]] and 2 RCTs (n = 225) [18,45] (Figure 1) [24,46]. Of the observational studies, 5 (38%) were prospective [34,35,37,38,41], 8 (62%) retrospective [19,33,36,39,40,[42], [43], [44]] and most (85%) were published in peer-reviewed journals (2 were abstracts from conference proceedings) [33,42]. Sample sizes ranged in observational studies between 224 and 88,315 patients, and sample sizes in the 2 RCTs were 27 and 198 patients [18,45]. All studies were non–industry-funded and published between 2008 and 2023. Studies were performed in Europe (53%) [34,35,37,39,41,[43], [44], [45]], North America (13%) [19,40], Oceania (7%) [33], Asia (7%) [36], or intercontinental (20%) [18,38,42], and most studies were multicenter (60%) [18,19,36,38,39,[41], [42], [43],45].Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses study flow diagram [24,46]. RCT, randomized controlled trial.

The study-level mean age was 70.1 (mean age within each study ranged from 59.9-76.7) years and the average proportion of females was 42% (Table 1) [18,19,[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]]. At baseline, the proportion of participants reported to have chronic respiratory diseases, cardiovascular diseases, and coronary artery disease was 28%, 26%, and 17%, respectively. Three observational studies reported inclusion of patients with immunocompromising conditions [37,38,43], representing 4% of included patients. One observational study included only patients with confirmed bacterial CAP [43], whereas all other studies did not report pathogen type. Three observational studies [36,38,40] and one RCT [45] included patients only with severe pneumonia.Table 1 Characteristics of individual trials, patient populations, and exposures.

Study	Design	No. of patients APT/control	Mean or median age (y)	% Female	% CAD	% CVD	% Severe CAPa	Type of APT (%)	Longest follow-up (d)b	
Bui and Rao [33], (2022)	Retrospective (conference proceeding)	117/336	72	52	22	NR	NR	Any APT (100)
- Type NR	30	
Cangemi et al. [34], (2014)	Prospective	123/155	70	38	36	NR	NR	ASA (100)	NR	
Chalmers et al. [35], (2008)	Prospective	311/696	66	50	NR	20	NR	ASA (100)	30	
Cilli et al. [36], (2018)	Retrospective	111/262	68	42	NR	NR	100	Any APT (100)
- ASA (74)
- Alternative (26)	NR	
Falcone et al. [37], (2015)	Prospective	390/615	75	41	NR	31	NR	ASA (100)	30	
Falcone et al. [38], (2019)	Prospective	383/910	77	38	NR	26	100	ASA (100)	30	
Gamst et al. [39], (2014)	Retrospective (administrative data)	18,195/70,120	73	47	9	NR	7	ASA (100)	365	
Gross et al. [19], (2013)	Retrospective (administrative data)	2908/20,974	NR	NR	NR	NR	NR	Clopidogrel (100)	NR	
Lu et al. [40], (2023)	Retrospective (administrative data)	182/580	NR	NR	NR	NR	100	ASA (100)	60	
Pieralli et al. [41], (2021)	Prospective	455/811	76	49	17	NR	NR	Any APT (100)
- Type NR	30	
Peyrani et al. [42], (2016)	Retrospective (abstract)	639/2698	NR	NR	NR	NR	NR	Any APT (100)
- Type NR	30	
Rögnvaldsson et al. [43], (2022)	Retrospective	128/687	67	48	17	NR	20	ASA (100)	365	
Winning et al. [44], (2009)	Retrospective	44/180	60	31	NR	NR	NR	Any APT (100)
- ASA (86)
- Clopidogrel (7)
- Other (7)	28	
Oz et al. [18], (2013)	RCT	91/94	67	34	0	NR	NR	ASA (100)	30	
Toner et al. [45], (2022)	RCT	14/13	NR	NR	NR	NR	100	ASA (100)	90	
APT, antiplatelet; ASA, acetylsalicylic acid; CAD, coronary artery disease; CAP, community-acquired pneumonia; CVD, cardiovascular disease; NR, not reported; RCT, randomized controlled trial.

a Severe CAP was defined as a requirement for intensive care unit admission for CAP.

b Longest follow-up for the primary outcome of mortality.

Of the 13 included observational studies, 7 (54%) were adjudicated to be of high quality [19,35,[37], [38], [39], [40],43], 3 (23%) were intermediate [34,36,41], and 3 (23%) were of low quality [33,42,44]. Only 6 (46%) reported an adjusted effect estimate of the primary outcome to account for possible confounders [19,35,[37], [38], [39],43]. Both included RCTs were determined to be at high risk of bias due to reporting unclear processes of randomization, allocation concealment, or lacking prespecified analysis plans [18,45].

3.2 Exposures

Observational studies evaluated the effect of ASA (54%) [34,35,[37], [38], [39],40,43], clopidogrel (8%) [19], or any antiplatelet (38%) [33,36,41,42,44]. In studies that included any antiplatelet agent, most of the exposure was to ASA (Table 1). Dosing of ASA was reported in 4 studies and was predominantly low dose (≤100 mg/d) [34,37,38,44]. All observational studies included patients with continued exposure to an antiplatelet agent that started before hospitalization. The comparator group in all studies received usual care (no antiplatelet agent), apart from one observational study which included a 2 × 2 comparison of exposure to ASA plus macrolide, ASA alone, macrolide alone, or usual care [38]. The largest RCT (n = 198) randomized patients to ASA 300 mg/d vs open-label usual care for up to 30 days [18], and the second RCT (n = 27) randomized patients to ASA 75 mg/d vs placebo for up to 14 days [45].

3.3 Primary outcomes

Adjusted all-cause mortality summary effect estimates from observational studies were meta-analyzed by HRs (Figure 2) or adjusted ORs (Figure 3). Results from RCTs were pooled separately (Figure 4). Meta-analysis of observational studies reporting HR demonstrated an association between reduced risk of death and exposure to antiplatelet agents compared with usual care (HR, 0.65; 95% CI, 0.46-0.91; I2 = 85%; 4 studies, 91,430 patients). In studies reporting adjusted OR, antiplatelet agent exposure was associated with reduced odds of dying over the study period (OR, 0.67; 95% CI, 0.45-1.00; I2 = 0%; 2 studies, 24,889 patients). Using GRADE framework, the certainty of the evidence was low due to risk of bias in observational study designs, inconsistent effect estimates with heterogeneity in the pooled effect, and potential for publication bias (Table 2). In the 2 included RCTs (n = 225 patients), the RR of all-cause mortality in patients randomized to receive ASA compared with usual care or placebo was 0.66 (95% CI, 0.20-2.25; I2 = 54%). The certainty of the evidence was low, as both RCTs were at high risk of bias and due to imprecision in the effect estimates (Table 2).Figure 2 Association of antiplatelet agents with mortality for observational studies reporting adjusted hazard ratios. Hazard Ratio IV, Random, 95% CI, Hazard Ratio, Inverse Variance Random Effect Model, 95% Confidence Interval; logHR, logarithm of each study Hazard Ratio; SE, standard error; Weight, weight (in %) indicates the influence an individual study has on the pooled effect estimate.

Figure 3 Association of antiplatelet agents with mortality for observational studies reporting adjusted odds ratios. logOR, logarithm of each study Odds Ratio; Odds Ratio IV, Random, 95% CI, Odds Ratio, Inverse Variance Random Effect Model, 95% Confidence Interval; SE, standard error; Weight, weight (in %) indicates the influence an individual study has on the pooled effect estimate.

Figure 4 Association of antiplatelet agents with mortality for randomized controlled trials reporting relative risk. Weight, weight (in %) indicates the influence an individual study has on the pooled effect estimate; Risk Ratio MH, Random, 95% CI, Risk Ratio, Mantel-Haenszel Random Effect Model, 95% Confidence Interval.

Table 2 Results from meta-analyses including summary effect measures, number of participants, and certainty of evidence.

Outcome	Relative effect adjusted hazard ratio (95% CI)	Relative effect adjusted odds ratio (95% CI)	Relative effect unadjusted relative risk (95% CI)	No. of participants (studies)	Certainty of evidence (GRADE)	
Observational studies	
 Adjusted mortalitya	0.65 (0.46-0.91)			91,430 (4 studies)	Low	
		0.67 (0.45-1.00)		24,889 (2 studies)	Low	
 Intensive care unit admission			0.91 (0.79-1.03)	25,854 (4 studies)	Very low	
 Use of invasive mechanical ventilation			0.96 (0.59-1.56)	25,177 (2 studies)	Very low	
 Use of any organ support			1.54 (0.78-3.03)	2755 (3 studies)	Very low	
 Myocardial infarction			6.69 (0.16-271.55)	1997 (3 studies)	Very low	
RCTs	
 Mortalitya			0.66 (0.20-2.25)	212 (2 RCTs)	Low	
 Myocardial infarction			0.10 (0.01-0.79)	185 (1 RCT)	Very low	
 Bleeding			No events	185 (1 RCT)	Very low	
GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; RCT, randomized controlled trial.

a Primary outcome and primary analysis.

Subgroup analyses for the mortality outcome reported in observational studies were conducted according to follow-up duration, illness severity, study size, study quality and risk of bias, type of antiplatelet, study method for CAP diagnosis (clinical definition vs administrative data set), and study source population (CAP study vs CAP population derived from a larger sample). These were not associated with significant differences in treatment effect and did not reduce statistical heterogeneity (Supplementary Figures S1–S7). In the context of substantial between-study heterogeneity, sensitivity analyses were performed based on study differences that did not reduce heterogeneity. Funnel plot analysis was not performed due to the limited number of included studies. There were insufficient data available to conduct subgroup analyses according to dose, duration, or prehospital exposure to the antiplatelet agent.

3.4 Secondary outcomes

As reported in a single RCT, ASA was not associated with an increased risk of bleeding, with no bleeding events reported in either the treatment or control group (n = 185) (Table 2) [18]. Antiplatelet agents were not associated with changes in intensive care unit admission, use of IMV or organ support, or the incidence of myocardial infarction (author-defined) (Table 2). One RCT reported a significant reduction in myocardial infarction in those randomized to aspirin compared with usual care (RR, 0.10; 95% CI, 0.01-0.79; 1 RCT, 185 patients) [18]; however, the unadjusted pooled analysis from observational studies demonstrated no benefit (RR, 6.69; 95% CI, 0.16-271.55; n = 1997, 3 studies). Venous thromboembolic events and need for cardiovascular organ support outcomes were not reported from any of the included studies.

4 Discussion

In this systematic review and meta-analysis of studies that included patients hospitalized for non–COVID-19 CAP, we found that exposure to antiplatelet agents was inconsistently associated with reduced mortality compared with usual care or placebo. In observational studies, the exposure to an antiplatelet agent was associated with a 35% lower adjusted hazard of death. However, observational studies were of varying quality and few reported adjusted outcome estimates. Among 2 small included RCTs, randomization to ASA was associated with nonsignificant reduction in the relative risk of mortality compared with usual care or placebo, although inferences were difficult to ascertain due to small sample sizes, low event rates, and considerable risk of bias. The GRADE certainty of evidence was low. We did not identify an increased risk of bleeding; however, this outcome was underreported. Experience with ASA in hospitalized COVID-19 patients would suggest an expected absolute increase in major bleeding events of 0.6% to 0.8% [15,17].

Antiplatelet agents reduce complications associated with thromboinflammatory diseases such as coronary artery disease, stroke, and other thrombo-occlusive cardiovascular conditions [47]. Very limited data suggest that antiplatelet agents may also improve outcomes in acute infection. A meta-analysis of RCTs evaluating the effect of ASA in acute infections demonstrated reduced mortality (RR, 0.44; 95% CI, 0.24-0.81; 4 RCTs, 538 patients) [48] but included only 1 RCT of CAP patients [18]. In response to observations of increased thrombosis in COVID-19 [49], 4 RCTs evaluated antiplatelet agents in hospitalized COVID-19 patients demonstrating mixed results [15,17,50,51]. In the REMAP-CAP Bayesian adaptive platform trial (n = 1546), critically ill patients randomized within the antiplatelet domain had a 95% probability of improved 6-month survival (HR, 0.85; 95% credible interval, 0.71-1.03) [14]. In the RECOVERY trial (n = 14,892), ASA was not associated with a reduction in mortality at 28 days (RR, 0.96; 95% CI, 0.89-1.04) or a difference in the proportion of patients who required ventilation or died (RR, 0.96; 95% CI, 0.90-1.03), but there was a significant reduction in thrombotic events (4.6% vs 5.3%; absolute difference, −0.6%; standard error, 0.4%) [17]. The COVID-PACT (n = 292) and ACTIV-4a (n = 1549) trials did not demonstrate significant benefit with ASA or P2Y12 inhibitors [15,50]. The risk of major bleeding was small but increased among patients randomized to receive antiplatelet agents. In the context of inconsistent results in COVID-19, insufficient quality of evidence in other infections, and important unanswered questions (eg, optimal type, dose, and duration of antiplatelet agents, impact of illness severity), antiplatelet agents are not currently recommended for the treatment of acute infections [52]. Although the mechanisms of action differ, the promise of targeting thrombo-inflammation in CAP may be supported by the observation that therapeutic-dose heparin improves outcomes in large RCTs of noncritically ill patients with COVID-19 [[53], [54], [55], [56], [57], [58]]. None of the included studies reported patients receiving anticoagulants, with or without an antiplatelet agent.

This systematic review builds on the evidence syntheses suggesting the possible benefit of antiplatelet agents in CAP and other infectious syndromes. While we broadly included observational studies of diverse CAP populations and illness severity, we also included studies of bacteremia, sepsis, acute respiratory distress syndrome, and acute lung injury, where the effect of antiplatelet agents was reported in CAP subgroups. The intent was to summarize the potential comprehensive impact of antiplatelet agents in CAP; however, the calculated summary estimates were associated with heterogeneity. Despite subgroup and sensitivity analyses, causes of heterogeneity could not be fully resolved. Since effect summary estimates consistently favored antiplatelet agents, unresolved heterogeneity could reflect uncertainty in the precise magnitude of the effect, rather than presence or absence of efficacy. However, heterogeneity may also reflect biases inherent to observational study designs or publication bias. Given the low certainty of the findings, the true effect might be markedly different from the estimated effect [32].

Due to widespread underreporting of secondary outcomes, the analyses were largely limited to unadjusted event rates from observational studies, with the potential for significant bias or confounding, and thus very low certainty of the findings. As summarized in Table 2, we did not find significant differences in any secondary outcomes associated with the use of antiplatelet agents vs usual care or placebo. The effect of antiplatelet agents on cardiovascular events is one outcome of particular interest. Infection significantly increases the risk of in-hospital and postdischarge myocardial infarction (MI), but evidence regarding therapies to reduce such events is lacking [7]. In the largest of the included RCTs, ASA (300 mg/d) significantly reduced MI compared with usual care (RR, 0.10; 95% CI, 0.01-0.79; n = 185) [18]. The authors used a robust definition of MI, but the sample size and event rates were small, follow-up was short (30 days), and the open-label comparator could have introduced bias. If 2 more events were observed in the experimental arm, the findings would have been nonsignificant (P > .05, fragility index = 2). In contrast, the risk of MI was increased in the unadjusted pooled analysis from observational studies, with wide confidence margins and considerable potential for confounding. More studies are needed to understand the effect of antiplatelet agents on cardiovascular outcomes in patients with CAP.

4.1 Strengths

Our systematic review addresses an important knowledge gap and is the first to systematically summarize the evidence for antiplatelet agents in non–COVID-19 CAP. We utilized a comprehensive search strategy which included electronic databases, conference abstracts, trial registries, and forward searches following recognized methodologic guidelines for the conduct and reporting of systematic reviews, as outlined in our published protocol [22]. Our study outcomes were patient-centered and included the evaluation of safety related to the intervention (major bleeding). The broad inclusion of various CAP populations increases the generalizability of findings to a large population of CAP patients.

4.2 Limitations

The inclusion and substantive weighting of observational studies in systematic reviews of treatment effects confer risks due to imbalances between treatment groups and potential for confounding. Patients exposed to antiplatelet agents may have greater risks of experiencing the outcome with more comorbidities. However, receipt of antiplatelet agents may reflect better access to care, leading to more timely and effective infection treatments. Alternatively, control group patients may have unrecognized cardiovascular disease and may fare worse when not receiving antiplatelet agents. While we prioritized adjusted effect estimates from included observational studies, where available, potential confounding associated with the exposure and the outcome could not be excluded. Additionally, each study controlled for different covariates, and studies reported 2 different statistical methods to estimate measures of effect (HR and OR) which limited our ability to derive a single summary effect measure. Due to the insufficient number of studies reporting data on the type of antiplatelet, dose, and duration of use, meaningful subgroup analyses could not be conducted. The median duration of follow-up among included studies was short (67% of studies reported ≤30-day follow-up). Clinical outcomes measured at longer follow-up intervals could yield significantly different results given the pathobiology of inflammation and thrombosis in CAP where the risk of cardiovascular outcomes is increased for weeks to months postdischarge. It was not possible to assess for publication bias due to the small number of included studies. Finally, CAP and its respiratory sequelae are increasingly recognized to be heterogeneous conditions, with variable activation of inflammation between patients [59]. The study design could not consider such molecular heterogeneity of host response [60], although it may bear consideration in future trials [61].

5 Conclusions

In hospitalized patients with non–COVID-19 CAP, use of antiplatelet agents may be associated with reduced mortality compared with usual care or placebo, but the certainty of evidence is low. High-quality RCTs are required to evaluate the potential clinical efficacy and safety of antiplatelet agents in CAP.

Supplementary material

Supplementary material

Funding

Funding has not been obtained for the completion of this systematic review.

Author contributions

The review was coordinated by a clinician scientist with infectious diseases and critical care training (S.A.L.), including development of the review question, literature search strategy, screening of relevant studies, data extraction and analysis, and preparation of the final manuscript. A second blinded reviewer (L.T.) with internal medicine training screened relevant studies, extracted data, and analyzed risk of biases in duplicate. Experts from a variety of fields provided content expertise, including infectious diseases (Y.K.., S.M.), critical care (P.R.L., A.A.M., B.R., J.H., E.C.G., S.M., J.C.M., A.F.T., R.Z.), hematology and thrombosis (B.L.H., R.Z., E.R., D.S.H.), cardiology (J.D.P., M.E.F., P.R.L.), internal medicine (J.N.), community health and epidemiology (S.Y.S.), and knowledge synthesis methodology (A.M.A.-S., N.A., R.R., Y.K., P.R.L., S.Y.S., S.M., J.C.M., A.F.T., R.Z.). An experienced librarian and medical information specialist with experience in systematic review search methodology (N.A.) developed and tested the search strategies through an iterative process in consultation with the review team. The search strategy was peer-reviewed by a second independent information specialist using the Peer Review of Electronic Search Strategies (PRESS) checklist. A statistician with specific expertise in meta-analysis (R.R.) conducted the analyses in conjunction with the first author (S.A.L.) and in consultation with the review team. A clinician scientist with systematic review expertise in clinical trials and prospective observational studies (A.M.A.-S.) provided methodological advice. Two clinician scientists with expertise in infectious diseases, hematology, and critical care (Y.K., R.Z.) provided project oversight, methodological advice, along with content expertise, and resolution of disagreements among reviewers. All authors have had significant contribution to the above work and have reviewed and approved of this manuscript.

Relationship Disclosure

S.A.L. has funding that is unrelated to this current project from Research Manitoba and the Canadian Institutes of Health Research (CIHR). A.A.M. has funding that is unrelated to this current project from the Health Sciences Centre Foundation, the CIHR, the Canada Foundation for Innovation, and Research Manitoba. M.E.F. has received consulting fees from Otitopic and research grant support from Amgen, Astra Zeneca, Novartis, and Novo Nordisk. E.C.G. receives salary support for research through a grant from the National Sanitarium Association and has funding unrelated to this work from CIHR. He has received personal fees for consulting or advisory board membership from Lungpacer, Stimit, Heecap, Getinge, Drager, Vyaire, Bioage, and Zoll. S.Y.S. has funding that is unrelated to this current project from CIHR and the Canada Research Chair Program. P.R.L. is supported by the Fonds de recherche du Québec (a government research funding body). R.Z. has funding that is unrelated to this work from Research Manitoba and CIHR and receives salary support from the Lyonel G Israels Research Chair in Hematology.

Open practices statement

The authors recognize the value of sharing results in the spirit of collaboration. Details of the methods were pre-registered on Open Science Framework on January 30, 2024, and are publicly available (DOI: https://doi.org/10.17605/OSF.IO/H2G7C). The study materials (search strategies and analysis code) and data extracted can be made available upon request.

Handling Editor: Dr Kristen Sanfilippo

Yoav Keynan and Ryan Zarychanski are co-senior authors.

The online version contains supplementary material available at https://doi.org/10.1016/j.rpth.2024.102526
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