Clinical Advances in Hematology & Oncology

April 2019 - Volume 17, Issue 4

Antiplatelet Agents for Preventing Vaso-occlusive Events in People With Sickle Cell Disease: A Systematic Review

Arturo Martí-Carvajal, MD, PhD, Mohamed A. Abd El Aziz, MBBCh, Cristina Martí-Amarista, MD, and Ivan Solà

Dr Martí-Carvajal is a professor of internal medicine, hematology, and public health at the University of Carabobo in Valencia, Venezuela. Dr Abd El Aziz is an obstetrics and gynecology resident at Benha University Hospitals in Benha, Egypt. Dr Cristina Martí-Amarista is a family medicine resident at Southside Hospital in Bay Shore, New York. Mr Solà is a researcher at the Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP) at the Universitat Autònoma de Barcelona in Barcelona, Spain.

Corresponding author: 
Arturo Martí-Carvajal, MD, PhD
Department of Public Health
Universidad de Carabobo
Campus Bárbula
Valencia 2006, Venezuela


Abstract: Background: Sickle cell disease (SCD) is the most common hemoglobinopathy, occurring worldwide, and vaso-occlusive events (VOEs) are its paramount, hallmark clinical manifestation. Evidence exists that platelets play an important role in generating VOEs. Objective: To assess the clinical benefits and harms of antiplatelet agents for preventing VOEs in patients with SCD. Methods: We conducted searches of the Cochrane Central Register of Controlled Trials (CENTRAL; up to 2018, issue 3 of 12), PubMed/MEDLINE (up to April 20, 2018), and the Excerpta Medica database (EMBASE; from 1980 to week 16 of 2018). We also searched the Latin American and Caribbean Health Sciences Literature (LILACS) database, the US Food and Drug Administration (FDA) website, the European Medicines Agency (EMA) website, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and We checked the bibliographies of included studies and any relevant systematic reviews. Our systematic review included randomized clinical trials (RCTs) conducted in people who had SCD without VOEs at trial entry. Eligible trials compared a single or combination treatment regimen (with each treatment classified as a conventional or nonconventional antiplatelet agent) with conventional care, placebo, or another regimen. No restrictions were placed on the route of administration, dose, frequency, or duration of treatment.

We selected RCTs, assessed the risk for bias, and extracted data in a duplicate and independent fashion. We estimated risk ratios for dichotomous outcomes and mean differences for continuous outcomes. We also subjected our analyses to a random-effects model, and Trial Sequential Analysis (TSA) was used. We used the grading of recommendations, assessment, development, and evaluation (GRADE) approach to assess the overall quality of data for each individual outcome. Results: We identified 5 RCTs (N=747) that met our criteria. Of these, 4 trials were multicenter and multinational. The trials included patients of all ages and assessed prasugrel, ticagrelor, crizanlizumab, and aspirin vs either placebo or no intervention. The most frequent route of administration was oral. The trials were small and carried a high risk for bias, given that pharmaceutical companies sponsored 4 of them. None of the trials reported information on quality of life. No meta-analysis was performed owing to heterogeneity in the ages of the participants and in the interventions. No single trial showed evidence of certainty regarding all-cause mortality. One trial showed uncertainty in comparing prasugrel vs placebo for preventing VOEs in patients younger than 18 years (relative risk [RR], 0.92; 95% CI, 0.80 to 1.06; low quality of evidence). TSA for this outcome suggested that a new trial should be conducted. One trial found a difference in the size effect of uncomplicated VOEs, favoring high-dose crizanlizumab vs placebo (mean difference, –1.50; 95% CI, –2.61 to –0.39; very low quality of evidence). No difference in VOEs was found in studies that compared either ticagrelor in children or prasugrel in adults vs placebo. The overall incidence of harms in any intervention did not differ from that in the control. Conclusions: The current evidence does not support or reject the use of any antiplatelet agent for preventing VOEs in people with SCD. This conclusion was based on small RCTs that carried a high risk for bias. No conclusive evidence exists regarding relevant clinical outcomes because the evidence is limited and of very low quality. 


Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide.1,2 The sickle hemoglobin is abnormal owing to a point mutation in the β-globin gene that results in the substitution of glutamic acid by valine at position 6 of the β-globin polypeptide chain.3 According to the World Health Organization (WHO), SCD is a major public health problem. An estimated 70% of patients with SCD live in Africa,2 and it is common among people of sub-Saharan African, Indian, Middle Eastern, or Mediterranean ancestry.4,5 SCD includes homozygous hemoglobin S (HbSS), hemoglobin S combined with hemoglobin C (HbSC), hemoglobin S associated with β-thalassemia (sickle β0-Thal and sickle β+-Thal), and other, less prevalent doubly heterozygous conditions that cause clinical disease.4,5 Sickle cell trait is generally asymptomatic and is not part of this review. 

SCD is associated with morbidity and early mortality globally.6 The paramount and hallmark clinical manifestation of SCD is the occurrence of painful crises—that is, vaso-occlusive events (VOEs)7 caused by microvascular obstruction.8 VOEs may also include stroke,9 acute chest syndrome,10 priapism,11 and acute splenic sequestration.12 The pathogenesis of VOEs is very complex.13 It is explained by severe vasculopathy14 that leads to a poor tolerance of any increase in blood viscosity or reduction in microcirculatory oxygenation.13 The vasculopathy in SCD implies endothelial damage15 that has an inflammatory component16 and a chronic hypercoagulable component.17 SCD is considered a thromboinflammatory disease,18 given that platelets are the bridge that links inflammation to coagulation in SCD.19

Platelets are blood cells that play a major role in blood clot formation, inflammation, and cross-talk between other blood cells and endothelium.20 Evidence exists of an effect of platelet hyperactivity in SCD on endothelium.21,22 Either alone or in combination with other blood cells, platelets play a role in the development of VOEs.23-26 Given that platelets play a pivotal role as mediators of inflammatory response, the use of antiplatelet agents for preventing VOEs in people with SCD appears to be logical.

Antiplatelet agents can be classified as conventional or nonconventional. The conventional antiplatelet agents are thromboxane inhibitors; platelet P2Y12 receptor inhibitors; agents that influence cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and adenosine metabolism; and glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists. 

The thromboxane inhibitors are aspirin, dazoxiben, sulotroban, and picotamide27; the platelet P2Y12 receptor inhibitors are thienopyridines (eg, ticlopidine, clopidogrel, and prasugrel) and nonthienopyridines (ticagrelor [Brilinta, AstraZeneca], cangrelor [Kengreal, Chiesi USA], and elinogrel)28-31; the agents that influence cAMP, cGMP, and adenosine metabolism are dipyridamole and cilostazol32; and the GPIIb/IIIa antagonists are abciximab (Reopro, Lilly), eptifibatide, and tirofiban (Aggrastat, Medicure Pharma).33,34 The nonconventional antiplatelet agents are those that modulate the inflammatory actions of platelets or otherwise modify the disease, such as crizanlizumab.35 

The role of antiplatelet agents in preventing VOEs is important for several reasons. First, VOEs are the hallmark sign of SCD.8,36 Second, VOEs reduce the quality of life of patients with this disease.37,38 Third, VOEs generally lead to hospitalization,39 have an unpredictable course, and can be fatal.7,39 Fourth, the only drug proven to be effective for preventing VOEs is hydroxyurea, which is not available widely and carries a risk for adverse events.6 Therefore, the clinical benefits and harms of antiplatelet agents for preventing VOEs in people with SCD must be assessed. 


Types of Studies 

The studies included in this review were parallel-design randomized controlled trials (RCTs).

Types of Participants

The study participants were people of all ages with SCD who did not have VOEs at trial entry. We included participants with a history of VOEs.

Types of Interventions

Eligible trials compared single or combination treatment regimens (each treatment was classified as a conventional or nonconventional antiplatelet agent) with conventional care, placebo, or another regimen for preventing VOEs in people with SCD. The compared interventions included conventional and nonconventional antiplatelet agents (see above). We had no restriction regarding route of administration, dose, frequency, or duration.

Types of Outcomes

The primary outcomes were the following: 

1. All-cause mortality during the trial;

2. Any VOE (eg, pain, stroke, acute chest syndrome, priapism, mesenteric vaso-occlusion, and any other VOE reported by trial authors) occurring at any time during the trial;

3. Adverse events (primarily any hemorrhage). We followed the recommendations outlined by Lineberry and colleagues.40

The secondary outcomes were quality of life (according to any validated scale, such as the Pediatric Quality of Life Inventory [PedsQL], the Sickle Cell Disease Quality of Life Inventory [SCD QoL], or the 36-Item Short Form Health Survey [SF-36]); number of days of hospitalization; and number of days of consumption of any type of analgesic. 

Collection and Review of Data

We followed the Cochrane Collaboration reviewed methods for collection and analysis of summary data.41 The protocol for this review was registered in the International Prospective Register of Systematic Reviews, also known as PROSPERO (CRD42018103524).

No limitations were set regarding publication status, country, duration of follow-up, or language. The search terms included the following: sickle cell, hemoglobinopathies, antiplatelet agents, vaso-occlusive, and prevention. We conducted searches of the Cochrane Central Register of Controlled Trials (CENTRAL; up to 2018, issue 3 of 12), PubMed/MEDLINE (up to April 20, 2018), and the Excerpta Medica database (EMBASE; from 1980 to week 16 of 2018; see Supplemental Material No. 1, “Search Strategies,” at We also searched the Latin American and Caribbean Health Sciences Literature (LILACS) database, the US Food and Drug Administration (FDA) website, the European Medicines Agency (EMA) website, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and We also checked the bibliographies of included studies and any relevant systematic reviews (see Supplemental Material No. 1).

All studies were examined independently by 2 reviewers according to the inclusion criteria. One of the review authors checked for discrepancies, which were resolved by consensus. One review author entered the data into Review Manager 5.3.42 A second author independently checked the data. Using a predesigned data extraction form, 2 reviewers independently extracted the data from the trial publications. The relevant data extracted from the included trials were study details (dates when research was conducted, geographic location, participant inclusion criteria, funding sources, publication date); participant characteristics (age, sex); SCD genotype; intervention details (type, duration, route of administration); outcome details (type of outcome, outcome assessment method); and bias assessment details (data necessary to assess the risk for bias, as described below).

Risk for Bias Assessment

We assessed the following risk for bias domains for each trial: allocation sequence generation, allocation concealment blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, for-profit bias, other bias.43-47

Overall, we judged trials as having a low risk for bias if we determined that they had a low risk for bias in either allocation sequence generation or allocation concealment.48,49 In all other cases, we judged the trials as being at high risk for bias.

Measures of Treatment Effect

For binary outcomes, such as any VOE, adverse events, and all-cause mortality, we calculated the relative risk (RR) with 95% CIs and Trial Sequential Analysis (TSA)–adjusted CI (see below).

For continuous outcomes, such as quality of life, number of days of hospitalization, number of days of consumption of any type of analgesic, and number of VOEs, we calculated the mean difference with 95% CIs. 

The unit of analysis was the participant. We used an intention-to-treat analysis. Owing to the lack of a meta-analysis and the small sample size of the trials, we were not able to conduct a sensitivity analysis as we had planned.50


Had we pooled the data for a meta-analysis, it would have been conducted as detailed in PROSPERO.51 We were unable to conduct the meta-analysis, however (see below), which in turn prevented us from conducting a full TSA.52 We did, however, conduct a TSA for 1 trial29 because it was a phase 3 trial that reported dichotomized data. To minimize random errors, we calculated the required information size (ie, the number of participants needed in a meta-analysis to detect or reject a certain plausible intervention effect).53 The planned diversity-adjusted required information size was going to be based on the event proportion in the control group, assumption of a plausible RR reduction of 10% or the RR reduction observed in the included trials with low risk for bias, a 5% risk for a type 1 error, a 20% risk for a type 2 error, and the empiric diversity of the meta-analysis.53 We used software from the Copenhagen Trial Unit to conduct the TSA.54,55 We used the grading of recommendations, assessment, development, and evaluation (GRADE) system to assess the quality of the body of evidence associated with the following outcomes: all-cause mortality, any VOE, adverse events (total adverse events and study treatment–related adverse events), and quality of life.56 We used GRADEPro software ( to construct summary of findings tables. 

Threshold for Clinical Relevance

To estimate the threshold for clinical relevance, we used a Bayes factor,57 which is a likelihood ratio that shows the relative strength of evidence for 2 theories.58,59 A Bayes factor provides a continuous measure of evidence for an experimental hypothesis (H1) over a null hypothesis (H0). When the Bayes factor is 1, the evidence does not favor either model over the other. As the Bayes factor increases above 1 (toward infinity), the evidence favors H1 over H0. As the Bayes factor decreases below 1 (toward 0), the evidence favors H0 over H1.58 We used a Dienes calculator to determine the Bayes factor.


Our search strategies found 5 trials (15 references) involving 747 randomly assigned participants who met our inclusion criteria29,60-63 (Figure 1) according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).64

The included trials were conducted between 1981 and 2017. Of the 5 trials, 4 studies were conducted multinationally,29 60,62 and the remaining study was conducted in Nigeria.61 One trial was phase 3,29 three were phase 2,60,62,63 and one did not report the phase.61 Two trials reported mainly pharmacokinetics60 and physiologic outcomes.61 One trial included only children,60 one included children and adolescents,29 two included only adults,62,63 and one included adolescents and adults.61

Two trials assessed oral prasugrel,29,63 one assessed ticagrelor,60 one assessed aspirin,61 and one assessed crizanlizumab.62 Four trials used placebo as the comparator,29,60,62,63 and one used proguanil and folic acid as the control.61 The FDA has not authorized the use of these drugs in people with SCD (see Supplemental Material No. 2 at

We excluded 5 studies because they were case reports,65 controlled clinical trials,66 or systematic reviews,67 or because they had a crossover design.68,69 We detected 1 ongoing trial, HESTIA-2 (A Study to Assess the Effect of Ticagrelor in Reducing the Number of Days With Pain in Patients With Sickle Cell Disease), which is a randomized, double-blind, double-dummy, parallel-group, placebo-controlled study assessing 2 doses of ticagrelor (10 or 45 mg) in 90 patients with SCD, whose ages range from 18 to 30 years.70 Recruitment has been completed. The primary outcome is change in the proportion of days with pain due to SCD; secondary outcomes are the average of the daily worst pain and change in the proportion of days with analgesic use. This trial will report safety data, such as number of major bleeding events or clinically relevant non-major bleeding events.

We detected 11 multiple publications, which were associated with 3 included trials and 1 excluded trial: the DOVE trial (A Study of Prasugrel in Pediatric Participants With Sickle Cell Disease; N=3),29 the SUSTAIN trial (Study to Assess Safety and Impact of SelG1 With or Without Hydroxyurea Therapy in Sickle Cell Disease Patients With Pain Crises; N=4),62 a trial by Wun and colleagues (N=3),63 and a trial by Chaplin and colleagues (N=1).65 We were unable to find the full text of 1 reference.71

Risk for Bias in Included Studies

Of the 5 trials, 3 (60%) were rated as having a low risk for selection bias because of their use of an appropriate random sequence generation method.29,60,62 None of the trials reported any information regarding allocation concealment, however, and thus were rated as having an unclear risk for selection bias from this perspective. Of the 5 trials, 2 (40%) showed a low risk for performance bias and detection bias,29,60 2 (40%) had a low risk for detection bias,29,62 3 (60%) had a low risk for attrition bias,29,60,63 and 4 (80%) had a low risk for reporting bias because relevant clinical outcomes were reported.29,60,62,63 Drug companies sponsored 4 trials.29,60,62,63 Thus, they were rated as having a high risk for funding bias. 

Effects of Interventions 

Data on the effects of interventions are based on 4 RCTs that included 647 participants.29,60,62,63 The trials reported no information about quality of life or number of days of consumption of any type of analgesic agents. One trial assessing aspirin plus proguanil and folic acid vs no intervention reported only physiologic endpoints.61

1. Primary Outcomes

(A) All-Cause Mortality

Prasugrel vs placebo:  A study in children and adolescents29 showed uncertainty regarding all-cause mortality with prasugrel vs placebo (1/170 [0.59%] vs 2/170 [1.2%]; RR, 0.50; 95% CI, 0.05 to 5.46; low quality of evidence owing to imprecision). The Bayes factor was 1.11. A TSA simulation with a proportion of 18% for all-cause mortality in the control group,71 an RR reduction of 20%, an alpha of 5%, a beta of 20%, and diversity of 30% suggested an RCT including 3654 participants for assessing the size effect of prasugrel vs placebo on all-cause mortality in participants with SCD. Another trial63 that included 62 adults reported no information on all-cause mortality.

Ticagrelor vs placebo:  One trial with 25 children reported no difference in all-cause mortality with ticagrelor vs placebo.60

Crizanlizumab vs placebo:  One trial62 showed evidence of uncertainty regarding the rate of all-cause mortality with crizanlizumab vs placebo (3/130 [2.3%] vs 2/62 [3.2%]; RR, 0.72; 95% CI, 0.12 to 4.17; very low quality of evidence owing to imprecision). The Bayes factor was 1.01. 

(B) Uncomplicated Vaso-occlusive Events

Prasugrel vs placebo:  The DOVE trial29 found no difference between prasugrel vs placebo in uncomplicated VOEs (113/171 [66.1%] vs 122/170 [71.8%]; RR, 0.92; 95% CI, 0.80 to 1.06; low quality of evidence owing to imprecision). The Bayes factor was 1.03. The TSA for uncomplicated VOEs suggested that a new RCT be conducted (Figure 2).

In adults,63 one trial of prasugrel vs placebo showed a very low quality of evidence owing to a risk for bias and imprecision (9/40 [22.5%] vs 7/19 [36.8%]; RR, 0.61; 95% CI, 0.27 to 1.39). The Bayes factor was 1.58. The TSA for this outcome suggested a new trial with 1279 adults according to the following alpha-spending boundaries: proportion in the control group of 36.9%, RR reduction of 20%, alpha of 5%, and beta of 20% (Figure not shown).

Ticagrelor vs placebo: The HESTIA-1 trial (A Pharmacokinetic and Pharmacodynamic Dose-ranging Phase II Study of Ticagrelor in Paediatric Patients With Sickle Cell Disease) showed uncertainty regarding the difference between ticagrelor and placebo in uncomplicated VOEs (mean difference, 0.40; 95% CI, –0.73 to 1.53; very low quality of evidence owing to imprecision).60

Crizanlizumab vs placebo  The SUSTAIN trial62 reported a difference between high-dose crizanlizumab and placebo in uncomplicated VOEs (mean difference, –1.50; 95% CI, –2.61 to –0.39; very low quality of evidence owing to execution or imprecision). The Bayes factor for uncomplicated VOEs was 1.07.

(C) Adverse Events

Prasugrel vs placebo:  The DOVE trial29 found no differences between prasugrel and placebo in serious hemorrhagic events (34/170 [19.4%] vs 33/170 [20%]; RR, 1.03; 95% CI, 0.67 to 1.58), serious nonhemorrhagic events (87/170 [51.17%] vs 96/170 [56.47%]; RR, 0.91; 95% CI, 0.74 to 1.10), and hemorrhagic events requiring medical intervention (11/170 [6.47%] vs 8/170 [4.7%]; RR, 1.38; 95% CI, 0.57 to 3.33). The quality of evidence was low owing to imprecision.

Regarding treatment-emergent hemorrhage, Wun and colleagues63 reported evidence of uncertainty (8/41 [19.5%] vs 1/19 [5.3%]; RR, 3.71; 95% CI, 0.50 to 27.57). The quality of evidence was very low owing to a risk for bias and imprecision.

Ticagrelor vs placebo:  Evidence existed of uncertainty regarding differences in serious adverse events (1/16 [25%] vs 1/7 [14.3%]; RR, 1.75; 95% CI, 0.24 to 12.97) and nonserious adverse events (12/16 [75%] vs 5/7 [71.42%]; RR, 1.05; 95% CI, 0.61 to 1.82) in patients taking ticagrelor vs those taking placebo.60 The quality of evidence was very low owing to imprecision. 

Crizanlizumab vs placebo:  The SUSTAIN trial,62 which included participants exposed to either crizanlizumab or placebo, showed uncertainty regarding the number of patients with at least one serious adverse event (38/130 [29.2%] vs 17/62 [27.4%]; RR, 1.07; 95% CI, 0.66 to 1.73) or the number of patients with at least one adverse event (113/130 [86.92%] vs 55/62 [88.7%]; RR, 0.98; 95% CI, 0.88 to 1.09). The quality of evidence was very low owing to imprecision.

2. Secondary Outcomes

(A) Complicated Vaso-occlusive Events

Prasugrel vs placebo:  The DOVE trial,29 which compared prasugrel with placebo, found evidence of uncertainty regarding differences in acute chest syndrome (15/171 [8.8%] vs 15/170 [8.8%]; RR, 0.99; 95% CI, 0.50 to 1.97; low quality of evidence owing to imprecision). Wun and colleagues63 reported no information about this outcome.

Ticagrelor vs placebo:  The HESTIA-1 trial,60 in a comparison of ticagrelor with placebo, reported evidence of uncertainty for differences in complicated VOEs (mean difference, 0.10; 95% CI, –0.22 to 0.42; very low quality of evidence owing to imprecision).

Crizanlizumab vs placebo:  The SUSTAIN trial62 reported no acute chest syndrome events in either group.

(B) Vaso-occlusive Event–Induced Hospitalization

Prasugrel vs placebo:  The DOVE trial29 reported no difference between prasugrel and placebo in the size effect for hospitalization owing to VOEs (69/171 [40.4%] vs 76/170 [44.7%]; RR, 0.90; 95% CI, 0.70 to 1.161; very low quality of evidence owing to imprecision). Wun and colleagues63 reported no information about this outcome.

Ticagrelor vs placebo:  The HESTIA-1 trial reported no information about VOE-induced hospitalization.60

Crizanlizumab vs placebo:  The SUSTAIN trial found no difference between high-dose crizanlizumab and placebo in the size effect for hospitalization owing to VOEs (mean difference, –1.75; 95% CI, –8.74 to 5.25; N=137; very low quality of evidence owing to imprecision).62


This systematic review of antiplatelet agents used to prevent VOEs in patients with SCD included 5 small RCTs (N=747). One trial included only adults; another trial included children, adolescents, and adults. These trials evaluated prasugrel,29,63 ticagrelor,60 aspirin,61 and crizanlizumab,62 comparing them with either placebo or no intervention. Crizanlizumab was administered intravenously. Overall, the trials were assessed as having a high risk for bias. Drug companies sponsored 4 of the 5 trials.29,60,62,63 The trials were conducted between 1981 and 2017, and 4 of the 5 trials were multicenter and multinational.29,60,62,63 One trial included none of the pre-specified outcomes of this systematic review.61

We were not able to conduct a meta-analysis for any intervention because of heterogeneity in the study populations, choice of study medication, and methods of assessing outcomes.

Trials assessing either prasugrel29 or crizanlizumab62 found no differences in all-cause mortality. Other trials reported either no deaths60 or no information regarding mortality.63 Only one trial reported a difference between crizanlizumab and placebo regarding uncomplicated VOEs.62 With respect to serious or nonserious adverse events or complicated VOEs, all trials showed no difference between study medications and control. In 2 trials that compared either prasugrel29 or high-dose crizanlizumab62 with placebo, no difference in the annual rate of days hospitalized was reported. No trial assessed, reported, or measured quality of life or number of days of consumption of any type of analgesic. The estimates of effect size were considered as very low owing to limitations in the trials related to either execution or imprecision (see Supplemental Material No. 3 at

The analyses and conclusions are based on 4 multicenter and multinational small RCTs rated as having a high risk for bias owing to flaws in design or execution.29,60,62,63 Thus, the overall completeness and applicability of the evidence could be considered low owing to potentially spurious findings. We identified heterogeneity in the sources of information, which consisted of a meeting abstract of a pharmacokinetic trial,60 two phase 2 trials,62,63 and one phase 3 trial.29 These trials differed in objectives, follow-up periods, or sample sizes. All of these factors have a negative effect on the results, either quantitatively or qualitatively (see below). One trial62 reported a difference between crizanlizumab and placebo in terms of uncomplicated VOEs, whereas another RCT reported neutral results (ie, no difference in effect size). Neutral effects should be considered not only “absence of evidence” but also “evidence of absence.”72 One trial29 was stopped when an interim analysis suggested that clinical benefit outcomes were not being reached.73,74 According to TSA, the prevention of VOEs in the DOVE trial29 should be considered a false-negative result (Figure 2). Likewise, we cannot rule out that other results are false negatives,29,60,63 nor can we rule out that the reduction in uncomplicated VOEs in the SUSTAIN trial62 is a false positive, owing to the smallness of the sample size and the low number of events.

Drug companies sponsored 4 trials,29,60,62,63 and the potential for bias related to drug company sponsorship has been described.75 However, these RCTs reported information related to relevant clinical outcomes, including harms, across studies. Nonetheless, the smallness of the sample sizes and the low number of adverse events prevented reliable conclusions from being drawn.

For all outcomes, the quality of evidence was rated as low or very low, which leads to a very low degree of confidence in the estimates of effect. The true effects of these interventions on all outcomes are likely to be substantially different. This finding is explained by the high risk for bias found in all trials across several bias domains (eg, uncertainty in randomness, unclear risk of performance and detection biases, and attrition bias). In addition, we downgraded the quality of evidence for all reported outcomes on the basis of the smallness of the sample sizes in all trials, which yields statistical imprecision and wide CIs. This imprecision may be the consequence of a low or very low number of events.75 Furthermore, evidence exists suggesting that RCTs conducted with small sample sizes are prone to selection bias.76,77 On the basis of an analysis of the quality of evidence, the results of the trials should be interpreted as overestimating effect or underestimating harm.78 

Because no meta-analysis was conducted, no statistical method could be used to detect publication bias. We believe that this systematic review has a low risk for publication bias, however, for the following reasons: our cautious search strategies (see Supplemental Material No. 1), our use of recommendations to reduce the chance of bias in elective inclusion and reporting of outcomes and analyses in systematic reviews of randomized trials of health care interventions,44 and the fact that 4 of 5 RCTs had a low risk for selective outcome reporting bias, meaning that the chance of suppression of information was low.79 

This systematic review has several limitations. First, as already discussed, it does not include a meta-analysis. As a result, the overall effect size and CI of any outcome or intervention are unknown. Furthermore, no subgroup analyses or sensitivity analyses were conducted. Second, the smallness of the sample sizes and the low or very low number of events in all the RCTs prevented TSA from being conducted for almost all outcomes. Third, the included RCTs lack methodologic strength. Nevertheless, this systematic review demonstrates the usefulness of evidence synthesis to find the therapeutic evidence available and appraise it critically. Finally, we were not able to obtain the full text of 1 study.71 We hope to obtain this for a future update of our systematic review.

It has been suggested that the treatment effects shown in single-center RCTs are larger than those shown in multicenter RCTs.80,81 Of 5 RCTs, 4 were multicenter and multinational, which represents a valuable finding of this review. This systematic review reported GRADE tables, which are an important tool for interpreting results and drawing conclusions.82 Whenever possible, we conducted TSA to assess the potential need for further trials.54

Recently, Sins and colleagues68 published an elegant systematic review of pharmacotherapeutic strategies in the prevention of acute, painful VOEs in SCD. Like us, they reported in the absence of meta-analysis. These 2 systematic reviews differ in many items. First, Sin and colleagues evaluated any pharmacologic strategies, whereas our review focused only on antiplatelet agents. Second, Sins and colleagues reported on 2 antiplatelet agents—the thromboxane inhibitor aspirin27 and the platelet P2Y12 receptor inhibitor ticlopidine28—in a section titled “Anticoagulation.” Third, unlike Sins and colleagues, we excluded crossover design trials.66-70 We concluded that these exclusions did not affect the results of our review. Both trials66-70 lack an appropriate description of the washout period and have other methodologic flaws. 


This systematic review found no clear difference between antiplatelet agents and either placebo or no intervention in preventing VOEs in patients with SCD. All the evidence was rated as being of either low or very low quality owing to flaws in design and execution, small sample sizes, and a very low number of events. A paucity of reporting was available regarding all-cause mortality, complicated VOEs, hospitalization due to VOEs, and number of days of consumption of any type of analgesic. No information exists regarding quality of life. The harms profile of the antiplatelet agents in patients with SCD remains unknown. Results from an ongoing RCT that is assessing ticagrelor vs placebo will provide new information regarding these questions. In the interim, physicians and health policymakers should be cautious about the use of antiplatelet agents for preventing VOEs in patients with SCD. 

There remains a need for powered RCTs to assess the benefits and harms of antiplatelet agents for preventing VOEs in people with SCD. Such trials should be designed according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)83 and reported according to the Consolidated Standards of Reporting Trials (CONSORT) to improve the quality of reporting on efficacy.84 The trials should follow recommendations regarding the reporting of adverse events.40 Future trials should be planned according to the Patient-Centered Outcomes Research Institute (PCORI) recommendations.85 New trials should include all-cause mortality, uncomplicated and complicated VOEs, and adverse events.


The authors have no financial disclosures.


1. Barnett R. Sickle cell anaemia. Lancet. 2017;389(10073):998. doi:

2. Lettre G, Bauer DE. Fetal haemoglobin in sickle-cell disease: from genetic epidemiology to new therapeutic strategies. Lancet. 2016;387(10037):2554-2564.

3. Hunt JA, Ingram VM. Allelomorphism and the chemical differences of the human haemoglobins A, S and C. Nature. 1958;181(4615):1062-1063.

4. Piel FB, Adamkiewicz TV, Amendah D, Williams TN, Gupta S, Grosse SD. Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium. Genet Med. 2016;18(3):265-274.

5. Piel FB, Williams TN. Subphenotypes of sickle cell disease in Africa. Blood. 2017;130(20):2157-2158.

6. Singh PC, Ballas SK. Emerging drugs for sickle cell anemia. Expert Opin Emerg Drugs. 2015;20(1):47-61.

7. Subramaniam S, Chao JH. Managing acute complications of sickle cell disease in pediatric patients. Pediatr Emerg Med Pract. 2016;13(11):1-28.

8. Savitt TL, Smith WR, Haywood C, Creary MS. Use of the word “Crisis” in sickle cell disease: the language of sickle cell. J Natl Med Assoc. 2014;106(1):23-30.

9. Menaa F. Stroke in sickle cell anemia patients: a need for multidisciplinary approaches. Atherosclerosis. 2013;229(2):496-503.

10. Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbade M, Davis B; BCSH Committee. Guideline on the management of acute chest syndrome in sickle cell disease. Br J Haematol. 2015;169(4):492-505.

11. Anele UA, Burnett AL. Erectile dysfunction after sickle cell disease-associated recurrent ischemic priapism: profile and risk factors. J Sex Med. 2015;12(3):713-719.

12. Brousse V, Buffet P, Rees D. The spleen and sickle cell disease: the sick(led) spleen. Br J Haematol. 2014;166(2):165-176.

13. Connes P, Alexy T, Detterich J, Romana M, Hardy-Dessources MD, Ballas SK. The role of blood rheology in sickle cell disease. Blood Rev. 2016;30(2):111-118.

14. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med. 2013;64:451-466.

15. Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program. 2008;1:177-185.

16. Owusu-Ansah A, Ihunnah CA, Walker AL, Ofori-Acquah SF. Inflammatory targets of therapy in sickle cell disease. Transl Res. 2016;167(1):281-297.

17. Whelihan MF, Lim MY, Mooberry MJ, et al. Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost. 2016;14(10):1941-1952.

18. Vercellotti GM, Belcher JD. Not simply misshapen red cells: multimolecular and cellular events in sickle vaso-occlusion. J Clin Invest. 2014;124(4):1462-1465.

19. Pakbaz Z, Wun T. Role of the hemostatic system on sickle cell disease pathophysiology and potential therapeutics. Hematol Oncol Clin North Am. 2014;28(2):355-374.

20. Linden MD. Platelet physiology. Methods Mol Biol. 2013;992:13-30.

21. Frelinger AL III, Jakubowski JA, Brooks JK, et al. Platelet activation and inhibition in sickle cell disease (pains) study. Platelets. 2014;25(1):27-35.

22. Proença-Ferreira R, Brugnerotto AF, Garrido VT, et al. Endothelial activation by platelets from sickle cell anemia patients. PLoS One. 2014;9(2):e89012.

23. Anea CB, Lyon M, Lee IA, et al. Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease. Am J Hematol. 2016;91(2):173-178.

24. Bennewitz MF, Jimenez MA, Vats R, et al. Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli. JCI Insight. 2017;2(1):e89761.

25. Opene M, Kurantsin-Mills J, Husain S, Ibe BO. Sickle erythrocytes and platelets augment lung leukotriene synthesis with downregulation of anti-inflammatory proteins: relevance in the pathology of the acute chest syndrome. Pulm Circ. 2014;4(3):482-495.

26. Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127(7):801-809.

27. Patrono C, Rocca B. Aspirin and other COX-1 inhibitors. Handb Exp Pharmacol. 2012;(210):137-164.

28. Bernlochner I, Sibbing D. Thienopyridines and other ADP-receptor antagonists. Handb Exp Pharmacol. 2012;(210):165-198.

29. Heeney MM, Hoppe CC, Abboud MR, et al; DOVE Investigators. A multinational trial of prasugrel for sickle cell vaso-occlusive event. N Engl J Med. 2016;374(7):625-635.

30. Kaul U, Mansoor AH. Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor-a long continuing journey. Indian Heart J. 2012;64(1):54-59.

31. Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev. 2007;25(4):357-374.

32. Rondina MT, Weyrich AS. Targeting phosphodiesterases in anti-platelet therapy. Handb Exp Pharmacol. 2012;(210):225-238.

33. Hook KM, Bennett JS. Glycoprotein IIb/IIIa antagonists. Handb Exp Pharmacol. 2012;(210):199-223.

34. Muñiz-Lozano A, Rollini F, Franchi F, Angiolillo DJ. Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice. Ther Adv Cardiovasc Dis. 2013;7(4):197-213.

35. Amison R, Page C, Pitchford S. Pharmacological modulation of the inflammatory actions of platelets. Handb Exp Pharmacol. 2012;(210):447-468.

36. Chiang EY, Frenette PS. Sickle cell vaso-occlusion. Hematol Oncol Clin North Am. 2005;19(5):771-784.

37. Lin RJ, Evans AT, Wakeman K, Unterbrink M. A mixed-methods study of pain-related quality of life in sickle cell vaso-occlusive crises. Hemoglobin. 2015;39(5):305-309.

38. Brandow AM, Brousseau DC, Pajewski NM, Panepinto JA. Vaso-occlusive painful events in sickle cell disease: impact on child well-being. Pediatr Blood Cancer. 2010;54(1):92-97.

39. Cecchini J, Fartoukh M. Sickle cell disease in the ICU. Curr Opin Crit Care. 2015;21(6):569-575.

40. Lineberry N, Berlin JA, Mansi B, et al. Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective. BMJ. 2016;355:i5078.

41. Higgins JPT, Green S, eds. The Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Updated March 2011. Accessed April 3, 2017.

42. Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

43. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2017;2:MR000033. doi:10.1002/14651858.MR000033.pub3. 

44. Page MJ, McKenzie JE, Kirkham J, et al. Bias due to selective inclusion and reporting of outcomes and analyses in systematic reviews of randomised trials of healthcare interventions. Cochrane Database Syst Rev. 2014;(10):MR000035. doi:10.1002/14651858.MR000035.pub2. 

45. Page MJ, Higgins JP, Clayton G, et al. Empirical evidence of study design biases in randomized trials: systematic review of meta-epidemiological studies. PLoS One. 2016;11(7):e0159267. 

46. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008;336(7644):601-605.

47. Odgaard-Jensen J, Vist GE, Timmer A, et al. Randomisation to protect against selection bias in healthcare trials. Cochrane Database Syst Rev. 2011;(4):MR000012. doi:10.1002/14651858.MR000012.pub3 

48. Pildal J, Hróbjartsson A, Jørgensen KJ, Hilden J, Altman DG, Gøtzsche PC. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol. 2007;36(4):847-857.

49. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999;319(7211):670-674.

50. Gamble C, Hollis S. Uncertainty method improved on best-worst case analysis in a binary meta-analysis. J Clin Epidemiol. 2005;58(6):579-588.

51. PROSPERO: International Prospective Register of Systematic Reviews. Accessed September 26, 2018.

52. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61(8):763-769.

53. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17(1):39.

54. Thorlund K, Imberger G, Walsh M, et al. The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis—a simulation study. PLoS One. 2011;6(10):e25491.

55. Copenhagen Trial Unit. TSA – Trial Sequential Analysis. Accessed September 26, 2018.

56. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-406.

57. Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120.

58. Dienes Z. Using Bayes to get the most out of non-significant results. Front Psychol. 2014;5:781.

59. Dienes Z, Coulton S, Heather N. Using Bayes factors to evaluate evidence for no effect: examples from the SIPS project. Addiction. 2018;113(2):240-246.

60. Hsu LL, Sarnaik S, Williams S, Amilon C, Wissmar J, Berggren A; HESTIA1 Investigators. A dose-ranging study of ticagrelor in children aged 3-17 years with sickle cell disease: a 2-part phase 2 study. Am J Hematol. 2018;93(12):1493-1500. doi:10.1002/ajh.25273. 

61. Osamo NO, Photiades DP, Famodu AA. Therapeutic effect of aspirin in sickle cell anaemia. Acta Haematol. 1981;66(2):102-107.

62. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439.

63. Wun T, Soulieres D, Frelinger AL, et al. A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease. J Hematol Oncol. 2013;6:17.

64. PRISMA: Transparent Reporting of Systematic Reviews and Meta-Analyses. Accessed October 1, 2018.

65. Chaplin H Jr, Alkjaersig N, Fletcher AP, Michael JM, Joist JH. Aspirin-dipyridamole prophylaxis of sickle cell disease pain crises. Thromb Haemost. 1980;43(3):218-221.

66. Greenberg J, Ohene-Frempong K, Halus J, Way C, Schwartz E. Trial of low doses of aspirin as prophylaxis in sickle cell disease. J Pediatr. 1983;102(5):781-784.

67. Semple MJ, Al-Hasani SF, Kioy P, Savidge GF. A double-blind trial of ticlopidine in sickle cell disease. Thromb Haemost. 1984;51(3):303-306.

68. Sins JWR, Mager DJ, Davis SCAT, Biemond BJ, Fijnvandraat K. Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: a systematic review. Blood Adv. 2017;1(19):1598-1616.

69. Zago MA, Costa FF, Ismael SJ, Tone LG, Bottura C. Treatment of sickle cell diseases with aspirin. Acta Haematol. 1984;72(1):61-64.

70. A study to assess the effect of ticagrelor in reducing the number of days with pain in patients with sickle cell disease (Hestia2) Identifier: NCT02482298. Accessed September 26, 2018.

71. Cabannes R, Lonsdorfer J, Castaigne JP, Ondo A, Plassard A, Zohoun I. Clinical and biological double-blind-study of ticlopidine in preventive treatment of sickle-cell disease crises. Agents Actions Suppl. 1984;15:199-212.

72. Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ. 1995;311(7003):485.

73. Identifier: NCT01794000. Accessed September 10, 2018.

74. European Medicines Agency. Assessment report for paediatric studies submitted according to Article 46 of the Regulation (EC) No 1901/2006. 2016. Accessed September 6, 2018.

75. Falk Delgado A, Falk Delgado A. The association of funding source on effect size in randomized controlled trials: 2013-2015 – a cross-sectional survey and meta-analysis. Trials. 2017;18(1):125.

76. Martí-Carvajal AJ. Chapter 2: Proper randomization reduces the chance of waste biomedical research. In: Berger VW, ed. Randomization, Masking, and Allocation Concealment. London, United Kingdom: Taylor & Francis Ltd; 2017.

77. Nguyen TL, Collins GS, Lamy A, et al. Simple randomization did not protect against bias in smaller trials. J Clin Epidemiol. 2017;84:105-113.

78. Szucs D, Ioannidis JP. Empirical assessment of published effect sizes and power in the recent cognitive neuroscience and psychology literature. PLoS Biol. 2017;15(3):e2000797.

79. Ioannidis JP. Meta-research: the art of getting it wrong. Res Synth Methods. 2010;1(3-4):169-184.

80. Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study. Ann Intern Med. 2011;155(1):39-51.

81. Unverzagt S, Prondzinsky R, Peinemann F. Single-center trials tend to provide larger treatment effects than multicenter trials: a systematic review. J Clin Epidemiol. 2013;66(11):1271-1280.

82. Schünemann HJ, Oxman AD, Vist GE, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration. Updated March 2011. Accessed April 3, 2017.

83. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207.

84. Turner L, Shamseer L, Altman DG, et al. Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of randomised controlled trials (RCTs) published in medical journals. Cochrane Database Syst Rev. 2012;11(11):MR000030. doi:10.1002/14651858.MR000030.pub2.

85. Fleurence R, Whicher D, Dunham K, Gerson J, Newhouse R, Luce B. The patient-centered outcomes research institute’s role in advancing methods for patient-centered outcomes research. Med Care. 2015;53(1):2-8.