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. Author manuscript; available in PMC: 2014 Jan 1.
Published in final edited form as: Minerva Anestesiol. 2012 Nov 22;79(1):33–43.

An updated meta-analysis to understand the variable efficacy of drotrecogin alfa (activated) in severe sepsis and septic shock

Peggy S Lai 1,✉, Alexis Matteau 2, Adam Iddriss 3, Jennifer CL Hawes 4, V Marco Ranieri 5, B Taylor Thompson 6
PMCID: PMC3725305  NIHMSID: NIHMS496608  PMID: 23174922

Abstract

BACKGROUND

Significant debate continues over the efficacy of drotrecogin alpha activated (DAA) in sepsis. This updated meta-analysis provides an updated summary effect estimate and explores the reasons for outcome heterogeneity in placebo-controlled randomized clinical trials of DAA on 28-day all-cause mortality in patients with severe sepsis or septic shock.

METHODS

Computer searches of MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, published abstracts from major intensive care meetings and examination of reference lists were used to identify five placebo-controlled randomized clinical trials with 7,260 patients. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 28-day incidence of severe bleeding and intracranial hemorrhage.

RESULTS

DAA was not associated with improved 28-day all-cause mortality in patients with severe sepsis or septic shock (pooled relative risk (RR) of 0.97 [95% CI 0.83-1.14]), and is associated with an increase in serious bleeding. The significant heterogeneity in the pooled RR for 28-day mortality (I2 value of 59.4%, χ2 p-value 0.043) is no longer present with exclusion of the post-study amendment portion of PROWESS (I2 value of 0%, χ2 p-value 0.44 without PROWESS post-amendment). Using meta-regression, the best ranked predictor of outcome heterogeneity was baseline mortality in the placebo arm, which was among the highest in PROWESS.

CONCLUSIONS

DAA is not associated with improved survival in patients with severe sepsis or septic shock. Further studies should be done to determine whether changes in supportive therapy for sepsis explain the variable efficacy of DAA in randomized controlled clinical trials observed over time.

Keywords: Severe sepsis, septic shock, Drotrecogin alfa (activated), meta-analysis

INTRODUCTION

Sepsis is a worldwide problem. More than 750,000 cases of sepsis occur annually in the United States[1], and sepsis accounts for a quarter of all admissions to the intensive care unit in Europe[2]. Historically, mortality rates for patients with severe sepsis or septic shock have been as high as 60%[3, 4]. While contemporary treatments for sepsis have improved mortality[5, 6], a substantial number of patients with sepsis still die, indicating the need for novel therapeutic options.

Recombinant human activated protein C (rhAPC) inhibits thrombosis, promotes fibrinolysis, and has anti-inflammatory properties[7, 8]. Drotrecogin alpha activated (DAA), a rhAPC, was approved in 2001 for the treatment of severe sepsis based on the results of the landmark PROWESS trial[9]. Subsequent large randomized controlled trials (RCTs) have failed to replicate the protective benefit of DAA on 28-day mortality [10-12], and in October 2011, Eli Lilly withdrew DAA from the market based on the preliminary results from the follow-up PROWESS-SHOCK trial that showed no mortality benefit at 28 days[13].

There remains significant debate regarding these conflicting findings[14, 15]. A recent meta-analysis performed after the withdrawal of DAA, which included both RCTs and observational studies, suggested that DAA was efficacious in “real life” use[16]. While meta-analyses are commonly used to derive a pooled effect estimate across studies, they also serve as a valuable way to explore reasons for outcome heterogeneity. As DAA is no longer available, the more important clinical question is not whether it is effective but rather why early RCTs were so promising while later RCTs showed no benefit, and why a discrepancy appears to exist in the efficacy of DAA between RCT conditions vs. in observational studies. In this study, our primary aim was to explore reasons for outcome heterogeneity across placebo-controlled randomized clinical trials of DAA vs. placebo on 28-day all-cause mortality in patients with severe sepsis or septic shock. Secondarily, we provide updated summary effect estimates on the efficacy of DAA on the primary endpoint of 28-day all-cause mortality, and on the secondary outcomes of severe bleeding and intracranial hemorrhage.

MATERIALS AND METHODS

Search Strategy and Study Selection

Please see the Online Supplement for a full description of the search strategy. A thorough literature search was conducted to retrieve all randomized control trials (RCTs) testing the efficacy of DAA on patients with severe sepsis or septic shock. The process of selection of publications for inclusion is as described in Figure 1. No restriction for language was applied. Peer-reviewed journal articles and published abstracts were identified from various sources from inception through March 31th, 2012 by two independent investigators (AI, JH).We searched MEDLINE (PubMed) using the following terms: (“Sepsis”[tiab] OR “Shock, Septic”[Mesh] OR “shock”[tiab]) AND (“drotrecogin alfa activated” [Supplementary Concept] OR “activated protein C”[tiab] OR “protein C”[tiab] OR “APC”[tiab] OR “APC alfa”[tiab] OR “rh APC”[tiab]) AND random*. EMBASE was searched using the following terms: (‘drotrecogin’/exp OR ‘activated protein C’/exp) AND (‘sepsis’/exp OR ‘septic shock’/exp) with the filter “randomized controlled trial” applied to obtain only RCTs. Both the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched with the unrestricted term, “drotrecogin”.

Figure 1.

Figure 1

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Flow diagram of literature search and study selection for inclusion in meta-analysis

The reference lists from included articles were hand-searched for additional relevant RCTs. Published abstracts from major intensive care medicine meetings (Critical Care Congress, American Thoracic Society, CHEST and European Society of Intensive Care Medicine) in the last 10 years were also reviewed, using the keyword “drotrecogin.”

Data Extraction

The study information was extracted independently by two authors (AM, PL) from each included study into a standardized data extraction spreadsheet designed and developed prior to the initiation of data extraction (see Online Supplement for full details). Disagreements were reconciled by the opinion of a third investigator (JH).

Assessment of methodological quality

Studies meeting the entry criteria detailed above were examined for quality using the CONSORT criteria[17]. Two investigators (PL, AM) independently assessed study attributes including adequacy of randomization, random allocation concealment, masking of treatment allocation, and completeness of follow-up.

Data Synthesis and Statistical Analysis

Confusion in the interpretation of results may arise from the fact that some RCTs with an active treatment control arm were given standard DAA therapy, which represents the active therapy received in most intervention arms of other RCTs. To avoid this problem, the primary analysis consisted only of RCTs using placebo as the comparator group. Individual study estimates of the treatment effect were assessed using risk ratios of the primary outcome, 28 day all-cause mortality, as well as for secondary outcomes of severe bleeding and intracranial bleeding. Severe bleeding was as defined by investigators of each individual study - a definition for this condition was not provided in all of the primary studies[18] although most defined serious bleeding as any intracranial hemorrhage, life threatening bleeding, or bleeding that required transfusion of 3 units of packed red cells on two consecutive days. For each outcome of interest, pooled risk estimates were calculated using a DerSimonian and Laird random effects model[19].

Heterogeneity in outcome was assessed using both the χ2 test of homogeneity (Cochran Q-statistic) and the I2 statistic. A Galbraith plot [20] was used to identify studies that were statistical outliers.

When significant heterogeneity was identified, sensitivity analyses were performed. A priori we planned to assess the effect of including or excluding the following studies: additional studies with non-placebo control arms, excluding pediatric studies, excluding the PROWESS study from adult-only patient population studies, and subdividing the PROWESS patient population into pre- and post-protocol amendment subgroups.

To explore potential clinical characteristics that may have contributed to outcome heterogeneity on 28-day mortality, exploratory univariate meta-regressions were conducted on covariates that could be extracted from at least 4 studies. These included the following study characteristics that were determined a priori; baseline mortality of the placebo group, year of publication, proportion of patients with diabetes or cancer, severe protein deficiency, mean APACHE score, number of organ failures, and source of infection. We anticipated that we were likely to be underpowered to detect significant differences, but as future RCTs in this area are unlikely to be performed, ranked predictors based on available data may be valuable.

Publication bias was assessed using a funnel plot and the methods of Begg[21] and Egger[22].

All analyses were conducted using STATA version 11.2 (College Station, TX). Our results were reported according to the PRISMA guidelines[23].

RESULTS

Figure 1 displays the flow diagram of our literature search. The literature search yielded 602 abstracts: 381 abstracts from Medline, Embase, and Cochrane Central Register of Controlled Trials; 22 trials from ClinicalTrials.gov; and 199 abstracts from major intensive care medicine meetings in the past ten years. Of those, 565 abstracts were excluded and 37 full-text articles were reviewed. 26 full-text articles were further excluded due to one or more of the following reasons; non-human study, did not study DAA, did not report primary outcome of 28-day mortality, duplicate search result or subgroup analysis using previously published RCT data, or was not a randomized trial. Of the remaining 11 RCTs, four RCTs were excluded, one due to duplicate search result[24] and three due to lack of outcome data[25-27]; an additional two RCTs[28, 29] were excluded as the comparator arm had received prior DAA.

Five placebo-controlled RCTs met our inclusion criteria[11, 12, 18, 30, 31]. No conflicts were noted in the study selection and data extraction process. All studies were judged to have adequate quality.

Study characteristics are described in Table 1. There were 743 of 3341 deaths (22.2%) in the DAA group and 736 of 3247 (22.6%) deaths in the control group. DAA had no effect on the primary endpoint of 28-day all-cause mortality, with a pooled relative risk (RR) of 0.97, 95% CI 0.83-1.14 (forest plot in Figure 2). Significant heterogeneity was identified in this analysis, with a Cochran's Q p-value=0.04 and a I2 value of 59.4% (95%CI 0-85).

Table 1.

Characteristics of Included Studies

Source Population N Interventions Outcome Mean Age Male (%) Diabetes (%) Mean APACHE II Score Vasopressor (%) Protein C Deficiency (%) Baseline Mortality (%)**
Bernard et al, 200131 (rhAPC) Adults with severe shock 131 Placebo (saline) or DAA (12, 18, 24, or 30 mg/kg/hr) for 48 or 96 hrs Primary: Coagulopathy Secondary: 28-day all-cause mortality, morbidity markers, organ dysfunction 59.3 63.9 22.3 17.3 69.4 50 34.2
Bernard et al, 20019 (PROWESS) Adults with systemic inflammation and organ failure due to acute infection 1690 Placebo (saline or albumin) or DAA (24 mg/kg/hr) for 96 hrs Primary: 28-day all-cause mortality
Secondary: Adverse events, changes in vital signs or laboratory variables; microbiologic cultures; development of neutralizing antibodies		 60.5 57 21.5 24.8 73.6 39.1 30.8
Abraham et al, 200510 (ADDRESS) Adults with severe sepsis and APACHE II score < 25 or single-organ failure 2613 Placebo (saline) or DAA (24 mg/kg/hr) for 96 hours Primary: 28-day all-cause mortality
Secondary: Serious bleeding events		 58.7 57.4 - 18.2 47.7 - 17.0’
Nadel et al, 200711 (RESOLVE) Children between 38 weeks and 17 years with sepsis-induced cardiovascular and respiratory failure 477 Placebo (saline) or DAA (24 mg/kg/hr) Primary: CTCOFR
Secondary: 28-day all-cause mortality, major complications, and safety		 2.5* 60.7 - - - 55.9 17.5
Ranieri et al, 201212 (PROWESS-SHOCK) Adults with infection, systemic inflammation and shock receiving fluids and vasopressors above threshold dose for 4 hours 1697 Placebo (saline) or DAA (24 mg/kg/hr) for 96 hours Primary: 28-day all-cause mortality
Secondary: 90-day mortality, organ dysfunction, and safety		 63.1 56.4 24.4 25.3 100 50.6 24.2
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Abbreviation: DAA, Drotrecogin alfa (activated); APACHE, Acute Physiology and Chronic Health Evaluation; CTCOFR, Composite Time to Complete Organ Failure Resolution

*

Median age

**

Baseline mortality in control arm.

Figure 2.

Figure 2

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Forest plot comparing the effect of DAA vs. placebo on risk ratio (RR) for 28-day all-cause mortality. The pooled RR of 0.97, 95% CI 0.83-1.14 demonstrates that DAA had no effect on 28-day all-cause mortality. CI, confidence interval.

Pooled estimates of RR for secondary endpoints showed an association between DAA and severe bleeding events (pooled RR 1.48, 95% CI 1.10-1.99, Figure 3) but not with intracranial bleeding events (pooled RR 1.52, 95% CI 0.78-2.99, Figure 4). Neither analysis had significant heterogeneity, with non-significant Cochran's Q p-values of 0.62 and 0.83, respectively, and I2 values of 0%.

Figure 3.

Figure 3

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Forest plot comparing the effect of DAA vs. placebo on risk ratio (RR) for severe bleeding. The pooled RR of 1.48, 95% CI 1.10-1.99) demonstrates that there is an association between DAA and severe bleeding events. CI, confidence interval.

Figure 4.

Figure 4

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Forest plot comparing the effect of DAA vs. placebo on risk ratio (RR) for intracranial hemorrhage. The pooled RR of 1.52, 95% CI 0.78-2.99 demonstrates that there is no statistically significant association between DAA and intracranial hemorrhage. CI, confidence interval.

Several sensitivity analyses were performed to identify trials contributing to heterogeneity. First, a pooled estimate of RR including all five placebo-control trials and two additional RCTs with an active-treatment control arm[28, 29] showed results similar to our main analysis (cumulative RR 1.05, 95% CI 0.89-1.23, Cochran's Q p-value =0.01, I2=63.9%). Second, one of the RCTs included in the main analysis studied a pediatric population and could be a source of heterogeneity. Omitting this trial did not lead to a significant change in either the effect estimate (pooled RR=0.97, 95% CI0.81-1.16) or heterogeneity (Cochran's Q p = 0.02, I2 value of 69.5%). Third, given published commentary debating structural problems with the PROWESS trial due to study changes midway through the trial[15, 32, 33], we focused on this trial as a source of heterogeneity.

Omitting PROWESS from the analysis led to a similar pooled RR (1.07, 95% CI 0.94-1.15) but the study effects were much more consistent with a Cochran's Q p=0.80 and I2 value of 0%. A debated feature of PROWESS was the difference in 28-day mortality of the DAA treated before and after amendments were made to the study protocol; only after the protocol amendment was a protective effect for DAA observed. As the primary endpoint was available separately for both periods in the trial[34], further analyses were made with PROWESS divided into pre- and post-amendment periods (Figure 5). Using a Galbraith plot, the PROWESS trial and more specifically, the post-amendment period of PROWESS was identified as a clear outlier (Figure 6). Excluding this portion of the trial (Supplemental Figure E1) again led to non-significant tests for heterogeneity (Cochran's Q p=0.72, I2 value of 0%, pooled RR 1.04, 95% CI 0.94-1.15).

Figure 5.

Figure 5

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Forest plot comparing the effect of DAA vs. placebo on risk ratio (RR) for 28-day all-cause mortality. Here, PROWESS is divided into pre- and post- amendment periods. Only PROWESS post-amendment demonstrates a protective effect of DAA on 28-day all-cause mortality, with pooled RR 0.71, 95% CI 0.57-0.87. CI, confidence interval.

Figure 6.

Figure 6

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Galbraith plot plotting the standardized effect estimate for DAA vs. placebo on 28-day mortality in each study against the standard error of each study. Here the PROWESS post-amendment period falls outside the 95% confidence interval and is a clear outlier.

To identify clinical characteristics associated with outcome heterogeneity, exploratory univariate meta-regression models were fitted with available study characteristics from the 5 placebo-controlled trials, but no single factor emerged as a statistically significant explanation for this heterogeneity. The three best predictors of variability were baseline mortality in the placebo group (p-value 0.14; placebo mortality highest in PROWESS), severe protein C deficiency at baseline (p-value 0.17), and publication year (p-value 0.19).

Publication bias was not suspected based on non-significant Begg and Egger tests and the symmetric appearance of RCTs in the funnel plot (see Supplementary Figure E2).

DISCUSSION

In this meta-analysis of RCTs, DAA does not reduce 28-day mortality in patients with severe sepsis or septic shock, and is associated with a statistically significant increase in severe bleeding. Our focus on exploring outcome heterogeneity identified the post-amendment portion of the PROWESS trial as the main source of statistical heterogeneity. Using meta-regression, the best ranked predictor of outcome heterogeneity was baseline mortality in the placebo arm, although it did not reach statistical significance.

The results of PROWESS have been disputed since 2001. Given that the PROWESS trial was terminated early as it met a priori stopping criteria for efficacy, chance has previously been cited as one reason for the favorable outcome[14]. In this meta-analysis we demonstrate that chance is unlikely to play a role in the results of PROWESS, and more specifically the post-amendment arm of PROWESS. The Galbraith plot identified the post-amendment arm of PROWESS as a clear statistical outlier, and while the Cochran's Q statistic is known to have low power in detecting heterogeneity, even with our small sample size our analysis of both the 5 placebo controlled trials and the 4 adult trials detected significant outcome heterogeneity. Only with the removal of the post-amendment arm of PROWESS did we fail to identify statistically significant heterogeneity.

PROWESS pre- and post- amendment differed by changes in inclusion and exclusion criteria, changes in the formulation of the study drug, and changes in the placebo used (albumin vs. saline). A FDA briefing document[34] indicated that the patient population post-amendment was significantly different from the pre-amendment population in terms of having fewer chronic underlying conditions, lower bleeding risk, and increased willingness to pursue aggressive care and may explain the differences in outcome between PROWESS pre- and post- amendment. However, subsequent trials used similar criteria[12, 18] resulting in study populations with similar characteristics, yet failed to demonstrate a mortality benefit for DAA. At first pass this may suggest that the variable outcome between PROWESS post-amendment and subsequent studies is not due to clinical heterogeneity.

It must be emphasized that since 2001, when PROWESS was published, there have been important changes in the management of severe sepsis and septic shock. Early fluid resuscitation[35] and increased attention to early administration of appropriate antibiotics and source control[36, 37] are likely explanations for falling sepsis mortality rates described in recent cohorts[5, 38, 39]. An important inclusion criterion of PROWESS-SHOCK was the requirement for at least 30 ml/kg of intravenous fluids early in the course. Further, patients in PROWESS-SHOCK were treated with antibiotics a median of 2.5 hours prior to shock onset, subsequently determined to have received initial appropriate antibiotics 84% of the time, and source control was judged to be adequate in 90% of subjects who needed it. These factors may have contributed to the lower mortality in the placebo arm of PROWESS-SHOCK versus PROWESS (24.2% versus 30.8%). Early volume resuscitation could explain the discrepancy in DAA efficacy between PROWESS and PROWESS-SHOCK; in the study by Rivers et al[35], those subjects receiving early goal directed therapy had a lower prothrombin time, d-dimer, and concentration of fibrin split-products. This favorable modulation of the coagulation system with early resuscitation may have reduced or eliminated the potential benefit of DAA. Thus patient populations in PROWESS post-amendment vs. subsequent studies may have differed not in terms of patient characteristics, but rather in terms of treatment variables known to affect outcome such as differences in adequacy of resuscitation.

There are no further reports of a change in the DAA formulation to the FDA since PROWESS[40]. Current evidence does not support a detrimental effect of albumin on mortality in patients with septic shock [41], and the 28-day mortality rate for the placebo arm of PROWESS pre- and post- amendment was not significantly different (30.2 versus 31.3%). Thus we feel the most likely explanation for the observed statistical heterogeneity in included RCTs is due to clinical heterogeneity from differences in early supportive care in PROWESS compared to subsequent RCTs.

Our results are consistent with a prior meta-analysis [42] published by the Cochrane collaboration which did not support the efficacy of DAA. Important differences between this study and ours are that PROWESS-SHOCK is included in our analysis, and the focus of the Cochrane study was not on the exploration of heterogeneity. More recently, a meta-analysis of DAA[16] which included 9 observational trials in addition to the RCTs found an 18% reduction in hospital mortality with the use of DAA compared to controls. The results of this study are consistent with ours; with the exception of PROWESS, none of the RCTs demonstrated a protective effect of DAA. The main difference lies in the inclusion of observational studies, which overwhelmingly favored the use of DAA. Why then this discrepancy between RCTs and observational studies? While RCTs, unlike observational trials, have strict inclusion criteria that may not be generalizable to patients seen in clinical practice, residual confounding can never be completely eliminated in observational studies, even after careful adjustment for measured confounders. In the case of DAA RCTs, the study drug had to be initiated within 24 hours of sepsis diagnosis, thus excluding patients that presented with late untreated sepsis. While the observational trials controlled for disease severity, they did not adjust for adequacy and timeliness of volume resuscitation and antibiotic administration. As in the case of PROWESS, DAA may indeed be effective in the right patient population with unresuscitated sepsis, but ineffective when a patient receives early goal directed therapy as seen in PROWESS-SHOCK.

This study is the first to use meta-analysis to explore sources of heterogeneity that contributed to the disparate efficacy of DAA on 28-day mortality in patients with severe sepsis or septic shock. The possibility that early resuscitation and antibiotic administration may contribute to the differential efficacy of DAA over time, along with the lack of benefit in any published subset of PROWESS-SHOCK, may reassure clinicians about the decision to withdrawal DAA from the market. Additionally, the exploration of heterogeneity here serves to guide future clinical trial design for further research in rhAPCs in sepsis, as measurement of early resuscitation and early antibiotic administration should be accounted for in future studies. Alternative non-anticoagulant rhAPC molecules that may be safe at higher doses are currently being studied[43] and may represent an alternative biologic therapy for treatment of septic shock.

The main limitation to our study relates to sample size based on the number of included trials; this was due to our decision to restrict the quality of evidence to placebo-controlled randomized clinical trials. This did not allow us to directly examine changes in supportive care as potential reasons for the differences in observed efficacy of DAA over time, as details of many aspects of supportive therapy were not reported in these trials and we were underpowered to do a true meta-regression study and could only perform an exploratory analysis. Additionally, the very nature of a meta-analysis also limits the granularity of the data used for primary analysis as the exact timing and adequacy of volume resuscitation and appropriate antibiotic administration was missing from all RCTs but PROWESS-SHOCK. An individual patient meta-analysis of the five placebo-controlled RCTs controlling for timing of both volume resuscitation and adequate antibiotic administration will address some of the limitations in our study.

CONCLUSION

This meta-analysis does not support the use of DAA in contemporary treatment of severe sepsis or septic shock. The favorable outcome of PROWESS post-amendment is unlikely to be due to chance. Further studies should be done to definitively determine whether timeliness of adequate volume resuscitation and antibiotic administration and the subsequent modulation of inflammation and coagulation explain the variable efficacy of DAA in treatment of severe sepsis and septic shock.

Supplementary Material

Supplementary Figure E1
Supplementary Figure E2
Supplementary data

KEY POINTS.

  • The efficacy of drotrecogin alpha activated (DAA) in severe sepsis or septic shock has been debated given different outcomes between earlier and later randomized controlled trials (RCTs), and between RCTs and observational trials

  • In this meta-analysis, DAA is not associated with improved 28-day survival in patients with severe sepsis or septic shock. We identified the post-amendment portion of the PROWESS trial as the main source of outcome heterogeneity

  • Given limitations in the sample size and reported data from the 5 included RCTs, this study could not conclusively identify the reasons for outcome heterogeneity. However, temporal changes in standard of care for treatment of sepsis such as early volume resuscitation and adequate antibiotic administration may explain outcome heterogeneity, and has not been evaluated in current studies of DAA in severe sepsis and septic shock

Table 2.

Primary and secondary endpoints.

Endpoint Pooled RR 95% Confidence Interval
28-day all-cause mortality
    5 RCTs 0.971 (0.829 – 1.137)
Severe bleeding
    5 RCTs 1.479 (1.101 – 1.987)
Intracranial bleeding
    4 RCTs 1.524 (0.777 – 2.991)
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ACKNOWLEDGEMENTS

We would like to thank Dr. CC Hsieh for his valuable input on this manuscript.

Contributor Information

Peggy S. Lai, Pulmonary and Critical Care Unit Department of Medicine Massachusetts General Hospital Boston, MA USA Tel: 617-875-9878 Fax: 617-724-9948.

Alexis Matteau, Division of Cardiovascular Medicine Brigham and Women's Hospital Boston, MA USA.

Adam Iddriss, Harvard School of Public Health Boston, MA USA.

Jennifer C.L. Hawes, Harvard School of Public Health Boston, MA USA.

V. Marco Ranieri, Ospedale S. Giovanni Battista-Molinnette Universita di Torino Italy.

B. Taylor Thompson, Pulmonary and Critical Care Unit Department of Medicine Massachusetts General Hospital Boston, MA USA.

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Supplementary Materials

Supplementary Figure E1
NIHMS496608-supplement-Supplementary_Figure_E1.tif (823.6KB, tif)
Supplementary Figure E2
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Supplementary data
NIHMS496608-supplement-Supplementary_data.docx (117.7KB, docx)

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