Simvastatin & Hyper-inflammatory ARDS: re-analysis of the HARP-2 trial
“For others, in spite of myself, from myself.”
A 52 year old man is admitted to the intensive care unit with bilateral pulmonary opacities, worsening gas-exchange and hypotension requiring peripherally-administered norepinephrine. His PaO2-to-FiO2 ratio is less than 100; he is intubated and considered for prone position. Two weeks prior to his presentation he was hiking in rural Maine and noted a few ticks attached to his skin but had no subsequent rash or therapy. The astute critical care fellow immediately commences doxycycline, clindamycin and quinine recalling her attending once saying ‘summer sepsis shouldn’t die without doxycycline.’ Upon initiation of quinine, she is warned by pharmacy that the patient’s home medication – simvastatin – can lead to severe myositis because of a cytochrome 3A4 interaction; she holds the patient’s home statin and jokes to the admitting resident that “… statins have no role in ARDS, anyway.”
One year ago marked the 50th anniversary of the first description of the acute respiratory distress syndrome [ARDS – initially coined adult respiratory distress syndrome]. In commemoration, I reviewed the phases of ARDS – with illustrations by Dr. Canepa – and related two molecular ‘sub-phenotypes’ of ARDS to two mechanical classifications initially described by Dr. Gattinoni in 1998.
In brief, retrospective analysis of the ARMA trial revealed a less-intense inflammatory brand of ARDS typified by lower IL-6 levels [amongst other biomarker differentiators] and designated ‘sub-phenotype 1.’ In distinction, ‘sub-phenotype 2’ was marked by high levels of IL-6, more intense systemic inflammation, higher vasopressor requirements and greater rate of mortality. These sub-phenotypes were then studied with respect to positive end-expiratory pressure [PEEP] application [re-analysis of the ALVEOLI trial] and fluid administration [re-analysis of the FACTT trial]. Notably, the hyper-inflammatory sub-phenotype 2 appeared to be better treated with higher PEEP and conservative fluid strategies, respectively.
Given the above, another cohort of ARDS patients – this time from the United Kingdom and Ireland – was retrospectively scrutinized for the aforementioned molecular phenotypes. Specifically, the patients from the HARP-2 trial were investigated. The initial HARP-2 inquiry – published in 2014 – evaluated the effect of simvastatin on ventilator-free days in ARDS as well as a number of secondary outcomes such as mortality and organ dysfunction; no significant difference was found in any outcomes.
Regarding HARP-2’s recent re-appraisal, the author’s hypothesized that 1. The sub-phenotypes found within the ARMA, ALVEOLI and FACTT trials would be recapitulated and 2. That hyper-inflammatory, sub-phenotype 2 patients would derive benefit from statin therapy [see cartoon].
Figure 1: potential role of simvastatin in inflammation - inflammation [e.g. infection] triggers macrophages and monocytes which elaborate various cytokines such as MPO [myeloperoxidase], MMP [matrix metalloproteinases], TNF-alpha all of which can directly or indirectly damage epithelial and endothelial lining. In vitro and in vivo, simvastatin has been found to hinder these inflammatory responses.What They Did
Similar to their previous explorations of ARMA, ALVEOLI and FACTT, the investigators used latent class analysis which they identify as a well-validated statistical tool used to characterize subgroups within a broader population. The patients they studied were from the HARP-2 trial – initially published in 2014. These patients were randomized to either placebo or 80 mg of simvastatin within 48 hours of ARDS diagnosis – by the Berlin Criteria.
What They Found
Previously, in the ARMA, ALVEOLI and FACTT cohorts – which totaled roughly 2000 patients – the authors found that nearly one-third of ARDS patients displayed a molecular phenotype that is hyper-inflammatory; this cluster of ARDS patients was termed sub-phenotype 2. Similarly, in the re-analysis of HARP-2, the authors found good evidence for the hyper-inflammatory sub-group and this comprised 35% of the group. This group was typified by higher IL-6, soluble tumour necrosis factor receptor 1, vasopressor use and 28-day mortality. Additionally, sub-phenotype 2 had lower platelet counts, fewer ventilator-free days and fewer non-pulmonary organ failure-free days.
There was no difference in 28-day mortality between those who received placebo and simvastatin in the hypo-inflammatory group [16% versus 17%, respectively]. In contradistinction – within the hyper-inflammatory sub-group – the provision of simvastatin conferred a 13% absolute risk reduction in 28-day mortality [from 45% to 32%] which was statistically-significant. Interestingly, the survival curves for those randomized to simvastatin versus placebo in the hyper-inflammatory sub-group separated nearly immediately and remained distinct through 90 days. Mirroring the mortality findings, ventilator-free days was also higher in the hyper-inflammatory group who received simvastatin as compared to placebo but ventilator-free days was not different within the hypo-inflammatory group. While ventilator-free days were clinically-significantly different, it did not reach statistical significance.
As previously argued, there is tacit linkage between direct, pulmonary ARDS – as described by Gattinoni – and the sub-phenotype 1 molecular classification. The corollary also appears to hold, that is, the hyper-inflammatory, sub-phenotype 2 resembles indirect, extra-pulmonary ARDS. The re-analysis of HARP-2 reinforces these suppositions – the distribution of direct and indirect ARDS risk factors was significantly different across the two molecular sub-phenotypes with risk factors for direct ARDS favouring sub-phenotype 1 and vice versa. Importantly, however, sepsis, pneumonia and aspiration were common among both groups which speaks to the messy nature of clinical medicine; direct and indirect ARDS are neither clinically nor molecularly mutually exclusive. For example, a bad aspiration pneumonia in the right lung [i.e. direct ARDS] can indirectly insult the left lung.
That these two molecular sub-phenotypes were found in yet another cohort – with astonishingly similar mortality rates [see table 1] – adds to their external validity. Additionally, disparate avenues of research converge as the same molecular flavour of ARDS seemingly benefits from higher PEEP, conservative fluids and now an anti-inflammatory pharmaceutical [i.e. simvastatin].
Table 1: mortality rates between sub-phenotype 1 and 2 in retro-spective analyses of previous ARDS trials. 90-days chosen as this metric directly reported in all sub-analyses
Given the above, should the use of steroids in ARDS be re-addressed using this molecular paradigm? What about NSAIDS, anti-TNF therapies, ketoconazole and/or immune nutrition [e.g. the OMEGA trial]? The reasonable reader may skeptically scrutinize these post-hoc assessments as statistical fishing expeditions. Further, because of the relatively small number of patients included in each sub-phenotype’s exposure to placebo or intervention, the observed absolute risk reduction in mortality is relatively fragile; definitive management recommendations cannot be – currently – conferred. Nevertheless, there is merit to the concept of ‘precision medicine,’ and the hypotheses generated by these authors certainly deserve prospective consideration.
Return to Case
The patient is continued on broad-spectrum antibiotics, including therapy for tick-borne zoonoses as a potential cause of ARDS; simvastatin is held given its interaction with quinine. Over 4 days the patient gradually improves whilst maintaining ‘higher’ PEEP, avoiding aggressive recruitment maneuvers and adopting conservative intravenous fluid management; neither prone positioning nor APRV are required. As suspected by the admitting fellow, Wright-Giesma staining of thin blood smears confirmed intra-erythrocytic parasites.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he is also the creator and author of a free hemodynamic curriculum at heart-lung.org