Trauma, An Issue of Anesthesiology Clinics (eBook)

Preface

Postmarketing Pharmaceutical Product Pitfalls in Trauma Care

Implementing novel therapies into daily medical practice requires thorough research before regulatory approval and thereafter awareness of cumulative postmarketing medical knowledge. This editorial addresses 2 postmarketing controversies affecting trauma treatment: the retraction of published articles regarding hydroxyethyl starch (HES) and the “back-door” (off-label use) introduction of recombinant factor VIIa (rFVIIa) for intractable hemorrhage in nonhemophiliacs.

In this issue, Galvagno et al, did not address the use of HES for fluid resuscitation in their review. This comes as no surprise because the routine use of HES has been recently revisited. In 2010, a group of medical journal editors retracted 88 articles published by Dr Joachim Boldt, a leading investigator in many publications studying the use of HES.1 A recent review on the use of HES concluded that “a shadow is cast on a bulk of literature on HES safety and efficacy.”2 Furthermore, the authors also noted that there is great concern due to the lack of safety data on new IV solutions using HES 130/0.4. These solutions were approved based on equivalence studies, which focused on elective surgeries––associated acute hypovolemia. These studies used other synthetic colloids as comparators, had small sample sizes, and were not suitable for assessing safety. It was concluded that “there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies.”3

A recent Cochrane meta-analysis reviewed randomized controlled trials comparing colloids to crystalloids used for volume replacement.4 The authors found no evidence that resuscitation with colloids reduced mortality compared to crystalloids in postoperative patients or those suffering from trauma or burns. The authors questioned the use of these colloids in these patient groups considering lack of proven effect on mortality and increased cost.

A recently published study shed additional light on the safety and efficacy of HES for volume resuscitation.5 In this study, 7000 intensive care unit patients, including some suffering from multiple trauma and traumatic brain injury, were randomly assigned to receive either 6% HES (130/0.4) or 0.9% sodium chloride (saline) as the sole intravenous fluid until intensive care unit discharge or death. No significant difference in 90-day mortality was found between the 2 groups. However, more patients in the HES group required renal-replacement therapy. This study provides additional support to concerns regarding possible adverse kidney effects (acute kidney injury and risk for renal replacement therapy) when using HES for volume resuscitation.2

The role of rFVIIa in the management of uncontrolled bleeding is addressed in the review, “Nonsurgical Techniques to Control Massive Bleeding,” by Zentai et al. This is a case where specific guidelines for a specific disease, namely Hemophilia A/B, were generalized to recommendations encompassing a larger population suffering from a different disease, namely, traumatic hemorrhage, based on relative small studies and case reports. rFVIIa (NovoSeven, Novo Nordisk, Bagsværd, Denmark) was approved in March 1999 by the FDA for the management of patients with hemophilia.6,7 Seven months later, in the November 1999 issue of The Lancet, Kenet et al, published the first description of off-label use of rFVIIa to control traumatic bleeding in a nonhemophilic patient.8 This has led to an eruption of publications describing the off-label use of rFVIIa in nonhemophiliacs. In 2005 a review article summarizing the preclinical studies used as the scientific basis for rFVIIa use in nonhemophiliacs was able to identify only 10 relevant articles.9 On the other hand, at the same time, numerous case reports and small case series describing the off-label use of rFVIIa were published. It was estimated that by the end of 2004 approximately 4500 patients were treated with rFVIIa for off-label indications, in the United States only.7 By the end of 2008 this number skyrocketed to almost 74,000, a 143-fold increase in off-label use of rFVIIa, as opposed to the 3.8-fold increase use for hemophilia A or B patients.10 At this time, rFVIIa became an integral part of the treatment for significant hemorrhage, almost a “must.” As most studies did not present a risk associated with its use, it was considered a safe drug. However, part of the medical community was concerned about the efficacy and safety of this very expensive drug for bleeding in nonhemophiliacs.

In 2005 Boffard et al, published the largest randomized controlled trial on the use of rFVIIa in trauma (301 patients).11 This study failed to demonstrate a decrease in mortality in patients suffering from penetrating or blunt trauma being treated with rFVIIa. In patients suffering from blunt trauma treated with rFVIIa, they showed a 2.6 reduction in blood units transfused and a reduced occurrence of acute respiratory distress syndrome. A similar frequency and severity of adverse events were found between the treatment groups. Nevertheless, the indiscriminate use of rFVIIa caused the Food and Drug Administration (FDA) to conduct its own inquiry that was published in 2006 and was based on the FDA’s Adverse Event Reporting System database.7 This report identified 185 arterial or venous thromboembolic adverse events, mostly in patients receiving the drug for off-label indications.

Where are we in 2013, following 13 years of off-label use? Yank et al, analyzed the existing data in a meta-analysis that included studies that compared the use of rFVIIa for 5 off-label indications: intracerebral hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy.12 A total of 62 higher scientific level reports were identified with a total of 3965 patients (2283 treated, 1682 controls). Off-label use of rFVIIa for intracerebral hemorrhage and cardiac surgery did not reduce mortality but increased the risk for thromboembolism. For body trauma, there was no increased risk for thromboembolism but also no difference in mortality. For the remaining indications, the available evidence was too limited.

A more recent Cochrane review analyzed the results of 29 studies.13 Sixteen of the trials were prospective (1361 patients, 729 received rFVIIa). A reduction in blood loss and blood transfusion was found, yet mortality did not differ. There was a trend against rFVIIa attributed to increased thromboembolic adverse events. Thirteen trials (2929 patients, 1878 received rFVIIa) examined the therapeutic use of rFVIIa. No statistically significant decrease in mortality or increase in thromboembolic complications was noted. However, when all trials were pooled together to examine the risk of thromboembolic events, a significant increase in total arterial events was observed (RR 1.45).

In their British Journal of Anesthesia editorial, Spahn et al, asked. “…where do we stand in May 2005? Are we obliged to give rFVIIa to patients with major bleeding to avoid accusation of substandard treatment or is rFVIIa treatment not indicated, owing to the lack of high level scientific evidence, lack of approval by any health authority, the potential of serious side-effects and its high cost?”14 In 2011, Avron and Kesselheim answer this question in their Annals of Internal Medicine editorial: “Although off-label prescribing by physicians is not illegal, physicians who persist in such use (i.e. prescribing rFVIIa–YGW MYS) in the face of clear evidence of inutility and harm could be subject to civil action by the affected patients or their heirs.”6