The term whistleblower comes from the phrase “blow the whistle”, which refers to a whistle being blown by a policeman or a referee to indicate an activity that is illegal or a foul [1]. Recently, whistleblowers have disseminated valuable information to the community through new media outlets, such as WikiLeaks. In medicine, whistleblowers serve to shed light on side-effects of drugs and, occasionally, improprieties that have yet to be highlighted or investigated. Since the 1960s, such whistleblowers have made public the unacceptable cardiovascular risks of the appetite suppressants aminorex, fenfluramine, dexfenfluramine, and benfluorex [2–14]. These drugs had few (if any) beneficial clinical effects; however, they significantly increased the risk of life-threatening complications such as pulmonary arterial hypertension (PAH) and/or valvular heart diseases.
One of the main objectives of the European Respiratory Journal (ERJ) is to provide updates for its readership on new therapeutic developments in the field of respiratory diseases. In doing so, the ERJ must of course provide a balanced view, highlighting not only the benefits of new treatments but also important potential adverse effects. The ERJ and its predecessor, the Bulletin Européen de Physiopathologie Respiratoire, have been an important platform for whistleblowers with respect to the field of cardiopulmonary medicine. Since the landmark review published by Gurtner [2] describing the links between PAH and the appetite suppressant aminorex, several original articles published in the ERJ have emphasised the major pulmonary vascular and valvular heart complications of fenfluramine derivatives [3, 8, 9, 11, 12]. These articles have clarified the cardiovascular risks associated with the use of these agents and demonstrated the fenfluramine-like cardiovascular side-effects of benfluorex. Indeed, recognition of this association led eventually to a complete ban of benfluorex from the market in France and resulted in a major medical and political scandal in France, emphasising the need to reassess the working procedures of French (and European) pharmacovigilance systems [15].
In addition to helping to bring to light the link between PAH and certain drugs and toxins, several studies published in the ERJ have also highlighted important side-effects of PAH-specific therapies [16–22]. European post-marketing surveillance of the endothelin receptor antagonist, bosentan, confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials and confirmed the need for monthly monitoring of liver transaminases in patients treated with this agent [16]. On a more serious note, cases of severe (and sometimes fatal) idiosyncratic liver failure have been reported with sitaxentan, another endothelin receptor antagonist used in the treatment of PAH, leading to the withdrawal of this agent from the market worldwide in December 2010 [17–21]. This also prompted an amendment to the most recent guidelines published jointly by the European Society of Cardiology and the European Respiratory Society [22, 23].
In order to help improve detection of potential drug-induced pulmonary vascular diseases, it is important to stress the critical importance of obtaining of a detailed history of a given individual’s current and prior drug exposure. In a recent issue of the ERJ, Dumitrescu et al. [24] reported a case of PAH induced by dasatinib, a tyrosine kinase inhibitor (TKI) that has proven to be a life-saving treatment in patients with chronic myelogenous leukaemia. Although TKIs are usually well tolerated, these agents nonetheless exhibit systemic toxicity [24–28]. Pulmonary complications, in particular pleural effusions, have been reported more frequently with dasatinib use compared with other TKIs [25]. In addition, isolated case reports have suggested that PAH may be a potential complication of dasatinib use [24, 26, 27]. On April 18, 2011, the French drug regulatory agency AFSSAPS revealed that 13 cases of pulmonary hypertension had been identified in dasatinib-treated patients in France [28]. These cases are currently being investigated further and the agency has made it a point of emphasis that prescribers should monitor for the possible development of pulmonary hypertension in dasatinib-treated patients [28]. As reported by Dumitrescu et al. [24], such cases of pulmonary hypertension occur after several months of exposure and may be, at least in part, reversible. This suggests a direct and specific effect of dasatinib on the pulmonary vasculature. Although clinical improvement was generally observed after withdrawal of dasatinib, some patients remained symptomatic and showed persistent haemodynamic impairment several months after discontinuation of this agent [28]. Clearly, further studies are needed in order to better understand dasatinib-induced pulmonary hypertension in humans.
In order to obtain additional important clinical data and also improve reporting of adverse drug effects in the future, the conducting of more so-called “pragmatic” trials could be invaluable. Such trials serve to further evaluate therapeutic approaches (both investigative and established) by testing the impact of pharmacological interventions in cohorts of patients deemed more representative of those encountered in day-to-day clinical practice. When performed properly, these trials can come up with unforeseen benefits as well as unforeseen adverse effects of new treatments [29, 30]. In any case, one must re-emphasise the need to declare all side-effects of drugs to local pharmacovigilance agencies and pharmaceutical companies, which should themselves regularly examine and, where necessary, update their practices. This should lead to periodically revised recommendations for a better and safe use of drugs as needed. Whistleblowers should intervene when the systems in place fail to accurately and effectively inform and/or react when a risk has been identified.
Footnotes
Statement of Interest
Statements of interest for M. Humbert and G. Simonneau can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
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