Article Reviews

Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128–2137.

In this French pulmonary hypertension (PH) registry study,1 Montani and colleagues describe cases of dasatinib-associated PH among their cohort of patients. Patients were included in the study if they were diagnosed with catheterization-confirmed PH in the setting of either (or both) a diagnosis of chronic myeloid leukemia (CML) or treatment with dasatinib, imatinib, or nilotinib between 2006 and 2010. Nine PH patients met these criteria, all of whom had received long-term treatment with dasatinib over a median of 34 months (range 8–48 months); no patients receiving imatinib or nilotinib developed PH. Hemodynamics were consistent with precapillary PH (normal wedge pressure) with variable severity, including several patients who had evidence of right heart failure. No secondary causes of PH were identified, including left heart disease, lung disease, or chronic pulmonary embolism. Treatment included an endothelin-1 receptor antagonist in 2 patients and a calcium channel blocker in 1 patient who responded to a vasodilator challenge, and dasatinib was discontinued in all 9 cases. Some improvement in hemodynamics was seen in most patients, but none of those who underwent follow-up catheterization had normalized their pulmonary arterial pressures.

In the same paper but using a combined dataset, Montani and colleagues also estimated the PH incidence rate among dasatinib-exposed patients. In addition to their 9 cases, 5 cases of PH associated with dasatinib were reported to the French pharmacovigilance agency, resulting in a total of at least 13 cases of PH over the study period. This was out of 2900 patients receiving dasatinib during these years, resulting in an incident rate of 0.45% among exposed individuals. Based on this and other reports, the French, European, and US drug agencies have published a warning on the risk of PH in patients treated with dasatinib. These results suggest that dasatinib is capable of causing pulmonary arterial hypertension (PAH), at least in a subset of patients, and that increased awareness and close follow-up of exposed patients is indicated. Strengths of this study include the comprehensive clinical and hemodynamic evaluation, the long-term follow-up, and the use of multiple data sources to identify cases within France. Montani and colleagues also provide a nice overview of the tyrosine kinase inhibitors and their various kinase and nonkinase targets, including future targets that they suggest are worth exploring in PH.

Karch SB, Mari F, Bartolini V, Bertol E. Aminorex poisoning in cocaine abusers. Int J Cardiol. 2012;158(3):344–346.

Cocaine has been suspected of causing PAH, based on case reports and on inconclusive results from diet-pill and other case-control studies.2–4 However, the mechanism through which this could occur has not been definitively determined, particularly because cocaine, as a monoamine reuptake inhibitor, is different mechanistically from the diet pills and other stimulants that have been associated with PAH.5 In this review article by Karch and colleagues,6 an alternative potential link between cocaine and PAH is described, based on recent work from their own laboratory. They propose that cocaine could be associated with PAH because it is often adulterated with levamisole, a drug whose metabolites include aminorex. Aminorex was associated with an epidemic of PH in Europe in the 1960s.

This unexpected metabolite was first identified after several dozen racehorses tested positive for aminorex, a banned stimulant in racing, and it was ultimately linked to the use of levamisole as an anthelminthic.7 Follow-up studies confirmed that levamisole could be converted to aminorex in both horses and humans.89 In their own recent work, Karch and colleagues report identifying levamisole and aminorex in over half of all cocaine-positive urine samples (62 of 154). Levamisole has also been identified in a majority of cocaine seized in the United States in recent years, and in many samples of cocaine in other countries. As a result, these authors raise a very valid concern: could aminorex exposure from cocaine lead to PAH?

They conclude their review by stating that: “The key issue to be addressed now is not whether humans convert levamisole to aminorex (we know they can), or whether aminorex can cause [PAH] (it does). The question that urgently requires answering is whether chronic users of levamisole-tainted cocaine actually convert enough levamisole into aminorex to cause [PAH]”. This does appear to be the key question, but unfortunately, it is not one that is going to be easy to answer, both because it is not clear what minimum levels of aminorex exposure might be required to cause PAH, and because of the widely varying dose and composition of drugs taken illicitly.

In summary, these 2 articles suggest that medication and drug exposures in PH patients are not just concerns of a prior era, but should remain a focus of both clinical assessment and future research in PH.