Iatrogenic rhabdomyolysis in a patient with ischemic heart disease

Cenjor Martín, Raquel; Gutiérrez-Madrid, Elena; Martín-Sánchez, Francisco Javier; Cuervo Pinto, Rafael
doi:10.1016/j.medcle.2016.06.045
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The recently published Acute Coronary Syndrome Management Guidelines<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> propose intensive combined therapies to achieve ambitious and specific goals&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In relation to the management of antiplatelet drugs&#44; the accepted combination consists of aspirin plus a P2Y12 platelet receptor blocker for at least the first year after the event&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Among the latter&#44; ticagrelor at doses of 90<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h has shown faster action&#44; decreased likelihood of stent thrombosis and increased safety in patients without specific coronary studies or waiting to perform them<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> when compared to other drugs in its class&#44; becoming the first alternative in the absence of contraindications in patients with moderate to high risk of ischemic events&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> However&#44; one must take into account the possible drug interactions of this drug with other frequently used&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 72-year-old man&#44; with no drug allergies and a history of low risk prostate adenocarcinoma under monitoring by Radiation Oncology and unstable angina due to total occlusion of the middle segment of the left anterior descending artery&#44; for which he underwent percutaneous revascularization with drug-eluting stent 3 months before his current Emergency Department consultation&#46; He was discharged from the Cardiology ward under treatment with enalapril 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; bisoprolol 5<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; aspirin 300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; ticagrelor 90<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h and atorvastatin 40<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#46; He went to the emergency department referring chest pain of mechanical characteristics during several days in the context of polymyalgia and malaise&#44; with irrelevant physical examination and history of having added to his usual treatment clarithromycin 250<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h due to a respiratory infection a week before&#46; A serial cardiac enzymes test was performed&#44; which ruled out new ischemic events&#44; although 15&#44;141<span class="elsevierStyleHsp" style=""></span>U&#47;l of serum creatine kinase was observed&#46; After diagnosis of rhabdomyolysis&#44; probably drug-induced&#44; fluid therapy was initiated&#44; and clarithromycin and atorvastatin were suspended&#44; with clinical and laboratory improvement within a few days &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; He was discharged with the recommendation of reintroducing atorvastatin at lower doses&#44; monitoring the levels of creatine kinase or replacing it by pravastatin&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">This case reflects an adverse event associated with the use of several drugs necessary and beneficial for the patient&#39;s basal disease<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> together with another drug prescribed for a specific use and limited time&#44; but acting through the same metabolic pathway&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Ticagrelor works by inhibiting the prothrombotic effects of ADP on the platelet&#44; antagonizing the P2Y12 receptor without the need of metabolic transformation&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> It has a faster action and less interpatient variability in plasma concentrations and antiplatelet effects than thienopyridines &#40;ticlopidine&#44; clopidogrel&#44; prasugrel&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> therefore its use is preferred to the latter ones&#46; The main enzymes responsible for the formation of the active metabolite are cytochrome P450 3A4 &#40;CYP3A4&#41; and&#44; to a lesser extent&#44; CYP3A5&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Atorvastatin is also metabolized by CYP3A4 and has high bioavailability &#40;12&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> As with other statins&#59; the most significant safety issue is myopathy&#44; which may progress into rhabdomyolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Rhabdomyolysis is a rare but especially severe side effect associated with the use of statins&#44; whose incidence is 1&#47;1000 to 1&#47;10&#44;000 in patients with standard doses of statins&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Ticagrelor SmPC &#40;Summary of Product Characteristics&#41; describes the possible interaction with atorvastatin by increasing the levels of active metabolites of the latter&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;9</span></a> We only found one case reported of rhabdomyolysis associated with the interaction of ticagrelor and atorvastatin 80<span class="elsevierStyleHsp" style=""></span>mg&#47;day with a time sequence of 2 months from the start of concomitant use of both drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Macrolides are potent inhibitors of CYP3A4&#44; so its use is contraindicated with ticagrelor &#40;increases their levels&#41;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> and should be avoided with statins &#40;increases their plasma concentrations&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Therefore&#44; the associated use causes an increase in active metabolites of statins by indirect effect &#40;macrolide-ticagrelor-statin&#41; and direct effect &#40;macrolide-statin&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Our patient had remained asymptomatic since the start of treatment with atorvastatin and ticagrelor&#44; starting with rhabdomyolysis one week after concomitant exposure to clarithromycin&#46; This time sequence is what makes us conclude that this macrolide&#44; through the mechanisms described&#44; triggers an increase in statin levels&#44; further enhanced by ticagrelor and causing rhabdomyolysis&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">This case leads to the consideration that it is necessary to take into account the interactions and side effects described when prescribing other drugs for the treatment of intercurrent common diseases regarding new therapies for secondary prevention of ischemic heart disease &#40;in our patient&#44; macrolides for a respiratory infection&#41;&#46;</p></span>"
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15&#8211;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Creatinine &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;67&#8211;1&#46;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Estimated glomerular filtration rate &#40;ml&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60&#8211;140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">135&#8211;145&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">136&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">135&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Potassium &#40;mmol&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;4&#8211;5&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Creatine kinase &#40;U&#47;l&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#8211;190&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#44;141&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8601&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5684&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Creatine kinase MB &#40;ng&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;1&#8211;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">58&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Troponin I &#40;ng&#47;ml&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;001&#8211;0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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