Clopidogrel

Clopidogrel increases the risk of bleeding. Use is contraindicated in patients with active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage). Additional risk factors for bleeding include age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment), body weight • Thienopyridine hypersensitivity: Because of structural similarities, cross-reactivity has been reported among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with hypersensitivity or hematologic reactions to previous thienopyridine use. Use of clopidogrel is contraindicated in patients with hypersensitivity to clopidogrel. Although desensitization may be considered for mild-to-moderate hypersensitivity, do not desensitize patients with prior life-threatening allergic reactions to clopidogrel (eg, toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, TTP) (Lokhandwala 2011).

Cases of TTP (usually occurring within the first 2 weeks of therapy), resulting in some fatalities, have been reported; urgent plasmapheresis is required. Disease-related concerns:

In patients with recent lacunar stroke (within 180 days), the use of clopidogrel in addition to aspirin did not significantly reduce the incidence of the primary outcome of stroke recurrence (any ischemic stroke or intracranial hemorrhage) compared to aspirin alone; the use of clopidogrel in addition to aspirin did however increase the risk of major hemorrhage and the rate of all-cause mortality (SPS3 Investigators, 2012).

Use with caution in patients with moderate to severe renal impairment (experience is limited). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Effectiveness of clopidogrel results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the CYP-450 system, principally CYP2C19. In patients who are homozygous for nonfunctional alleles of the CYP2C19 genes (termed “CYP2C19 poor metabolizers”), clopidogrel at recommended doses forms less of the active metabolite and has a reduced effect on platelet activity. Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. Genetic testing may be considered prior to initiating clopidogrel in patients at moderate or high risk for poor outcomes (eg, PCI in patients with extensive and/or very complex disease). The optimal dose for CYP2C19 poor metabolizers has yet to be determined. After initiation of clopidogrel, functional testing (eg, VerifyNow® P2Y12 assay) may also be done to determine clopidogrel responsiveness (Holmes, 2010).

An individualized and multidisciplinary approach should be utilized to determine therapy discontinuation and management in patients with acute lower GI bleed (LGIB) who are on antiplatelet medications; risk of ongoing bleeding should be weighed with risk of thromboembolic events. In patients receiving dual antiplatelet therapy (aspirin plus P2Y12 receptor blocker [eg, clopidogrel, prasugrel, ticagrelor, ticlopidine]) or thienopyridine monotherapy, the thienopyridine should generally be resumed as soon as possible and at least within 7 days, taking into account control of bleeding and cardiovascular risk (aspirin should not be discontinued); however, dual antiplatelet therapy should not be discontinued in the 90 days post-acute coronary syndrome or 30 days post-coronary stenting (Strate 2016).

In patients undergoing elective surgery, consider discontinuing 5 days before surgery (except in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist; AHA/ACC/SCAI/ACS/ADA Science Advisory provides recommendations) (Grines 2007). Elective noncardiac surgery should not be performed in patients in whom dual antiplatelet therapy (DAPT) will need to be discontinued perioperatively within 30 days following bare metal stent (BMS) placement or within 12 months after drug-eluting stent (DES) placement. In patients undergoing urgent non-cardiac surgery during the first 4 to 6 weeks after BMS or DES placement, continue DAPT. In patients with stents undergoing surgery that requires discontinuation of the P2Y12 inhibitor (eg, clopidogrel), continue aspirin and re-start the P2Y12 inhibitor as soon as possible after surgery (ACC/AHA [Fleisher 2014]). In patients undergoing elective CABG, discontinue clopidogrel at least 5 days before procedure; when urgent CABG is necessary, the ACCF/AHA CABG guidelines recommend discontinuation for at least 24 hours prior to surgery (ACCF/AHA [Hillis 2011]). The ACCF/AHA STEMI guidelines recommend discontinuation for at least 24 hours prior to on-pump CABG if possible; off-pump CABG may be performed within 24 hours of clopidogrel administration if the benefits of prompt revascularization outweigh the risks of bleeding (ACCF/AHA [O'Gara 2013])

Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. Duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement (ACC/AHA [Levine 2016]; AHA/ACC/SCAI/ACS/ADA [Grines 2007]).