title: Exploring the ticagrelor-statin interplay in the PLATO trial.
abstract: BACKGROUND
  Much emphasis has been placed on a ticagrelor-aspirin (ASA) interaction in the Platelet Inhibition and Patient Outcomes (PLATO) trial, despite this particular interaction being inconclusive. However, a potential ticagrelor-statin interplay occurred and may be important in PLATO, especially considering the remarkable and yet unexplained mortality advantage.
  
  
  OBJECTIVE
  To explore the ticagrelor-statin interaction in the PLATO trial.
  
  
  RESULTS
  The background statin use in hospital or at discharge was similar between ticagrelor (89.7%) and clopidogrel (89.2%) PLATO arms, respectively. In patients on statins, ticagrelor significantly decreased all-cause mortality (30 day and through study end), vascular mortality (30 day and through study end) and exhibited a trend in benefit for 30-day major adverse cardiovascular events (MACE) compared to clopidogrel: hazard ratio, HR = 0.55, 95% confidence interval, CI = 0.36-0.84 (p = 0.005), and HR = 0.69, 95% CI = 0.52-0.92 (p = 0.012); HR = 0.70, 95% CI = 0.51-0.96 (p = 0.030), and HR = 0.68, 95% CI = 0.49-0.94 (p = 0.020), and HR = 0.75, 95% CI = 0.55-1.01 (p = 0.057), respectively. These results may be attributed to the fact that ticagrelor, in contrast to clopidogrel, significantly increases the potency of CYP3A4-metabolized statins, which in turn may increase the vascular benefit derived from the statin, giving an unfair advantage to ticagrelor. Moreover, inappropriate statin dosing restrictions (underdosing of simvastatin and lovastatin) were deliberately utilized in PLATO, potentially contributing to the beneficial effect of ticagrelor.
  
  
  CONCLUSIONS
  In patients on statins, both vascular and all-cause mortality rates were significantly reduced with ticagrelor in the PLATO trial. However, this benefit may in part be driven by an increased efficacy of CYP3A4-metabolized statins on top of ticagrelor and/or from the inappropriate dose restriction of simvastatin and lovastatin in the clopidogrel arm.
authors: Wegman’s Pharmacy 500 South Meadow Street Ithaca, NY 14850, USA. jjdinicol @ gmail.com
authors: James J
authors: JJ
authors: Dinicolantonio
authors: Victor L
authors: VL
authors: Serebruany
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000401:mortality*; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017326:Clinical Trials, Phase III as Topic; D000077144:Clopidogrel; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008148:Lovastatin / Q000008:administration & dosage; D015337:Multicenter Studies as Topic; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic; D019821:Simvastatin / Q000008:administration & dosage; D000077486:Ticagrelor; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D008148:Lovastatin; D000077144:Clopidogrel; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine