Exploring the ticagrelor-statin interplay in the PLATO trial

James J. Dinicolantonio, Victor L. Serebruany

Research output: Contribution to journalArticle

Abstract

Context: 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.

Original languageEnglish (US)
Pages (from-to)105-107
Number of pages3
JournalCardiology
Volume124
Issue number2
DOIs
StatePublished - Mar 2013

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
clopidogrel
Blood Vessels
Cytochrome P-450 CYP3A
Lovastatin
Simvastatin
Mortality
Ticagrelor
(1,2-diamino-4-nitrobenzene)dichloroplatinum(II)
Aspirin
Blood Platelets
Confidence Intervals

Keywords

  • Acute coronary syndromes
  • Clopidogrel
  • Dosing
  • Mortality
  • Statins
  • Ticagrelor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

Dinicolantonio, J. J., & Serebruany, V. L. (2013). Exploring the ticagrelor-statin interplay in the PLATO trial. Cardiology, 124(2), 105-107. https://doi.org/10.1159/000346151

Exploring the ticagrelor-statin interplay in the PLATO trial. / Dinicolantonio, James J.; Serebruany, Victor L.

In: Cardiology, Vol. 124, No. 2, 03.2013, p. 105-107.

Research output: Contribution to journalArticle

Dinicolantonio, JJ & Serebruany, VL 2013, 'Exploring the ticagrelor-statin interplay in the PLATO trial', Cardiology, vol. 124, no. 2, pp. 105-107. https://doi.org/10.1159/000346151
Dinicolantonio, James J. ; Serebruany, Victor L. / Exploring the ticagrelor-statin interplay in the PLATO trial. In: Cardiology. 2013 ; Vol. 124, No. 2. pp. 105-107.
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abstract = "Context: 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.",
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N2 - Context: 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.

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