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The PLATO trial was funded by AstraZeneca Shaun Goodman:

Proton Pump Inhibitor Use is Likely a Marker for, Rather than a Cause of, a Higher Risk of Cardiovascular Events: Insights from PLATO. Shaun G. Goodman, Robert Clare, Karen S. Pieper, Stefan K. James, José C. Nicolau, Robert F. Storey, Warren J. Cantor, Dominick J. Angiolillo,

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The PLATO trial was funded by AstraZeneca Shaun Goodman:

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  1. Proton Pump Inhibitor Use is Likely a Marker for, Rather than a Cause of, a Higher Risk of Cardiovascular Events: Insights from PLATO Shaun G. Goodman, Robert Clare, Karen S. Pieper, Stefan K. James, José C. Nicolau, Robert F. Storey, Warren J. Cantor, Dominick J. Angiolillo, Steen Husted, Christopher P. Cannon, Ph. Gabriel Steg, Kenneth W. Mahaffey, Jan Kilhamn, Robert A. Harrington, Lars Wallentin, on behalf of the PLATO Trial Investigators

  2. Disclosures/Conflicts of Interest • The PLATO trial was funded by AstraZeneca • Shaun Goodman: • Significant research grant support from Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Sanofi Aventis • Modest consultant/advisory board honoraria from Astra Zeneca, Bristol Myers Squibb, Lilly, Merck, Teva • Other Author Disclosure Information available in the abstract: Circulation 2010;122:A12092 • Ticagrelor is not yet approved for use

  3. ADP Receptor Antagonists and Proton Pump Inhibitors • Conflicting data exist regarding the potential adverse interaction between clopidogrel and proton pump inhibitors (PPIs) • PPIs inhibit the cytochrome P450 2C19 isoenzyme and conversion of clopidogrel into its active metabolite • In contrast, ticagrelor is an ADP P2Y12 inhibitor that does not require biotransformation and has no known interaction with PPIs

  4. Objective • To examine the association between proton pump inhibitor (PPI) use and clinical outcomes for acute coronary syndrome (ACS) patients randomized to clopidogrel or ticagrelor

  5. PLATO Study Design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Ticagrelor (n=9333) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) Clopidogrel (n=9291) If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) 6–12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding James et al Am Heart J 2009;157:599-605

  6. PLATO Main Endpoints Major Bleeding CV Death, MI, Stroke 13 15 12 11.7 Clopidogrel 11 Ticagrelor 11.6 10 9.8 11.2 9 10 Clopidogrel Ticagrelor 8 7 K-M estimated rate (% per year) K-M estimated rate (% per year) 6 5 HR 0.84 (95% CI 0.77–0.92), p=0.0003 HR 1.04 (95% CI 0.95–1.13), p=0.43 5 4 3 2 1 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months Months No. at risk 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047 Wallentin et al N Engl J Med 2009;361:1045-57

  7. Methods • Pre-specified subgroup analysis • Proton pump inhibitor use was at the physician’s discretion • Multivariable Cox model with propensity adjustment and landmark analysis • The primary endpoint was the 1-year composite of CV death, MI, or stroke

  8. Primary and Secondary Analyses End of follow-up Median Time to Death/Censoring (IQR) = 358 Days (266, 369) Landmark Days 2, 4, 9, 30 Landmark Day 60 Landmark Day 90 Landmark Day 180 PLATO Trial • Any PPI vs. Non-PPI Gastric Supressive (e.g., H2 antagonist) therapy • Any PPI vs. no GI therapy PPI use at randomization All analyses were stratified by randomized treatment arm

  9. PPI Use at Randomization 18601 of 18624 (99.9%) patients had documentation regarding PPI use prior to randomization → 6539 (35.2%) were taking a PPI * Type of PPI available in n=6538

  10. Selected Baseline and Index Event Characteristics All p<0.05

  11. Primary Outcome by Randomized Treatment and PPI Use % of Patients with CV Death/MI/Stroke 14 13.03 12 10.96 10.92 10 9.19 8 6 Clopidogrel + PPI (n=3255) Ticagrelor + PPI (n=3284) Clopidogrel + No PPI (n=6020) Ticagrelor + No PPI (n=6040) 4 2 0 0 50 100 150 200 250 300 350 400 Days

  12. Unadjusted and Adjusted* Cardiovascular Outcomes by Randomized Treatment and PPI Use Hazard Ratio & 95% CI + PP2Y12 *PPI Clopidogrel 1.22 (1.08,1.39) 0.96 Unadjusted Cardiovascular Death, MI or Stroke Ticagrelor 1.23 (1.07,1.41) Clopidogrel 1.20 (1.04,1.38) *Propensity Adjusted 0.72 Ticagrelor 1.24 (1.06,1.45) Clopidogrel 1.27 (1.11,1.45) 0.84 Unadjusted Ticagrelor 1.24 (1.08,1.44) Cardiovascular Death or MI Clopidogrel 1.20 (1.03,1.40) *Propensity Adjusted 0.94 Ticagrelor 1.26 (1.07,1.48) 0.8 1.0 1.2 1.4 1.6 No PPI Better PPI Worse + P2Y12 inhibitor Treatment * PPI interaction P-value

  13. 1-Year Non-CABG PLATO Major Bleeding* by Randomized Treatment and PPI Use % of Patients 6 Pinteraction for P2Y12 *PPI=0.17 5 4.90 4.39 4.24 4 3.43 3 +Hazard Ratio 1.30 (95% CI 1.00-1.70) +Hazard Ratio 1.02 (95% CI 0.80-1.29) 2 1 0 PPI No PPI PPI No PPI Ticagrelor Clopidogrel * Kaplan-Meier estimates + Propensity-adjusted

  14. Additional Analyses • Patients (n=1826) on non-PPI gastrointestinal drugs (e.g. H2 receptor antagonists) prior to randomization were at similar risk to those on a PPI • Clopidogrel: HR 0.98 (0.79-1.23) • Ticagrelor: HR 0.89 (0.73-1.10) • Patients (n=10236) on no gastric therapy were at significantly lower risk of the primary endpoint • Clopidogrel: HR 1.29 (1.12-1.49) • Ticagrelor: HR 1.30 (1.14-1.49) • Landmark analyses accounting for PPI use (at days 2, 4, 9, 30, 60, 90, and 180) post-randomization showed no increased risk of the primary endpoint in those receiving a PPI • Except in patients who prematurely discontinued study treatment (clopidogrel or ticagrelor) from day 180 post-randomization (PPI vs. no PPI: HR 4.31 [1.70-10.95]) PPI vs. non PPI GI treatment PPI vs. no GI treatment

  15. Limitations • Pre-defined subgroup analysis with multiple comparisons → individual subgroups may have been underpowered to show an association between PPI use and clinical outcomes • Use of a PPI was not randomized → potential for residual confounding despite multivariable adjustment and propensity score for the decision to treat with a PPI • PPIs could be initiated or discontinued during the course of follow-up → landmark analyses employed • Different types of PPIs with potentially different effects on CYP2C19 and clopidogrel metabolism

  16. Conclusions • The apparent association between PPI and clopidogrel use and adverse events is highly confounded • PPI use may simply be a marker for, rather than a cause of, a higher risk of CV events • Regardless of PPI use, ticagrelor was superior to clopidogrel in preventing ischemic events

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