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Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients

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Abstract

Background

Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis-generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD).

Methods

We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time-series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days.

Results

Patients’ mean age was 75.5 ± 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002).

Conclusion

This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable.

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Abbreviations

AA:

Arachidonic acid

ACE:

Angiotensine converting enzyme

AT II:

Angiotensin II

Ca:

Calcium

CABG:

Coronary bypass grafting

COPD:

Chronic obstructive pulmonary disease

CAD:

Chronic artery disease

CKD:

Chronic kidney disease

COX:

Cyclooxygenase

GFR:

Glomerular filtration rate

HDL:

High density lipoprotein

HTPR:

High on-treatment platelet reactivity

LDL:

Low-density lipoprotein

LTA:

Light transmission aggregometry

MACCE:

Major adverse cardiac and cerebrovascular events

MI:

Myocardial infarction

MoA:

Maximum of aggregation

PCI:

Percutaneous coronary intervention

S.D.:

Standard deviation

TG:

Triglyceride

T½:

Half-life

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Acknowledgments

The authors thank Kirsten Bartkowski for experimental support.

Funding

This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 46-2016, to L.D., No. 16-2014 to A.P.).

Author information

Author notes

  1. Lisa Dannenberg and Tobias Petzold contributed equally to this work.

Authors and Affiliations

  1. Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Düsseldorf, Germany

    Lisa Dannenberg, Alina Achilles, David Naguib, Saif Zako, Carolin Helten, René M‘Pembele, Philipp Mourikis, Tobias Zeus, Malte Kelm & Amin Polzin

  2. Department of Cardiology, LMU München, Munich, Germany

    Tobias Petzold

  3. DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany

    Tobias Petzold

  4. Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Düsseldorf, Germany

    Yanina Podsvyadek, Maria Grandoch & Thomas Hohlfeld

  5. West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Institute of Pathophysiology, Essen, Germany

    Bodo Levkau

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  1. Lisa Dannenberg
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Contributions

L.D., T.P., and A.A. designed the study, analyzed, and interpreted data and wrote the manuscript. D.N., S.Z., C.H., R.M., and P.M. collected data and revised the manuscript. A.P., T.H., M.K., T.Z., B.L., M.G., and Y.P. supervised the study and revised the manuscript.

Corresponding author

Correspondence to Lisa Dannenberg.

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Ethical approval

The study conformed to the Declaration of Helsinki and was approved by the University of Düsseldorf Ethics Committee.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Dannenberg, L., Petzold, T., Achilles, A. et al. Dose reduction, oral application, and order of intake to preserve aspirin antiplatelet effects in dipyrone co-medicated chronic artery disease patients. Eur J Clin Pharmacol 75, 13–20 (2019). https://doi.org/10.1007/s00228-018-2560-z

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