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Effects of Ibuprofen on the Magnitude and Duration of Aspirin's Inhibition of Platelet Aggregation: Clinical Consequences in Stroke Prophylaxis

From the Departments of Neurology (Dr F. M. Gengo, Dr Bates), Pharmacy (Dr F. M. Gengo, Dr Rubin), and Pharmaceutical Sciences (Dr Mager), University at Buffalo, Buffalo, New York and Dent Neurologic Institute, Buffalo, New York (Dr F. M. Gengo, Mr Robson, Dr Rainka, Mr M. F. Gengo, Dr Bates). Preliminary data presented at the 35th annual meeting of the American College of Clinical Pharmacology Cambridge Massachusetts.

Address for reprints: Fran Gengo, PharmD, FCP, Dent Neurologic Institute, 3980 Sheridan Drive, Suite 200, Amherst, NY 14226; e-mail: fgengo{at}buffalo.edu.

	ABSTRACT

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This study was designed to measure the magnitude and duration of inhibition of platelet aggregation following doses of aspirin or ibuprofen alone or taken in combination in a group of healthy volunteers. Ten normal volunteer subjects underwent 3 randomized treatment sessions: aspirin 325 mg alone, ibuprofen 400 mg alone, and ibuprofen 400 mg, followed by dosing with aspirin 325 mg 2 hours thereafter. In addition, a confirmatory study was performed in patients. Over 27 months, a cohort of patients treated with aspirin for secondary stroke prophylaxis while concomitantly taking a nonsteroidal anti-inflammatory drug (NSAID) was identified. A significant reduction was found in both the magnitude and duration of aspirin's inhibitory effect on platelet aggregation when ibuprofen was given prior to aspirin administration in normal volunteer subjects. During a 27-month period, a cohort of 28 patients took regular daily doses of ibuprofen or naproxen. Of these 28 patients, 18 returned for follow-up testing in the absence of this pharmacodynamic interaction. None of these 18 patients demonstrated inhibition of platelet aggregation while on both NSAID and aspirin; however, all showed inhibition of aggregation following discontinuation of the NSAID. Notably, 13 of these 18 patients (72%) had experienced a recurrent ischemic episode while taking aspirin and NSAIDs concomitantly. These data suggest that ibuprofen prevents the irreversible inhibition of platelet aggregation produced by aspirin needed for secondary stroke prophylaxis, and this interaction can have clinical consequences for patients taking aspirin.

Key Words: Platelet aggregation • aspirin • ibuprofen • nonsteroidal anti-inflammatory drug • stroke

Aspirin produces an inhibition of platelet aggregation by acetylating a serine moiety on the cyclooxygenase (COX)-1 enzyme in platelets. This irreversible binding of the COX-1 enzyme renders the platelet permanently unable to aggregate. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen act similarly to inhibit the activity of platelet cyclooxygenase; however, their effects are reversible, and the duration of their inhibition of platelet aggregation is related closely to their half-life.^1,2 The half-life of ibuprofen is generally reported to be between 2 and 4 hours, and the half-life of naproxen is generally reported to be around 12 hours.

There have been several previous studies in healthy volunteers investigating the interaction of these 2 compounds as they compete for the cyclooxygenase enzyme. We have reported previously that ibuprofen 200 mg dosed prior to a 325-mg dose of aspirin significantly reduced in duration the inhibition of platelet aggregation of aspirin alone.³ The effects of ibuprofen on platelet aggregation were significantly related to plasma concentrations of the S-isomer of ibuprofen. Catella–Lawson and associates⁴ reported the results from combinations of aspirin 81 mg taken 2 hours before ibuprofen 400 mg every morning and the same medications in reverse order taken for 6 days. They reported a significant interaction when aspirin is taken following ibuprofen. Capone and associates⁵ published similar findings evaluating the interaction of naproxen with low-dose aspirin in healthy subjects. In contrast, data reported by Cryer et al⁶ failed to show any interaction between aspirin and ibuprofen.

These previous studies report data measuring platelet response prior to dosing and then at a single time point in time following administration of aspirin and an NSAID. None has described the specific time course of the effects of aspirin alone and then aspirin with ibuprofen. Some of the conflicting data in these reports may be because platelets are able to aggregate during times when NSAID concentrations are low but not at earlier times while NSAID concentrations remain high. For this reason, the first part of our study was conducted in normal volunteers. It was designed to describe the full time course of inhibition of platelet aggregation following aspirin alone and then aspirin concomitantly taken with ibuprofen. The second part of this study includes data from 27 patients treated with aspirin for secondary stroke prophylaxis and 1 patient treated for factor V Leiden who had been taking either ibuprofen or naproxen daily and concomitantly with aspirin, confirming the interaction as well as its clinical consequences. Although epidemiological reports suggest greater risk of cardiac ischemic events, there have been no reports regarding the clinical consequences of this interaction when aspirin is used for stroke prophylaxis. The Food and Drug Administration (FDA) currently warns that ibuprofen might render aspirin therapy less effective but states that the clinical implication of this interaction has not been evaluated in clinical endpoint studies.⁷ The data from patients in this present study report both platelet aggregation data and the apparent clinical consequences of the aspirin-NSAID interaction.

	METHODS

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Normal Volunteer Study
This was a single-blinded, randomized 3-way complete crossover design study. The protocol was reviewed and approved by the Institutional Review Committee of the University at Buffalo (SUNY). Informed consent was obtained from 6 male and 4 female volunteers between the ages of 21 and 32 years old. Exclusion criteria included subjects with an allergy to aspirin or ibuprofen, as well as subjects who were smokers, had any systemic diseases, had any history of bleeding disorders, or were pregnant. Subjects did not use any NSAID or aspirin for 1 week prior to the study, and throughout the study period, subjects could not use ethanol for 48 hours prior to each study session.

Subjects provided informed consent, underwent screening, and were randomized to receive 1 of 3 treatments with a minimum 6-day washout period between treatments, or when platelet aggregation resumed following the previous treatment arm. All subjects had to demonstrate platelet aggregation at time 0 (predose) of each treatment arm. Treatments consisted of ibuprofen 400 mg, aspirin 325 mg, and ibuprofen 400 mg subsequently followed by a 325-mg dose of aspirin 2 hours thereafter.

Two 4.5-mL blood samples were collected into tubes containing 3.8% sodium citrate at times corresponding to 0, 1, 2, 4, 6, 8, 12, 24, and 48 hours post-dose and then every 24 hours until platelet function returned to baseline. Platelet aggregation in wholeblood samples was measured using an impedance aggregometer (Model 700, Chrono-Log Corporation, Havertown, Pennsylvania). Measurements were performed at 37°C at a stirring speed of 1200 rpm. Whole blood (500 µL) was diluted 1-to-1 with 0.9% NaCl and prewarmed for 5 minutes at 37°C. After the electrode was placed, platelet aggregation in response to collagen 1 µg/mL, collagen 5 µg/mL, and arachidonate 0.5 mM was measured in ohms of impedance. Collagen and arachidonate were purchased from Chrono-Log Corporation.

Results from platelet aggregation studies in volunteers underwent a repeated-measures analysis of variance (ANOVA) for treatment and time. Subsequent Tukey testing was then applied to determine which treatment and time variables produced statistically significant differences in platelet aggregation. When platelet function had returned to baseline, the last measurement was carried forward to 96 hours.

Stroke Patient Cohort
This observational study was conducted in the course of routine clinical care. For a 27-month period, consecutive patients treated at the Dent Neurologic Institute (Amherst, New York) who were receiving aspirin and who also reported regularly taking ibuprofen or naproxen were identified. Twenty-seven patients were taking aspirin for secondary stroke prophylaxis, whereas 1 patient was taking aspirin for factor V Leiden (N = 28). These patients were either taking aspirin alone or along with an antiplatelet regimen containing dipyridamole or clopidogrel. Total daily aspirin dose was noted. Each of these patients had signed informed consent to act as a research participant in a protocol reviewed and approved by the Institutional Review Committee of the University at Buffalo (SUNY). Each had platelet function testing conducted using whole-blood impedance aggregometry in response to collagen 1 µg/mL, collagen 5 µg/mL, and arachidonate 0.5 mM, as stated previously. This testing was initially conducted while the patient was concomitantly taking both aspirin and the NSAID. Patients were tested at a time when the NSAID concentrations would have been very low so that only the platelet response to aspirin would have been observed. This was at least 6 hours after the ibuprofen dose and 12 hours after the naproxen dose. Eighteen patients were willing to return for retesting 2 to 4 weeks after either discontinuing the NSAID or taking it at a time to avoid the interaction with aspirin. Retesting was done at a time when the NSAID concentration would have been low, and only the platelet response to aspirin would be observed. Patients who chose to discontinue the NSAID were advised that they could substitute a non-NSAID analgesic such as acetaminophen. Urine was collected on both occasions to test for the presence of salicylates indicating compliance to aspirin therapy.

Data from platelet aggregation studies in the patient cohort underwent a paired Student t test comparing response to collagen 1 µg/mL and arachidonate 0.5 mM before and after discontinuing the NSAID.

	RESULTS

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Normal Volunteer Study
In the normal volunteers, maximum reduction of platelet aggregation in response to both collagen 1 µg/mL and arachidonate was evident 2 hours following the administration of aspirin alone (Figure 1). The mean maximum inhibition of the response to collagen 1 µg/mL was 3.5 ohms, which represents a 76% reduction in platelet aggregation as compared with baseline. The same measurement for arachidonate 0.5 mM was 1.1 ohms or a 91% reduction as compared with baseline. Following administration of aspirin alone, platelet function did not return to baseline values until between 72 and 96 hours. The mean time of platelet aggregation returning to baseline was 91.2 ± 18.9 hours in response to collagen 1 µg/mL and 80.9 ± 31.87 hours in response to arachidonate.

View larger version (22K): [in this window] [in a new window]   Figure 1. Magnitude and time course of aggregation induced by collagen 1 µg/mL following aspirin 325 mg, ibuprofen 400 mg, and aspirin 325 mg following administration of ibuprofen 400 mg. Mean and standard deviation (n = 10).

Following coadministration of ibuprofen and aspirin, inhibition of platelet aggregation was the same as was observed following ibuprofen (Figure 1). The coadministration of ibuprofen with aspirin significantly reduced the magnitude and duration of aspirin inhibitory effects on platelet aggregation (sum of squares [SS] = 475.6, F = 2.56, P < .007).

The mean time of platelet aggregation returning to baseline was 5.5 ± 0.93 hours for collagen 1 µg/mL and 5 ± 1.10 hours for arachidonate 0.5 mM. Platelet inhibition was not seen in 1 patient in response to collagen 1 µg/mL and 4 patients in response to arachidonate 0.5 mM. The inhibition of platelet aggregation following aspirin alone was very similar in magnitude and duration, whether measured in response to collagen 1 µg/mL or arachidonate 0.5 mM. This strong correlation is shown in Figure 2 (R² = 0.94).

View larger version (11K): [in this window] [in a new window]   Figure 2. Correlation between platelet aggregation in response to collagen (1 µg/mL) and arachidonate (0.5 mM) orthogonal regression analysis (R2 = 0.94).

Stroke Patient Cohort
A total of 28 patients were identified as simultaneously taking aspirin along with either ibuprofen or naproxen. All of these 28 patients showed platelet nonresponsiveness to their current antiplatelet therapy. Of these 28 patients, 18 patients agreed to not take an NSAID concomitantly with their aspirin antiplatelet regimen and also to return for follow-up testing. This 18-patient cohort included 6 men and 12 women, average age 60 ± 16 years. The average daily dose of aspirin at the time of the interaction was 108 ± 69 mg/day. This dose ranged from 50 mg/day of aspirin with dipyrimadole, up to 325 mg/day. Thirteen of these 18 subjects (72%) were being seen in the clinic because they had experienced another cerebral ischemic event while concomitantly receiving aspirin and the NSAID daily. Of these 18 patients, 14 were taking ibuprofen ranging from 200 to 800 mg/dose concomitantly with aspirin. Four were taking naproxen in doses ranging from 220 to 500 mg/dose concomitantly with aspirin. All were taking a dose of their NSAID within 1 hour of the time that they took their daily dose of aspirin.

All 18 tested positive for the presence of salicylates in their urine at both visits, thus indicating compliance with their aspirin dosing.

While simultaneously taking aspirin and their NSAID, there was no significant inhibition of platelet aggregation in response to collagen 1 µg/mL and arachidonate 0.5 mM. Platelet function testing in patients concomitantly receiving aspirin and NSAIDs was similar to drug-free control subjects. Following elimination of the pharmacodynamic interaction, significant inhibition of platelet aggregation by aspirin was shown in response to collagen and arachidonate in all of the 18 patients. Aggregation to collagen 1 µg/mL decreased significantly from 14.13 ± 4.15 to 5.16 ± 2.09 ohms of resistance (P = 5.37 x 10^–14). In addition, aggregation to arachidonate decreased significantly from 8.23 ± 7.65 to 0.53 ± 0.87 ohms of resistance (P = 8.1 x 10^–4), whereas the ratio of aggregation to collagen 1 µg/mL compared with collagen 5 µg/mL decreased from 0.59 ± 0.19 to 0.25 ± 0.11 (P = 1.92 x 10^–7).

Eleven patients did have their aspirin dose increased prior to follow-up testing, 1 patient's dose was decreased, and 6 patients' aspirin doses remained the same. The average daily dose of aspirin at the time of follow-up testing was 223 ± 115 mg/day. This dose ranged from 50 mg/day of aspirin with dipyrimamole, up to 375 mg/day.

	DISCUSSION

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Normal Volunteer Study
Platelet aggregation profiles from healthy volunteers demonstrate that both the magnitude and duration of inhibition of platelet aggregation produced by aspirin 325 mg are significantly reduced when taken in close temporal proximity to a modest dose of ibuprofen. Within 4 to 6 hours after taking aspirin along with ibuprofen, platelet function is not different from measures at drug-free baseline. These data confirm some previously published studies conducted in volunteers. The present data, however, include the magnitude and time course of each drug administered separately as well as the drugs administered in combination. It is clear from the data presented that at an aspirin dose as high as 325 mg, when taken during a time when ibuprofen concentrations are present, produces no change in platelet function other than that produced by the ibuprofen. Despite the aspirin, platelets were able to aggregate in as little as 4 hours. This suggests that patients taking aspirin and ibuprofen together would have no antiplatelet effect from taking aspirin for as much as 18 to 20 hours each day.

It has been debated whether platelet response to aspirin should be assessed in response to collagen or arachidonate. The data presented here show that platelet function can be measured to either agonist and that the platelet aggregation in response to collagen is highly correlated to platelet aggregation in response to arachidonate (Figure 2).

Stroke Patient Cohort
The data presented from our patient cohort demonstrate that this interaction occurs not only under the controlled circumstances of a clinical trial but also occurs in patients taking these drugs under real-world circumstances. The patients, all of whom were compliant with taking aspirin and were using an NSAID on a regular basis, showed no inhibition of platelet aggregation during the ongoing aspirin–NSAID interaction. Removal of the NSAID interaction reliably restored platelet responsiveness to aspirin.

Several previous reports failed to show significant interaction following multiple days of coadministration of both aspirin and NSAIDs.^4,6 One possibility for this lack of interaction is that measures were made at only 1 time point following chronic coadministration. The inhibition of platelet aggregation or reduction of thromboxane B₂ may have been observed at a time when NSAID concentrations were sufficiently high to inhibit them. Lower NSAID concentrations may not result in an antiplatelet effect but may continue to bind to COX-1, thereby preventing the antiplatelet effect of aspirin. Our study was specifically designed only to capture the influence of the aspirin, if any, and not to capture the NSAID's effect on platelet aggregation. Furthermore, these previous studies were conducted in healthy volunteers, whereas our patients all had multiple vascular risk factors, including a prior stroke. This possibility is supported by a number of epidemiological studies suggesting increased risk of cardiovascular events in various populations of patients treated with both aspirin and NSAIDs.^8-10

Kimmel and colleagues⁸ published a case control study comparing patients experiencing first myocardial infarction identified prospectively with controls identified randomly. Aspirin alone was associated with a decreased risk of myocardial infarction in patients not using NSAIDs but did not decrease the risk of myocardial infarction in patients using both aspirin and NSAIDs.

Kurth et al⁹ found that patients enrolled in the Physician's Health Study, randomized to receive aspirin but who were also using an NSAID, were at increased risk of adverse cardiovascular events compared with patients using aspirin alone. The greatest risk was found in those patients who used NSAIDs more than 60 days per year.

Patients in the present study were those using NSAIDs on a regular basis. This may represent one explanation for the relatively high occurrence of another cerebral ischemic event. McDonald and Wei¹⁰ studied patients with established cardiac disease using both aspirin and ibuprofen and found that these patients had an increased risk of cardiovascular mortality compared with patients taking aspirin alone. In contrast, Ko and colleagues¹¹ found that older patients who had survived a first myocardial infarction and were prescribed aspirin and NSAIDs in combination had a similar mortality rate to patients prescribed aspirin alone. We are not aware of any reports regarding this interaction increasing the risk of stroke.

In the present study involving all but 1 patient treated with aspirin for secondary stroke prophylaxis, we were able to identify the NSAID being used; account for all prescription and over-the-counter drug use, including information detailing the timing and frequency of their NSAID use; and confirm that each was compliant in taking aspirin based on the presence of urinary salicylates. In this cohort of 18 patients, 13 were seen because of another cerebrovascular event. It is possible that these ischemic events would have occurred irrespective of this interaction. However, the likelihood that 13 of 18 patients taking aspirin and NSAIDs, with none showing inhibition of platelet aggregation, would by chance alone have another ischemic event seems remote. Some may argue that these data are confounded by the fact that the aspirin dose was changed in some patients prior to follow-up testing. However, the data presented from our normal volunteer study showed that an NSAID could interact with aspirin doses as high as 325 mg and prohibit aspirin from effectively inhibiting platelet aggregation.

In summary, the pharmacodynamics and clinical data presented here support recent FDA warnings that "patients who use immediate-release aspirin (not enteric-coated) and take a single dose of ibuprofen, 400mg, should dose the ibuprofen at least 30 minutes or longer after aspirin ingestion, or more than 8 hours before aspirin ingestion to avoid attenuation of aspirin's effect."⁷ In addition, our data suggest that naproxen or ibuprofen, in as little as over-the-counter doses, can produce this pharmacodynamic interaction.

The present study is limited by its small sample size. However, it is the first study to demonstrate the clinical consequences of the aspirin-NSAID interaction in patients being treated for secondary stroke prophylaxis, as well as present data to support the possible mechanism by which these patients developed new ischemic events. The FDA states that the clinical consequences of this interaction are unclear. We believe these data provide further evidence of the clinical consequences of this interaction. Because of the outcomes seen in our patient population, we believe that it would be unethical to subject patients using aspirin for secondary stroke prophylaxis to this interaction in a controlled clinical trail. However, more data should be collected from patients who have taken this combination.

	ACKNOWLEDGEMENTS

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Financial disclosure: None declared.

	REFERENCES

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1. Evans AM. Pharmacodynamics and pharmacokinetics of the profens: enantioselectivity, clinical implications, and special reference to S(+)-ibuprofen. J Clin Pharmacol. 1996;36: 7S-15S.[Abstract]

2. Shah A, Woodruff M, Agarwal V, Liu P, Sundaresan P. Pharmacokinetics, safety, and tolerability of BAY 12-9566 and nonsteroidal anti-inflammatory agents (naproxen, ibuprofen) during coadministration in patients with osteoarthritis. J Clin Pharmacol. 2001;41: 330-339.[Abstract]

3. Fullerton T, Solomon B, Kinkel P, Gengo FM. Pharmacodynamics of the (S)-ibuprofen/aspirin interaction of human antiplatelet activity. J Clin Pharmacol. 1992;32: 742.

4. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345: 1809-1817.[Abstract/Free Full Text]

5. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol. 2005;45: 1295-1301.[Abstract/Free Full Text]

6. Cryer B, Berlin RG, Cooper SA, Hsu C, Wason S. Double-blind, randomized, parallel, placebo-controlled study of ibuprofen effects of thromboxane B2 concentrations in aspirin-treated healthy adult volunteers. Clin Ther. 2005;27: 185-191.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Food and Drug Administration. Concomitant Use of Ibuprofen and Aspirin: Potential for Attenuation of the Anti-Platelet Affect of Aspirin. Rockville, MD: Food and Drug Administration; 2006. Available at: http://www.fda.gov/cder/drug/infopage/ibuprofen/science_papter.htm.

8. Kimmel SE, Berlin JA, Reilly M, et al. The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardial. 2004;43: 985-990.[Abstract/Free Full Text]

9. Kurth T, Glynn RJ, Walker AM, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal anti-inflammatory drugs. Circulation. 2003;108: 1191-1195.[Abstract/Free Full Text]

10. McDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361: 573-577.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Ko D, Wang Y, Berger A, Radford M, Krumholz H. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Am Heart J. 2002;143: 475-481.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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