Inconsistency of different methods for assessing ex vivo platelet function: relevance for the detection of aspirin resistance.

BACKGROUND: Assays to evaluate platelet function are often interchangeably used to assess "resistance" to aspirin. We compared different platelet function assays in patients treated or untreated with aspirin. DESIGN AND METHODS: Platelet function was evaluated in 162 subjects, 85 of whom were not being treated with any antiplatelet drug and 77 of whom were receiving chronic therapy with low-dose aspirin. Platelet Function Analyzer collagen/ADP- and collagen/epinephrine closure times, as well as light transmittance aggregometry in response to ADP, collagen and arachidonic acid (this last in 47 aspirin-treated patients) were determined. In 43 aspirin-treated patients, serum thromboxane B(2) levels were also measured. RESULTS: In untreated patients, collagen/ADP- and collagen/epinephrine-closure times were correlated with each other (r=0.5, P=0.0001), but did not correlate with ADP- or collagen-induced aggregation. In patients treated with aspirin, collagen/ADP-closure time values were not different from those in untreated patients, while the collagen/epinephrine-closure time was prolonged. ADP-induced aggregation was unaffected by aspirin, while collagen-induced aggregation was reduced. Arachidonic acid-induced aggregation was almost completely suppressed (% maximum light transmittance aggregometry =5 ± 13%). There was, however, no correlation between the various platelet function tests. Serum thromboxane B(2), an index of platelet cyclooxygenase-1 activity, was almost completely suppressed (down to 8 ± 17 ng/mL) in treated patients, and was not correlated with arachidonic acid-, ADP- and collagen-induced aggregation or with collagen/ADP-closure time, but was inversely correlated with collagen/epinephrine-closure time. CONCLUSIONS: There is a high heterogeneity of results of tests evaluating inhibition of platelet function by aspirin, and the results of functional tests do not match biochemical measurement of cyclooxygenase-1 activity. Extreme caution should, therefore, be used in defining "resistance" to aspirin on the basis of the results of these tests.

Aspirin-triggered lipoxin in patients treated with aspirin and selective vs. nonselective COX-2 inhibitors.

AIMS: Cyclooxygenase (COX)-2 inhibition has been reported to suppress the biosynthesis of the gastroprotective lipoxygenase metabolite 15(R)-epi-lipoxin A(4), also termed 'aspirin-triggered lipoxin' (ATL). We tested the hypothesis that the co-administration of aspirin with either the selective COX-2 inhibitor celecoxib or the nonselective COX inhibitor ibuprofen reduces ATL biosynthesis. METHODS: We measured the urinary excretion of ATL in 24 patients with both ischaemic heart disease and osteoarthritis, chronically treated with aspirin and co-administered celecoxib 200 mg b.i.d., ibuprofen 600 mg t.i.d., or placebo for 7 days. RESULTS: Baseline ATL was comparable in the three groups. On days 1 and 7, 4 h after co-administration of celecoxib or ibuprofen, ATL levels did not show significant variations (day 1: 0.24 +/- 0.33, 0.26 +/- 0.21 and 0.37 +/- 0.22 ng mg(-1) creatinine, respectively; day 7: 0.21 +/- 0.13, 0.35 +/- 0.15 and 0.23 +/- 0.18 ng mg(-1) creatinine, respectively). CONCLUSIONS: Neither selective nor nonselective COX-2 inhibition appreciably interferes with ATL biosynthesis, suggesting that this mediator is not involved in exacerbating gastrotoxicity by the association of aspirin with COX-2 inhibitors.

Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension.

Increased blood pressure (BP) may stimulate vascular inflammation, which may itself induce pathological arterial changes. BP variability has been associated with target-organ damage and future cardiovascular complications. We hypothesized that BP variability, as derived from ambulatory BP monitoring, is related to inflammatory markers in newly diagnosed hypertension. Systolic (S) and diastolic (D) BP variabilities were assessed as the SD of 24-h pressure recordings in a cohort of 190 recently (<6 months) diagnosed, untreated hypertensive subjects. Target organ damage, assessed by measuring the carotid artery intima-media thickness, left ventricular mass index, and microalbuminuria, was related to plasma high-sensitivity C-reactive protein (hsCRP) and soluble (s) E-selectin, an endothelium-specific molecule. The patients' age (mean+/-SD) was 53.0+/-8.5 years, and 59% were male. Multivariable analysis identified awake SBP variability (95% confidence interval [CI]: 0.002-0.042, p=0.034) as an independent correlate of hsCRP and awake SBP (95% CI: 0.003-0.014, p=0.003), awake SBP variability (95% CI: 0.003-0.035, p=0.018), and microalbuminuria (95% CI: 0.075-0.280, p=0.001) as independent correlates of sE-selectin. When patients were divided into low and high awake SBP variability groups, age (p=0.001), hsCRP (p=0.0001), and sE-selectin (p=0.005) were significantly different in the two groups. After adjusting for age, these differences remained significant (p=0.022 and p=0.001 for hsCRP and sE-selectin, respectively). In recently diagnosed hypertensive subjects, hsCRP and sE-selectin levels are related to awake SBP variability. High SBP variability is likely associated with vascular inflammation in newly diagnosed hypertension, independent of SBP. (Hypertens Res 2008; 31: 2137-2146).

Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease.

BACKGROUND AND OBJECTIVE: We performed a placebo-controlled, randomized study to address whether celecoxib or ibuprofen undermines the functional range of inhibition of platelet cyclooxygenase (COX)-1 activity by aspirin in patients with osteoarthritis and stable ischemic heart disease. METHODS: Twenty-four patients who were undergoing long-term treatment with aspirin (100 mg daily) for cardioprotection were coadministered celecoxib, 200 mg twice daily, ibuprofen, 600 mg 3 times daily, or placebo for 7 days. RESULTS: The coadministration of placebo or celecoxib did not undermine the aspirin-related inhibition of platelet COX-1 activity, as assessed by measurements of serum thromboxane B(2) (TXB(2)) levels, as well as platelet function. In contrast, a significant (P < .001) increase in serum TXB(2) level was detected on day 7 before drug administration (median, 19.13 ng/mL [range, 1-47.5 ng/mL]) and at 24 hours after the coadministration of aspirin and ibuprofen (median, 22.28 ng/mL [range, 4.9-44.4 ng/mL]) versus baseline (median, 1.65 ng/mL [range, 0.55-79.8 ng/mL]); this was associated with a significant increase in arachidonic acid-induced platelet aggregation (P < .01) and adenosine diphosphate-induced platelet aggregation (P < .05) and a decrease in the time to form an occlusive thrombus in the platelet function analyzer (P < .01). The urinary excretion of 11-dehydro-TXB(2), an index of systemic thromboxane biosynthesis, was not significantly affected by the coadministration of treatment drugs. At steady state, a comparable and persistent inhibition of lipopolysaccharide-stimulated prostaglandin E(2) generation, a marker of COX-2 activity ex vivo, was caused by ibuprofen (>or=80%) or celecoxib (>or=70%) but not placebo. CONCLUSIONS: Unlike ibuprofen, celecoxib did not interfere with the inhibition of platelet COX-1 activity and function by aspirin despite a comparable suppression of COX-2 ex vivo in patients with osteoarthritis and stable ischemic heart disease.