Obstructive Sleep Apnea Syndrome Is Associated With Increased Risk Of Low-antiplatelet Response Of Clopidogrel In Patients With Unstable Angina

Objective: To address the question of the relationship between low antiplatelet response of clopidogrel and Obstructive Sleep Apnea Syndrome (OSAS), we performed a new analysis of the randomized study. In this study, we investigate the morbidity of OSAS in unstable angina pectoris patients who receiving standard dose of clopidogrel, assay the antiplatelet response of clopidogrel and the concentration of serum adrenaline and norepinephrine in all patients.Methods: This was a randomized study of consecutive 112 patients hospitalized with unstable angina pectoris from February, 2008 to December, 2009. In brief, major inclusion criteria were: (1) age >40years and <80 years; and (2) unstable angina pectoris diagnosed according to American College of Cardiology/American Heart Association(2002) : Committee on the Management of Patients with Unstable Angina. Major exclusion criteria were: (1) acute myocardial infarction, stroke, intracraninal hemorrhage, surgery or trauma within 3 months. (2) contraindication of the use of low-molecular weight heparin, clopidogrel, or aspirin. (3) administration of agents such as clopidogrel or platelet glycoprotein IIb/IIIa inhibitor tirofiban before admission, and using tirofiban during this study. (4) severe disease or function abnormity in vital organs. (5) unwilling to undergo coronary angiography examination or a sleep study.All patients enrolled were allocated to receive a clopidogrel 300mg orally as a loading dose, and then 75mg per day, routinely aspirin(300mg orally per day),low molecular weight heparin twice daily, and Statins ,ACE inhibitors,β-Blockers et al. Platelet aggregation was induced by the addition of adenosine diphosphate(ADP) at a final concentration of 5μmol/L; parameters were measured on samples obtained at baseline and 2nd, 4th, 6th day. Patients were stratified into 4 quartiles based on ADP-induced platelet aggregation expressed as percentage of baseline activity. All patients were examined for the presence of sleep-disordered breathing by ApneaLink. An obstructive apnea is a > 10-second pause in respiration. Obstructive hypopneas are decreases in, but not complete cessation of ventilation, with an associated fall in oxygen saturation >4%. A diagnosis of OSAS is accepted when a patient has an apnea-hypopnea index (AHI; number of apneas and hypopneas per hour of sleep) > 5. The concentration serum adrenaline and norepinephrine were measured in the morning at 6 a.m. after the sleep study.Data were analyzed using SPSS 13.0 software. Continuous variables were presented as mean±SD. Changes between groups were assessed with one-way analysis of variance (ANOVA) or Kruskl-Wallis H test. Categorical variables were presented as percentages in the 4 groups and tested for linear trend withΧ2 analysis. A 2-tailed Fisher's exact test was used to compare in the first quartile with patients in the second through fourth quartiles. Platelet activity was expressed as a percentage over baseline value. Changes in platelet activity were evaluated with paired t test or Wilcoxon rank-sum test. A P value <0.05 was considered significance.Result: There were no significant differences in the age, gender, smoking, hypertension, dyslipidemia, obesity, heart function and medicine treatment in all 4 quartiles. However, there was a significant differences in the number of diabetes patients in the first quartile (P=0.0038) compared with other quartiles.At day 2 platelet aggregation were inhibited to 63.91% of baseline(P<0.01) and at day 4 to 90.90% (P>0.05) and 88.38% (P>0.05)of baseline, respectively, in the first quartile. At each of these time points, platelet activity was significantly higher than in patients in other quartiles. At day 6 platelet aggregation were reduced to 49.30%, 32.37%, and 29.75% of baseline respectively in group 2 through 4 (P<0.01 for all). Platelet aggregation was reduced significantly in patients in the second through fourth quartiles at day 6,but,it showed a lower reduction in the first quartile (P>0.05) (Fig 2).Compared with that in the first group(60.7%), the morbidity of OSAS in the second and third were 25.0% and 14.3% (P<0.05), only 3.6% in the fourth group (P<0.01). Meanwhile, the concentration of serum adrenaline and norepinephrine were higher in the first quartile than others (P<0.05).Conclusion: OSAS is a reliable indicator of low clopidogrel response in unstable angina patients, and higher concentration of epinephrine and norepinephrine in OSAS patients play a more important role in this situation.