| Background:Aspirin-clopidogrel antiplatelet dual therapy is prescribed worldwide, with PPIs included esomeprazole and pantoprazole were frequently associated to prevent gastrointestinal bleeding. In recent years, many studies have reported PPIs and aspirin-clopidogrel antiplatelet dual therapy in combination will lead to increased cardiovascular events, but the clinical impact of these results remains uncertain and needs merits further investigation.Objective:(1) To detect the plasma p selectin levels, platelet maximum aggregation rate and 5-min platelet aggregation rate in patients with coronary heart disease (CHD) who needed to receive dual anti-platelet therapy before and after proton pump inhibitors pantoprazole and esomeprazole intervention.(2) To investigate the effect of CYP2C19 genotype on antiplatelet function of clopidogrel and its effect on the treatment of combined intervention.(3) To observe the occurrence of gastrointestinal symptoms, cardiovascular events in patient with CHD who treated with pantoprazole or esomeprazole.MethodsA total of 340 patients with CHD who needed to receive dual anti-platelet therapy of asprin and clopidogral were randomly divided into three groups, including the control group (142 patients), pantoprazole group (86 patient) and esomeprazole group (112 patients). Patients in the control group did not receive any medicine for stomach except for original drug treatment and the other two PPIs groups were treated with esomeprazole (20mg qd), pantoprazole (40mg qd) anderapy the basic therapy for 6 months. CYP2C19 * 2 genotype, platelet maximum aggregation rate and 5-min platelet aggregation rate were detected before treatment. Stool apecimens of all patients were collected to detect occult blood. Six months after therapeutic intervention, P selectin, platelet aggregation, platelet maximum aggregation rate and 5-min platelet aggregation rate were detected. The patients were followed up through the whole process and the cardiovascular events, gastrointestinal symptoms and bleeding events were recorded.Results316 CHD patients completed the study, including 133 patients of control group, 80 and 103 patients were in pantoprazole and esomeprazole group, respectively. The other 24 patients included 9 patients in control group, 6 patients in pantoprazole and 9 patients in esomeprazole were lost due to drug discontinuance, change of medicine, failure of follow-up visit. The lost rate of each group were 6.34% (control), 6.98%,(pantoprazole) and 8.04% (esomeprozole), respectively. The general situation of the three groups of patients including age, gender, comorbidities, hepatic and renal functions, heart function, combined use of drugs were comparable.(1) Platelet maximum aggregation rate(PMAR): PMAR in the control group before and after intervention were 36.09±0.84% and 37.73±24.05, showing no significant difference, P> 0.05. In esomeprazole group, PMAR before and after treatment were 35.54±0.97% and 40.40±20.51%, showing no significant difference, P >0.05. In pantoprazole group, PMAR before and after treatment were 35.54±0.97% and 39.85±16.82%, showing no significant difference, P> 0.05.(2) 5 min platelet maximum aggregation rate(5 min-PMAR): 5 min-PMAR in the control group before and after intervention were 30.61±5.33% and 33.48±2.23%, showing no significant difference, P >0.05. In esomeprazole group, 5 min-PMAR before and after treatment were 32.07±4.21% and 36.20±2.23%, showing no significant difference, P >0.05. In pantoprazole group, 5 min-PMAR before and after treatment were 31.28±8.64% and 35.98±7.38%, showing no significant difference, P >0.05.(3) P selectin: Before treatment, p selectin in control group, pantoprazole and esomeprazole group were(66.30±9.50)ng/l,(62.3±16.99)ng/L and(66.57±18.62)ng/L. No significant differences was found among the three groups, P >0.05. But after treatment, p selectin in control group, pantoprazole and esomeprazole groups were(63.06±14.38)ng/l(,84.62±31.02)ng/L and(77.47±35.74)ng/L. p selectin in control group was significantly lower than that in pantoprazole and esomeprazole group after treatment, P <0.001. but there was on difference between pantoprazole and esomeprazole groups, P >0.05.(4) Distribution of CYP2C19 * 2 genotype: Among the 316 patients, 105 of 316 (33.2%) patients were wild type, 165 of 316 patients (52.2%) were mutation miscellaneous zygote type and 46 of 316 (14.6%) patients were homozygous mutant type. In the control group, the persantage of wild type, mutation miscellaneous zygote and homozygous mutant type were 28.6% (38/133), 55.6% (74/133) and 15.8% (21/133) respectively. In the pantoprazole group, these persantage were 37.5% patients(30/80), 50.0%(40/80),and 12.5%(10/80,)respectively. While in the esomeprazole group, 35.9% (37/103), 49.5% (51/103) and 14.6% (15/103 ), respectively. There was no difference among the three groups on genotype distribution.(5) Change of platelet aggregation before and after treatment in different CYP2C19 * 2 genotype: In the patients with wild type, PMAR and 5 min- PMAR were 46.97±8.97% and 38.67±9.72% before intervention. After treatment, PMAR and 5 min- PMAR rate were 37.98±17.91% and 33.89±15.27%, without significant difference, P >0.05. In the patients with heterozygous mutant type, PMAR and 5 min- PMAR were 45.63±10.49% and 35.57±9.93% before treatment and 39.25±22.45% and 34.49±18.24% after treatment.No significant difference was found between them, P >0.05. While in patients with homozygous mutant type, PMAR and 5 min-PMAR were 52.42±9.88%, 37.24±10.06% before treatment and 47.59±17.43%, 40.49±18.03% after treatment, no significant difference was found, P >0.05. But as compared with the patients with homozygous mutant type, PMAR and 5 min- PMAR in patients with wild type after treatment increased significantly, P <0.05.(6) Effect of CYP2C19 * 2 genotype on platelet aggregation rate amnog different intervention groups.In the control group, no significant difference was found in PMAR and 5 min- PMAR before and after treatment in all three genotype subgroups . In the pantoprazole group, PMAR and 5 min- PMAR in the wild-type subgroup were 37.08±12.74% and 33.93±13.94% before treatment and 39.67±16.68%, 32.3±18.86% after treatment. In the heterozygous mutant subgroup, these values were 35.69±13.23% and 36.79±12.65% before intervention and 38.70±17.17% and 35.63±18.67% after intervention. While in the homozygous mutant group, they were 38.81±14.23%, 37.61±15.33% and 42.00±16.53%, 41.3±17.46%, respectively. No significant difference was found before and after treatment in all three genotype subgroups in pantoprazole group, all P >0.05. .But as compared with those in wild-type subgroup afer intervention, 5 min- PMAR in homozygous mutant subgroup increased significantly, P <0.05. In the esomeprazole group, PMAR and 5 min- PMAR and in the wild-type subgroup were 40.44±14.49%, 37.62±17.43% before treatment and 41.32±18.67%, 34.62±13.43% after treatment. These values were 41.45±16.73%, 38.76±15.13% before treatment and 37.45±16.73%, 37.56±19.15% after treatment in the heterozygous mutant subgroup. While in the homozygous mutant subgroup, they were 40.63±10.83%, 39.87±14.56% and 54.6±15.84%, 42.87±16.57%. There was a significant diffenrence both in PMAR and 5 min- PMAR in the homozygous mutant subgroup before and after treatment, P <0.05. And there were significant differences both in the the PMAR and 5 min- PMAR between the wild-type and homozygous mutant subgroups after ibternvention, P <0.05. (7) In the first month follow-up, gastrointestinal symptoms including abdominal pain, bloating, acid reflux, heartburn, abdominal discomfort, diarrhea, nausea and vomiting were found in 29 patients in control group, and the incidence was 21.8%,. While in the pantoprazole and esomeprazole group, there were 8 and 6 patients and the incidence was 10.0% and 5.82%, respectively, which were significantly lower than that in control group. In the sixth month follow-up, the incidences of gastrointestinal symptoms were 14.28%, 2.5% and 4.85% in control, pantoprazole and esomeprazole groups, respectively. In other words, PPIs including esomeprazole and pantoprazole can significantly decrease the incidence of gastrointestinal symptoms in patients taking anti-platelet drugs In all selected patients occurred in 11 patients with gastrointestinal bleeding, 4 cases of the control group, the genotype is heterozygous type 2, homozygous mutant 2, pantoprazole group 3 cases, in which wild-type patients, homozygote type 2 , In esomeprazole group had 4 patients with gastrointestinal bleeding, 2 patients of wild-type, homozygote type 2 patients.(8) Cardiovascular events. During the first month follow-up, there were no significant differences in MACE (cardiac death, myoctardial and hospital admissions due to chest pain) among control, pantoprazole and esomeprazole groups, In all MACE in the control group, 2 homozygous patients,3 wild-type patients, 2 heterozygous, pantoprazole and 2 patients are mutant homozygous, 2 heterozygous patients and 1 wild-type patients, In the esomeprazole group, 3 of whom were homozygous mutant type, 2 heterozygous patients and 1 wild-type patients ,all P> 0.05.; But in the sixth month follow-up , there were 2 cardiac death patients, 2 myoctradial patients, 1 TVR pantent and 4 hospital admissions due to chest pain in esomeprozole. The total incidence of MACE was 8.74%. While in pantoprazole group, there were 1 cardiac death patient, 1 myoctradial patient, 1 TVR pantent and 5 hospital admissions due to chest pain, the incidence of MACE was 6.25%. In control group, there were 1 cardiac death patient, 2 myoctradial patients, 1 TVR pantent and 5 hospital admissions due to chest pain, the incidence of MACE was 6.76%. No significant differences were found among the three groups, P >0.05. Homozygous mutation of the control group 3, wild-type 4, 2 heterozygous, and 2 of pantoprazole are mutant homozygous, heterozygous 2, wild-type 1, esomeprazole group, 4 Are homozygous mutant type, 3 heterozygous, wild-type 2. Esomeprazole group homozygote incidence of MACE more than the wild type, but the difference was not statistically significant.Conclusions(1) PPI esomeprazole and pantoprazole can prevent gastrointestinal symptoms induced by dual antiplatelet drugs.(2) The antiplatelet effect of clopidogrel and aspirin were related to genotypes and PPIs. In mutant homozygous subgroup, the anti-platelet effect of aspirin and clopidogrel can be inhibited by combining use of PPI, especially when combining use of esomeprazole.(3) In patients receiving dual antiplatelet drug, PPI pantoprazole and esomeprazole can reduce the incidence of gastrointestinal symptoms, but might lead to an increase in cardiovascular events. |
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