Dietmar Trenk

Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents

OBJECTIVES We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement. BACKGROUND The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel. METHODS The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 mumol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction. RESULTS Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction. CONCLUSIONS Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236).

Impact of cytochrome P450 3A4-metabolized statins on the antiplatelet effect of a 600-mg loading dose clopidogrel and on clinical outcome in patients undergoing elective coronary stent placement

Early studies suggested interactions between statins and clopidogrel. Based on the outcome and platelet data, there is now huge evidence of no interactions between statins and 75 to 300 mg clopidogrel; however, data with 600-mg loading are lacking. In a pre-specified analysis of the EXCELSIOR cohort, we investigated the interaction between statins, especially cytochrome P4503A4-metabolized atorvastatin and simvastatin, and the antiplatelet effects of a 600-mg loading dose of clopidogrel. We analyzed 1,395 patients scheduled for coronary angiography (CA). Patients received clopidogrel 600 mg at least two hours before CA and 75 mg daily thereafter in case of percutaneous coronary intervention (PCI). Statin medication on admission was continued unaltered until discharge. Platelet function was assessed by optical aggregometry and flow cytometry of adenosine diphosphate (ADP)-stimulated surface expression of CD62P, CD63 and PAC-1 before clopidogrel and immediately before CA. Residual platelet aggregation (RPA) after addition of ADP 5 muM was similar irrespective of statin treatment at baseline (p = 0.968). RPA at CA was 46.2 +/- 16.8% in patients without statin (n = 682), 45.5 +/- 17.0% in patients with atorvastatin (n = 255), 45.8 +/- 16.3% with simvastatin (n = 335), 47.3 +/- 14.9% with fluvastatin (n = 42) and 45.9 +/- 16.2% with pravastatin (n = 81; p = 0.962). Consistent results were obtained by flow cytometry. In patients with PCI (n = 553), the one-year incidence of death, myocardial infarction and target lesion reintervention did not differ between cohorts stratified according to statin co-medication (p = 0.645). Thus, peri-interventional atorvastatin and simvastatin had no effect on the antiplatelet activity of a loading dose of clopidogrel 600 mg and did not affect clinical outcome after PCI.

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery

AbstractObjective: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. Methods: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. Results: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 μg · kg−1 · day−1). The total plasma concentration (2.19 vs. 2.43 μg · ml−1), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng · ml−1) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/Cuss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml · kg−1 · h−1). Conclusions: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160␣years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery.

Antiplatelet response to the 150-mg maintenance dose of clopidogrel in patients with insufficient platelet inhibition after clopidogrel loading for elective coronary stent placement.

AIMS Our prospective study sought to investigate whether inadequate platelet responses to clopidogrel can be corrected by increasing the daily maintenance dose from 75 mg to 150 mg. METHODS AND RESULTS In 117 patients with elective PCI after loading with 600 mg clopidogrel, we determined residual platelet aggregation in response to 5 micromol/l ADP (RPA) by optical aggregometry after the first 75 mg maintenance dose (baseline), and at days 14 and 28. In patients with RPA >14% at baseline, we increased the daily dose to 150 mg. Fifty-seven additional patients without dose adjustment served as historic control. In 39 patients with baseline RPA >14%, the increase in maintenance dose to 150 mg reduced median RPA significantly (P<0.001) from 24% [interquartile range: 18-32%] at baseline to 14% [8-20%1 at 14 days without any further significant change. In patients with RPA < or = 14%, who continued on 75 mg clopidogrel, RPA increased during the first 14 days by 4.5% (0-14%; P<0.001). At 14 days, the study group with selective dose adjustment had a significantly lower RPA than the control group without dose adjustment (10.0% [4-20%1 versus 17.0% [9-32%], P<0.001). CONCLUSIONS In patients with a low initial response to clopidogrel, platelet inhibition can be improved by increasing the maintenance dose to 150 mg.

Digital pulse plethysmography as a non-invasive method for predicting drug-induced changes in left ventricular preload

Objective: Changes in the contour of the plethysmographically recorded digital pulse curve after nitrate ingestion are well known, but it has not been fully established whether these changes reflect nitrate action on left ventricular (LV) preload or afterload. Therefore, we compared the pulse wave contour after administration of equieffective doses of nitroglycerin and nifedipine.Methods:In 20 patients with coronary artery disease we measured aortic blood pressure curve in the aorta ascendens, digital volume pulse curve with a photoelectric pulse pickup, Riva Rocci blood pressure and heart rate after administration of either 0.8 mg nitroglycerin or 10 mg nifedipine.Results:Peak plasma concentrations of nitroglycerin and nifedipine were achieved 5 min and 20 min after ingestion of the drugs. Systolic aortic blood pressure decreased after both nitroglycerin and nifedipine to 19.4 mmHg, but diastolic blood pressure decreased only after nifedipine by 10.5 mmHg (P < 0.05). Riva Rocci blood pressures showed a similar time course. Heart rate increased from 67.4 to 70.9 beats⋅min−1 after nitroglycerin and from 58.9 to 69.4 beats⋅min−1 after nifedipine. The calculated a/b ratio of the aortic pressure curve increased after both medications (nitroglycerin, from 1.66 to 1.99; nifedipine, from 1.66 to 1.93) and its time course mimicked that of the systolic blood pressure. The a/b ratio of the digital pulse curve did not change after nifedipine, but showed a pronounced rise after nitroglycerin from 1.29 to 1.84.With regard to pharmacological actions, nitroglycerin causes a reduction in LV preload and afterload, whereas nifedipine has only LV-afterload-reducing activity.Conclusion:We conclude, that the reduction in afterload did not cause the typical changes in wave contour of the peripheral pulse curve which occur with organic nitrates. Most likely changes in the a/b ratio reflect changes in LV preload.

Identification of 5-HT3 receptors on human platelets: increased surface immunoreactivity after activation with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP).

Identification of 5-HT3 receptors on human platelets: Increased surface immunoreactivity after activation with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP) -

Factors responsible for interindividual differences in the dose requirement of phenprocoumon

SummaryThe total and unbound plasma concentrations of phenprocoumon and the prothrombin complex activity were determined in 51 patients on phenprocoumon.A 7-fold difference in the dosing rate (10–70 µg/kg/day) was required to maintain the prothrombin complex activity at 11–30% of normal. The variation in dosing requirement was mainly due to inter-individual differences in the intrinsic clearance of phenprocoumon and only to a minor degree to differences in sensitivity to it.On average patients with myocardial infarction required only 2/3 of the daily dose of phenprocoumon of post cardiac surgery patients and patients with thrombosis and emboli. That difference appeared to be due to higher clearance in surgical patients and to greater resistance to phenprocoumon in patients with thrombosis and emboli. The total clearance in patients varied approximately 5-fold. It was better predicted by the interindividual intrinsic clearance (r=0.84) than by the unbound fraction (r=0.15).

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray Cmax was higher (39.0 ng·ml-1) and tmax was shorter (3.9 min) than after the sublingual (22.8 ng·ml-1 and 13.8 min) and peroral (16.9 ng·ml-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (emax=130%) and the time to emax (temax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.

Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve

SummaryThe time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PADd at rest (≥15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min.The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.

Pharmacodynamic and Pharmacokinetic Evaluation of a New Transdermal Delivery System with a Time‐Dependent Release of Glyceryl Trinitrate

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo‐controlled study design with an application period of active drug of 4 successive days. The adhesive‐type matrix system contains 20‐mg GTN and released about 75% in a time‐dependent manner. The plasma concentrations of GTN and its metabolites 1–2‐ and 1–3 glyceryl dinitrate reflected the time‐dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b‐ratio of the digital pulse (height of the peak of the systolic wave divided by the height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.