Knud Erik Pedersen

Regression of Coronary Atherosclerosis by Simvastatin A Serial Intravascular Ultrasound Study

Background—Angiography of the coronary arteries reflects only changes in luminal dimensions. With intravascular ultrasound, cross-sectional images can be obtained and area measurements can be added to calculate volumes of the external elastic membrane (EEM), plaque plus media (P+M), and lumen. The aim of this study was to investigate the effect of lipid lowering by simvastatin on coronary atherosclerotic P+M as changes in volumes of EEM, P+M, and lumen. Methods and Results—In 40 male patients with hypercholesterolemia, ischemic heart disease, and a nonsignificant coronary artery lesion in a not previously revascularized coronary artery, serial intravascular ultrasound studies with an ECG-triggered pullback were performed at baseline, after 3 months on a lipid-lowering diet, and after another 12 months on simvastatin 40 mg/d. Mean length of the analyzed atherosclerotic segments was 5.9±3.3 mm. After 12 months on simvastatin, a significant reduction in P+M volume of 6.3% (P = 0.002) was observed, whereas only a nonsignificant reduction in EEM volume of 1.8% was seen without any concomitant change in lumen volume. A significant reduction in total cholesterol of 31.0% (6.1±0.8 versus 4.2±0.7 mmol/L, P <0.001) and LDL cholesterol of 42.6% (4.0±0.8 versus 2.2±0.6 mmol/L, P <0.001) was obtained. Conclusions—Lipid-lowering therapy with simvastatin for 12 months is associated with a significant P+M regression in coronary arteries measured as reduction in P+M and EEM volumes without any concomitant change in lumen volume.

Digoxin-verapamil interaction

To explore a possible interaction between digoxin and verapamil, a single‐dose kinetic study of digoxin was performed and then repeated after 10 days of verapamil treatment in eight healthy subjects. Verapamil diminished the apparent central distribution volume of digoxin from 0.83 ± 0.25 to 0.64 ± 0.17 l/kg (P < 0.05) and reduced total body clearance of digoxin from 3.28 ± 0.58 to 2.15 ± 0.66 ml/min/kg (P < 0.001) by impairing both renal and extrarenal clearance. Biological digoxin half‐life rose from 38.6 ± 8.5 to 50.5 ± 8.3 hr (P < 0.005). Reduction of renal clearance of digoxin may be due to inhibition of tubular secretion. The underlying mechanisms of extrarenal interaction are not known, but impaired hepatic degradation of digoxin induced by verapamil should be considered.

Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated With Percutaneous Coronary Intervention The Scandinavian Organization for Randomized Trials With Clinical Outcome IV (SORT OUT IV)

Background —Among drug-eluting stents released to date, the sirolimus-eluting stent has demonstrated the least amount of late lumen loss, but its efficacy and safety have not been compared head-to-head with the next-generation everolimus-eluting stent. Methods and Results —The S candinavian O rganization for R andomized T rials with Clinical O utcome IV trial was a randomized multicenter, single-blind, all-comer, two-arm, non-inferiority trial comparing the everolimus-eluting stent with the sirolimus-eluting stent in patients with coronary artery disease. The primary end point was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The non-inferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9-month and 18-month follow-up. 1,390 patients were assigned to receive the everolimus-eluting stent, and 1,384 patients were assigned to receive the sirolimus-eluting stent. At 9-month follow-up, 68 \[4.9%] patients treated with the everolimus-eluting stent versus 72 [5.2%] patients treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio (HR) =0.94; 95% confidence interval (CI): 0.67-1.31) ( p for non-inferiority=0.01). At 18-month follow-up, this differential remained: 99 [7.2%] patients treated with the everolimus-eluting stent versus 105 [7.6%\] (HR=0.94, 95% CI: 0.71-1.23). At 9-month follow-up, rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 [0.1%] patients versus 9 [0.7%] patients, (HR=0.22, 95% CI:0.05-1.02)).At 18-monthfollow-up, this difference was sustained (3 [0.2%] patients versus 12 [0.9%] patients; (HR=0.25, 95% CI:0.07-0.88). Conclusions —The everolimus-eluting stent was found to be non-inferior to the sirolimus-eluting stent. Clinical Trial Registration Information —ClinicalTrials.gov; [NCT00552877][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00552877&atom=%2Fcirculationaha%2Fearly%2F2012%2F02%2F03%2FCIRCULATIONAHA.111.063644.atomBackground— Among drug-eluting stents released to date, the sirolimus-eluting stent has demonstrated the least amount of late lumen loss, but its efficacy and safety have not been compared head-to-head with the next-generation everolimus-eluting stent. Methods and Results— The Scandinavian Organization for Randomized Trials with Clinical Outcome IV (SORT OUT IV) trial was a randomized multicenter, single-blind, all-comer, 2-arm, noninferiority trial comparing the everolimus-eluting stent with the sirolimus-eluting stent in patients with coronary artery disease. The primary end point was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The noninferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9- and 18-month follow-ups. A total of 1390 patients were assigned to receive the everolimus-eluting stent and 1384 patients to the sirolimus-eluting stent. At the 9-month follow-up, 68 patients (4.9%) treated with the everolimus-eluting stent compared with 72 patients (5.2%) treated with the sirolimus-eluting stent experienced the primary end point (hazard ratio, 0.94; 95% confidence interval, 0.67–1.31; P for noninferiority=0.01). At the 18-month follow-up, this differential remained: 99 patients (7.2%) treated with the everolimus-eluting stent versus 105 (7.6%) treated with the sirolimus-eluting stent (hazard ratio, 0.94; 95% confidence interval, 0.71–1.23). At the 9-month follow-up, the rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 patients [0.1%] versus 9 patients [0.7%]; hazard ratio, 0.22; 95% confidence interval, 0.05–1.02). At the 18-month follow-up, this difference was sustained (3 patients [0.2%] versus 12 patients [0.9%]; hazard ratio, 0.25; 95% confidence interval, 0.07–0.88). Conclusion— The everolimus-eluting stent was found to be noninferior to the sirolimus-eluting stent. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00552877.

The long-term effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects

SummarySingle-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21±0.01 ng/ml (SE) to 0.34±0.01 ng/ml (p<0.01), and renal digoxin clearance had fallen from 197.57±17.37 ml/min to 128.20±10.33 ml/min (p<0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27±0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46±3.23% before to 69.78±3.69% (p<0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.

Effect of Quinidine on Digoxin Bioavailability

SummaryTo evaluate the possible effect of quinidine on digoxin bioavailability, the steady state digoxin kinetics was examined with and without concomitant quinidine therapy, in 7 cardiac patients after simultaneous administration of oral digoxin and intravenous [3H]-digoxin. In the presence of quinidine, the absorption rate constant of digoxin (ka) increased from 2.72±1.04 to 3.53±1.34 h−1 (p<0.05), whereas lag time and peak time decreased from 0.16±0.10 to 0.05±0.04 h (p<0.05) and from 0.92±0.27 to 0.69±0.19 h (p<0.02), respectively. Predose plasma digoxin increased from 0.41±0.25 to 0.70±0.31 ng/ml (p<0.02), while peak plasma digoxin increased from 0.93±0.34 to 1.63±0.46 ng/ml (p<0.02). The systemic availability of digoxin increased from 68.48±13.35 to 79.09±14.89% (p<0.05) in the presence of quinidine. Quinidine had no effect on the biotransformation pattern of digoxin, as assessed by thin layer chromatography. Quinidine increases the rate and extent of digoxin absorption, and this interaction contributes significantly to the elevation in plasma digoxin during both its distribution and elimination phases.

Effect of nifedipine on digoxin kinetics in healthy subjects

Verapamil has been shown to reduce total‐body digoxin clearance by 35% due to impairments of both renal and extrarenal clearances. Our study was undertaken to evaluate the influence of the related calcium antagonist nifedipine on single‐dose digoxin kinetics. Nifedipine increased extrarenal clearance of digoxin from 1.09 ± 0.30(SD) to 1.45 ± 0.23 ml/min/kg (P < 0.05) and reduced the total urinary recovery of the drug from 69.2% ± 5.9(SD) to 64.3% ± 5.2 (P < 0.05). There were no significant changes in renal digoxin clearance, distribution, or biological half‐life or in digoxin distribution volumes during nifedipine coadministration.

Influence of verapamil on the inotropism and pharmacokinetics of digoxin

SummaryVerapamil has been demonstrated to inhibit the elimination of digoxin and to increase its steady state plasma level by 60–80%. Animal studies suggest that verapamil abolishes the intropic action of other drugs such as ouabain and dopamine. The clinical consequences of this drug interaction were investigated by examining the inotropic activity of single doses of digoxin (assessed from systolic time intervals), with and without coadministration of verapamil. Verapamil decreased total-body clearance of digoxin from 4.68±0.41 to 3.29±0.26 ml/min/kg (p<0.001) and increased the plasma half-life of the drug from 33.50±2.38 to 41.31±2.27 h (p<0.01). Verapamil had no influence on the base-line values of the systolic time intervals. Both in the absence and presence of verapamil, digoxin caused significant shortening of the total electromechanical systole and the left ventricular ejection time. However, compared to control conditions, the decay of these changes was slower in the presence of verapamil, in parallel with the prolongation of the plasma half-life of digoxin. A linear relationship was established between reductions in the systolic time intervals and the computer-derived concentration of digoxin in the deep compartment. These regression lines, which represent the concentration-effect relationships of the inotropism of digoxin, were not affected by verapamil. Thus, verapamil per se had no measurable effect either on base-line contractile function of the heart or on digoxin-induced inotropism. The elevated plasma digoxin concentration induced by verapamil appears cardioactive in terms of inotropism.

Clinical Outcome After Primary Percutaneous Coronary Intervention With Drug-Eluting and Bare Metal Stents in Patients With ST-Segment Elevation Myocardial Infarction

Background—The use of drug-eluting stents (DESs) versus bare metal stents (BMSs) in primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction is a matter of debate. Therefore, we examined the risk of target lesion revascularization (TLR), stent thrombosis, myocardial infarction, and death after the implantation of DES or BMS in primary PCI patients in Western Denmark. Methods and Results—A total of 3756 consecutive patients with ST-segment elevation myocardial infarction treated with primary PCI and stent implantation, recorded in the Western Denmark Heart Registry from January 2002 through June 2005, were followed up for 2 years. We used Cox regression analysis to control for confounding. The 2-year incidence of definite stent thrombosis was 1.9% in the DES group and 1.1% in the BMS group (adjusted relative risk [RR]=1.53; 95% CI=0.84 to 2.78; P=0.17). Very late definite stent thrombosis (≥12 months) was seen in 0.4% in the DES group and 0.06% in the BMS group (adjusted RR=6.74; 95% CI=1.23 to 37.00; P=0.03). The 2-year incidence of myocardial infarction was similar in the 2 groups, 5.2% in the DES group versus 6.3% in the BMS group (P=0.28; adjusted RR=1.13; 95% CI=0.81 to 1.59; P=0.47). All-cause 2-year mortality was 7.8% in the DES group and 11.4% in BMS group (P<0.004; adjusted RR=0.79; 95% CI=0.60 to 1.04; P=0.09). The 2-year incidence of target lesion revascularization was 7.2% in the DES group and 8.7% in the BMS group (P=0.09; adjusted RR=0.70; 95% CI=0.52 to 0.92; P=0.012). Conclusions—In ST-segment elevation myocardial infarction patients treated with primary PCI, target lesion revascularization was reduced by 30% in patients treated with a DES. The risk of very late definite stent thrombosis was low but increased in patients treated with DES. DES was not associated with increased risk of myocardial infarction or death, when compared with BMS.

Comparison of Intravascular Ultrasound and Angiographic Assessment of Coronary Reference Segment Size in Patients With Type 2 Diabetes Mellitus

During percutaneous coronary intervention, the reference segment is assessed angiographically. This report described the discrepancy between angiographic and intravascular ultrasound (IVUS) assessment of reference segment size in patients with type 2 diabetes mellitus. Preintervention IVUS was used to study 62 de novo lesions in 41 patients with type 2 diabetes mellitus. The lesion site was the image slice with the smallest lumen cross-sectional area (CSA). The proximal and distal reference segments were the most normal-looking segments within 5 mm proximal and distal to the lesion. Plaque burden was measured as plaque CSA/external elastic membrane (EEM) CSA. Using IVUS, the reference lumen diameter was 2.80 +/- 0.42 mm and the reference EEM diameter was 4.17 +/- 0.56 mm. The angiographic reference diameter was 2.63 +/- 0.36 mm. Mean difference between the IVUS EEM diameter and angiographic reference diameter was 1.56 +/- 0.55 mm. The mean difference between the IVUS reference lumen diameter and angiographic reference lumen diameter was 0.18 +/- 0.44 mm. Plaque burden in the reference segment correlated inversely with the difference between IVUS and quantitative coronary angiographic reference lumen diameter (slope = -0.12, 95% confidence interval -0.17 to -0.07, p <0.001), but it was not related to the absolute angiographic reference lumen diameter. Thus, reference segment diameters in type 2 diabetic patients were larger using IVUS than angiography, especially in the setting of larger plaque burden. In conclusion, these findings combined with inadequate remodeling may explain the angiographic appearance of small arteries in diabetic patients.

Late lumen loss and intima hyperplasia after sirolimus-eluting and zotarolimus-eluting stent implantation in diabetic patients: the diabetes and drug-eluting stent (DiabeDES III) angiography and intravascular ultrasound trial

AIMS Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to neointimal hyperplasia (NIH). The aim of this study was to use quantitative coronary angiography (QCA) and volumetric intravascular ultrasound (IVUS) to evaluate the effects of the sirolimus-eluting Cypher® stent (SES) and the zotarolimus-eluting Endeavor® stent (ZES) on angiographic late lumen loss and intima hyperplasia in diabetic patients. METHODS AND RESULTS In the DiabeDES III trial, 127 patients were randomised to SES or ZES stent implantation. Angiographic 10-month follow-up data were available in 105 patients, including 48 SES and 57 ZES treated patients. Angiographic endpoints were in-stent late lumen loss and minimal lumen diameter. IVUS endpoints included NIH volume and in-stent percent volume obstruction. Baseline clinical characteristics and lesion parameters were similar in the two groups. At 10-month follow-up, angiographic in-stent late lumen loss (0.14±0.37 mm vs. 0.74±0.45 mm, p<0.001) was reduced and minimum lumen diameter was higher (2.36±0.53 mm vs. 1.96±0.65, p<0.001) in the SES group as compared to the ZES group. As compared to the ZES group, NIH volume was significantly reduced in the SES group (median [interquartile range]: 0.0 mm3 [0.0 to 1.2] vs. 16.5 mm3 [6.2 to 31.1], p<0.001). In-stent% volume obstruction was significantly reduced in SES as compared to ZES (median [interquartile range]: 0.0% [0.0-0.7] vs. 13.0% [6.7-20.8], p<0.001). CONCLUSIONS In diabetic patients, the SES reduced angiographic late lumen loss and inhibited NIH more effectively than ZES.