Clinical Pharmacology

This meta-analysis combined the results of randomized clinical trials to compare the efficacy of drug-eluting stents with that of bare metal stents in percutaneous coronary interventions to ascertain which revascularization strategy is most safe and effective. The literature identified 13 published studies, and 8 were included in the main metaanalysis, thus allowing a meta-analysis on 3,860 patients for the effect on all major adverse clinical events (MACEs) combined and for target vessel revascularization. Metaanalyses were performed for combined MACEs, patient MACEs, and thrombosis. Regression meta-analyses were performed to examine the effect of certain variables on the efficacy of drug-eluting stents compared with bare metal stents. Meta-analysis of all trials showed that drug-eluting stents produced significant decreases in the need for percutaneous revascularization (relative risk [RR] 0.30, 95% confidence interval [CI] 0.22 to 0.40) and coronary artery bypass grafting (RR 0.54, 95% CI 0.32 to 0.89). Drugeluting stents significantly decreased all MACEs combined (RR 0.40, 95% CI 0.33 to 0.49) but were not associated with an increased risk of stent thrombosis or death. These results were confirmed at analysis as stratified by type of eluting stent, because the need for percutaneous revascularization was significantly lower for sirolimus-eluting stents (RR 0.23, 95% CI 0.15 to 0.35) and paclitaxel-eluting stents (RR 0.39, 95% CIl 0.29 to 0.53). ᮊ2005 by Excerpta Medica Inc.

Reduction of nitrite (NO 2 Ϫ ) provides a major source of nitric oxide (NO) in the circulation, especially in hypoxemic conditions. Our previous studies suggest that xanthine oxidoreductase (XOR) is an important nitrite reductase in the heart and kidney. Herein, we have demonstrated that conversion of nitrite to NO by blood vessels and RBCs was enhanced in the presence of the XOR substrate xanthine (10 mol/L) and attenuated by the XOR inhibitor allopurinol (100 mol/L) in acidic and hypoxic conditions only. Whereas endothelial nitric oxide synthase (eNOS) inhibition had no effect on vascular nitrite reductase activity, in RBCs L-NAME, L-NMMA, and L-arginine inhibited nitrite-derived NO production by Ͼ50% (PϽ0.01) at pH 7.4 and 6.8 under hypoxic conditions. Western blot and immunohistochemical analysis of RBC membranes confirmed the presence of eNOS and abundant XOR on whole RBCs. Thus, XOR and eNOS are ideally situated on the membranes of RBCs and blood vessels to generate intravascular vasodilator NO from nitrite during ischemic episodes. In addition to the proposed role of deoxyhemoglobin, our findings suggest that the nitrite reductase activity within the circulation, under hypoxic conditions (at physiological pH), is mediated by eNOS; however, as acidosis develops, a substantial role for XOR becomes evident. (Circ Res. 2008;103:957-964.)

Aims Cardiac magnetic resonance perfusion imaging (CMRI) is a promising technique for non-invasive measurement of myocardial perfusion reserve. Fractional flow reserve (FFR) is an established invasive method for functional assessment of coronary artery disease (CAD). To prospectively assess the diagnostic value of CMRI for the detection of haemodynamically significant coronary lesions, compared with coronary angiography (CA) and FFR. Methods and results Forty-three patients with suspected or known CAD underwent CA, CMRI, and FFR measurement. First pass magnetic resonance perfusion examination was performed during hyperaemia (140 mg/kg/min adenosine over 6 min) and at rest. One hundred and twenty-nine perfusion territories were assessed by semi-quantitative evaluation of signal intensity-time curves using the myocardial perfusion reserve index (MPRI) [upslope stress(corrected) /upslope rest(corrected) ]. Perfusion territories were categorized as normal (coronary stenosis 50%), intermediate (stenosis . 50% and FFR . 0.75), or severe (stenosis . 50% and FFR 0.75 or total occlusion). MPRI values (+SD) were significantly different between the three categories [normal, 2.2 + 0.5 vs. intermediate, 1.8 + 0.5 (P ¼ 0.005) and intermediate vs. severe, 1.2 + 0.3 (P , 0.001)]. An MPRI cut-off value of 1.5 (derived from receiver operating characteristics analysis) distinguished haemodynamically relevant (severe) from non-relevant (normal and intermediate) stenoses with a sensitivity of 88% (CI 74-100%) and a specificity of 90% (CI 84-96%). Conclusion In contrast to earlier studies that compared CMRI with morphological examination (CA) alone, the present study compared CMRI with CA plus a standard invasive functional assessment (FFR) and demonstrated that CMRI is able to distinguish haemodynamically relevant from non-relevant coronary lesions with a high sensitivity and specificity and may therefore contribute to clinical decision-making.

clinical characteristics and outcome for patients undergoing small versus large culprit vessel PPCI in our unit. Methods: We included all patients who underwent PPCI in our unit between Sept 2009 and May 2011. They were divided into two groups according to the size of the largest balloon or stent used in the culprit lesion. Results: Of the 1132 patients who underwent PPCI in our unit during the study period, we excluded 30 (2.7%) patients who did not have either a balloon or stent used in the culprit lesion. Of the remaining 1102 patients, 569 (51.6%) had small (Յ3 mm) vessel PPCI and 533 (48.4%) had large (Ͼ3 mm) vessel PPCI. Patients with small vessel PPCI were significantly older, more likely to be female and have anterior STEMI with less use of thrombectomy device, but with significantly higher drug eluting stent (DES) usage. There was significantly higher in-hospital mortality (5.3% vs 2.8%, OR 1.9, 95% CI 1-3.6, p 0.047), 30-day mortality (8.4% vs 3.6%,OR 2.5, 95% CI 1.4-4.3, p 0.0009) and 30-day stent thrombosis (1.2% vs 0, p 0.02) in the small vessel PPCI group compared to large vessel PPCI group. On binary logistic regression analysis of small vessel PPCI patients (covariates used: female sex, Age Ͼ75 yrs, cardiogenic shock, diabetes, LAD PCI and DES use), the positive predictors of 30-day mortality were age Ͼ75 yrs (OR 6.1, 95% CI 2.9 to 12.5, pϽ0.0001) and cardiogenic shock (OR 9.9, 95% CI 4.3-22.6, pϽ0.0001) with DES use (OR 0.4, 95% CI 0.2-0.8, p 0.01) being the only negative predictor of mortality. N (%) Small (<3 mm) vessel Large (> 3 mm) vessel p value N‫؍‬ 569 N‫؍‬ 533 Age (meanϮSD, range) 66.8Ϯ13.5, 25-96 62.9Ϯ13.1, 26-99 Ͻ0.0001 Age Ͼ 75 yrs 172 (30.2) 94 (17.6) Ͻ0.0001 Female 203 (35.7) 94 (17.6) Ͻ0.0001 Diabetes 68 (11.8) 63 (11.8) 1.0 Cardiogenic shock 42 (7.4) 42 (7.9) 0.73 Previous MI 65 (11.4) 69 (12.9) 0.46 Previous PCI 33 (5.8) 42 (7.9) 0.19 Previous CABG 11 (1.9) 16 (3) 0.33 LAD PCI 293 (51.5) 218 (40.9) 0.0005 Thrombectomy use 363 (63.8) 424 (79.5) Ͻ0.0001 Drug eluting stent use (at least one) 363 (63.8) 289 (54.2) 0.001

In normal conditions, nitric oxide (NO) is oxidized to the anion nitrite, but in hypoxia, this nitrite may be reduced back to NO by the nitrite reductase action of deoxygenated hemoglobin, acidic disproportionation, or xanthine oxidoreductase (XOR). Herein, is investigated the effects of topical sodium nitrite administration in a rat model of renal ischemia/reperfusion (I/R) injury. Rats were subjected to 60 min of bilateral renal ischemia and 6 h of reperfusion in the absence or presence of sodium nitrite (30 nmol) administered topically 1 min before reperfusion. Serum creatinine, serum aspartate aminotransferase, creatinine clearance, fractional excretion of Na ؉ , and plasma nitrite/nitrate concentrations were measured. The nitrite-derived NO-generating capacity of renal tissue was determined under acidic and hypoxic conditions by ozone chemiluminescence in homogenates of kidneys that were subjected to sham, ischemia-only, and I/R conditions. Nitrite significantly attenuated renal dysfunction and injury, an effect that was abolished by previous treatment of rats with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (2.5 mol intravenously 5 min before ischemia and 50 nmol topically 6 min before reperfusion). Renal tissue homogenates produced significant amounts of NO from nitrite, an effect that was attenuated significantly by the xanthine oxidoreductase inhibitor allopurinol. Taken together, these findings demonstrate that topically administered sodium nitrite protects the rat kidney against I/R injury and dysfunction in vivo via the generation, in part, of xanthine oxidoreductase-catalyzed NO production. These observations suggest that nitrite therapy might prove beneficial in protecting kidney function and integrity during periods of I/R such as those encountered in renal transplantation.

Aims. We investigate the effect of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors on long-term outcomes following percutaneous coronary intervention (PCI) after non-ST elevation myocardial infarction (NSTEMI). Meta-analyses indicate that these agents are associated with improved short-term outcomes. However, many trials were undertaken before the routine use of P2Y 12 inhibitors. Recent studies yield conflicting results and registry data have suggested that GP IIb/IIIa inhibitors may cause more bleeding than what trials indicate. Methods and Results. This retrospective observational study involves 3047 patients receiving dual-antiplatelet therapy who underwent PCI for NSTEMI. Primary outcome was all-cause mortality. Major adverse cardiac events (MACE) were a secondary outcome. Mean follow-up was 4.6 years. Patients treated with GP IIb/IIIa inhibitors were younger with fewer comorbidities. Although the unadjusted Kaplan-Meier analysis suggested that GP IIb/IIIa inhibitor use was associated with improved outcomes, multivariate analysis (including propensity scoring) showed no benefit for either survival ( = 0.136) or MACE ( = 0.614). GP IIb/IIIa inhibitor use was associated with an increased risk of major bleeding ( = 0.021). Conclusion. Although GP IIb/IIIa inhibitor use appeared to improve outcomes after PCI for NSTEMI, patients who received GP IIb/IIIa inhibitors tended to be at lower risk. After multivariate adjustment we observed no improvement in MACE or survival and an increased risk of major bleeding.

This meta-analysis combined the results of randomized clinical trials to compare the efficacy of drug-eluting stents with that of bare metal stents in percutaneous coronary interventions to ascertain which revascularization strategy is most safe and effective. The literature identified 13 published studies, and 8 were included in the main metaanalysis, thus allowing a meta-analysis on 3,860 patients for the effect on all major adverse clinical events (MACEs) combined and for target vessel revascularization. Metaanalyses were performed for combined MACEs, patient MACEs, and thrombosis. Regression meta-analyses were performed to examine the effect of certain variables on the efficacy of drug-eluting stents compared with bare metal stents. Meta-analysis of all trials showed that drug-eluting stents produced significant decreases in the need for percutaneous revascularization (relative risk [RR] 0.30, 95% confidence interval [CI] 0.22 to 0.40) and coronary artery bypass grafting (RR 0.54, 95% CI 0.32 to 0.89). Drugeluting stents significantly decreased all MACEs combined (RR 0.40, 95% CI 0.33 to 0.49) but were not associated with an increased risk of stent thrombosis or death. These results were confirmed at analysis as stratified by type of eluting stent, because the need for percutaneous revascularization was significantly lower for sirolimus-eluting stents (RR 0.23, 95% CI 0.15 to 0.35) and paclitaxel-eluting stents (RR 0.39, 95% CIl 0.29 to 0.53). ᮊ2005 by Excerpta Medica Inc.

Aims Cardiac magnetic resonance perfusion imaging (CMRI) is a promising technique for non-invasive measurement of myocardial perfusion reserve. Fractional flow reserve (FFR) is an established invasive method for functional assessment of coronary artery disease (CAD). To prospectively assess the diagnostic value of CMRI for the detection of haemodynamically significant coronary lesions, compared with coronary angiography (CA) and FFR. Methods and results Forty-three patients with suspected or known CAD underwent CA, CMRI, and FFR measurement. First pass magnetic resonance perfusion examination was performed during hyperaemia (140 mg/kg/min adenosine over 6 min) and at rest. One hundred and twenty-nine perfusion territories were assessed by semi-quantitative evaluation of signal intensity-time curves using the myocardial perfusion reserve index (MPRI) [upslope stress(corrected) /upslope rest(corrected) ]. Perfusion territories were categorized as normal (coronary stenosis 50%), intermediate (stenosis . 50% and FFR . 0.75), or severe (stenosis . 50% and FFR 0.75 or total occlusion). MPRI values (+SD) were significantly different between the three categories [normal, 2.2 + 0.5 vs. intermediate, 1.8 + 0.5 (P ¼ 0.005) and intermediate vs. severe, 1.2 + 0.3 (P , 0.001)]. An MPRI cut-off value of 1.5 (derived from receiver operating characteristics analysis) distinguished haemodynamically relevant (severe) from non-relevant (normal and intermediate) stenoses with a sensitivity of 88% (CI 74-100%) and a specificity of 90% (CI 84-96%). Conclusion In contrast to earlier studies that compared CMRI with morphological examination (CA) alone, the present study compared CMRI with CA plus a standard invasive functional assessment (FFR) and demonstrated that CMRI is able to distinguish haemodynamically relevant from non-relevant coronary lesions with a high sensitivity and specificity and may therefore contribute to clinical decision-making.

slowing dramatically from 2006 to 2008. JoinPoint regression analysis of different age groups demonstrates that the slower rate of decline from 2006 may be due to stubbornly high numbers of deaths in the 35e44 age group. Lastly the National figures on mortality from CHD are shown to be misleading as many people are still dying from CHD just when they have crossed the 75-year old exclusion criteria; as a result a delay in mortality is presented as prevention of mortality from CHD. Discussion There is a danger that previous successes are being offset by high rates in the younger cohorts, and that the overall trend may be eventually be reversed. There is still work to be done in reducing risk factors and also applying treatments that have had a proven positive impact (such as revascularisation) more effectively. Statistically significant changes in declining CHD mortality rates. Future work This 10 000 word report formed the basis of a funding application to the British Heart Foundation for a follow-up to the United Kingdom Heart Attack Study.