Erick Schampaert

Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS)

BACKGROUND Sirolimus-eluting stents have been developed to prevent restenosis in the treatment of coronary artery disease. We investigated the risk of restenosis with use of sirolimus-eluting stents compared with bare-metal stents to assess possible differences. METHODS We enrolled 352 patients in whom one coronary artery required treatment, with diameter 2.5-3.0 mm and lesion length 15-32 mm. We randomly assigned patients sirolimus-eluting stents (n=175) or bare-metal stents (control, n=177). At 8 months we assessed differences in minimum lumen diameter and binary restenosis within the lesion (restenosis of > or =50% diameter, including 5 mm vessel segments proximal and distal to stented segment). Patients were also followed up for 9 months for major adverse cardiac events. Analysis was by intention to treat. FINDINGS Stent implantation was successful in 100% of sirolimus-stent patients and 99.4% of controls. The mean diameter of treated coronary arteries was 2.55 mm (SD 0.37) and mean lesion length was 15.0 mm (6.0). Multiple stents were implanted in 170 (48%) patients. At 8 months, minimum lumen diameter was significantly higher with sirolimus-eluting stents than with control stents (2.22 vs 1.33 mm, p<0.0001). The rate of binary restenosis was significantly reduced with sirolimus-eluting stents compared with control stents (5.9 vs 42.3%, p=0.0001). Significantly fewer patients with sirolimus-eluting stents had major adverse cardiac events at 9 months than did controls (8.0 vs 22.6%, p=0.0002), due mainly to a lower need for target-lesion revascularisations (4.0 vs 20.9%, p<0.0001). INTERPRETATION Sirolimus-eluting stents are better than bare-metal stents for treatment of single long atherosclerotic lesions in a coronary vessel smaller than 3 mm in diameter.

Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions

Background—Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis. Methods and Results—This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was ≈200 mm3, and the least squares mean change at end of treatment was 0.7 mm3 for placebo and 7.7, 4.1, and 4.8 mm3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 [unadjusted P=0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (P<0.05 in all groups). Conclusions—Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.

5-year clinical outcomes after sirolimus-eluting stent implantation insights from a patient-level pooled analysis of 4 randomized trials comparing sirolimus-eluting stents with bare-metal stents.

OBJECTIVES Five-year clinical follow-up has been scheduled per protocol by the 4 Cypher (Cordis/Johnson & Johnson, Warren, New Jersey) sirolimus-eluting stent (SES) versus bare-metal stent (BMS) randomized trials. BACKGROUND A delayed arterial healing response after drug-eluting stent implantation has raised concerns about the long-term safety of drug-eluting stents. METHODS In a pooled analysis of 4 randomized trials, 1,748 patients were assigned to receive either an SES (n = 878) or BMS (n = 870). RESULTS At 5 years, there was no significant difference in the rate of death, myocardial infarction (MI), or the composite of death/MI between the 2 groups (15.1% in the SES group vs. 13.6% in the BMS group; p = 0.36). The 5-year incidence of stent thrombosis by the Academic Research Consortium definition did not differ between SES and BMS (definite/probable stent thrombosis, 2.1% vs. 2.0%; p = 0.99). The incidence of very late stent thrombosis was also similar between the SES and BMS groups (1.4% vs. 0.7%; p = 0.22). The annualized rates of definite/probable stent thrombosis after 1 year were 0.4% for SES and 0.2% for BMS. The 5-year incidence of target vessel revascularization was significantly lower in the SES group (15.2% vs. 30.1%; p < 0.0001). CONCLUSIONS In this patient-level pooled analysis, overall use of SES compared with BMS demonstrated persistent superior efficacy at 5 years in terms of a reduction in target vessel revascularization, without an increase in rates of death, MI, or stent thrombosis. (The Initial Double-Blind Drug-Eluting Stent vs Bare-Metal Stent Study, NCT00233805; The Study of the BX Velocity Stent in the Treatment of De Novo Artery Lesions, NCT00381420; Study of Sirolimus-Coated BX VELOCITY Balloon-Expandable Stent in Treatment of de Novo Native Coronary Artery Lesions [SIRIUS], NCT00232765; The Study of the BX VELOCITY Stent In Patients With De Novo Coronary Artery Lesions, NCT00235144).

Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients

AIMS We investigated the comparability of platelet function tests in quantifying platelet inhibition achieved by clopidogrel. METHODS AND RESULTS This pre-specified substudy of a randomized, double-blind trial included 116 patients with stable coronary artery disease requiring diagnostic angiography. Patients received clopidogrel for 1 (300 or 600 mg) or 7 days (300 + 75 or 150 mg daily) before the procedure. Blood samples obtained before clopidogrel initiation and before diagnostic coronary angiography were assayed using light transmission aggregometry [adenosine diphosphate (ADP) 5 and 20 microM as the agonist], whole-blood aggregometry (ADP 5 and 20 microM), PFA-100 (Collagen-ADP cartridge), and VerifyNow P2Y12. Although all assays studied were found sensitive to clopidogrel ingestion, none could distinguish categorically between patients who had, or not, ingested clopidogrel. Agreement between assays to identify patients with insufficient inhibition of platelet aggregation by clopidogrel was low. CONCLUSION The assessment of platelet function inhibition by clopidogrel is highly test-specific. Decision to increase clopidogrel dosage may vary on the basis of the assay used, thus highlighting the need for unambiguous guidelines with respect to assay selection, as platelet function assays are not interchangeable. At present, platelet function testing evaluating clopidogrel efficacy cannot be recommended in routine clinical practice.

Assessment of VerifyNow P2Y12 assay accuracy in evaluating clopidogrel-induced platelet inhibition.

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from −142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from −49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.

Delays to reperfusion therapy in acute ST-segment elevation myocardial infarction: results from the AMI-QUEBEC Study

Background: Through the AMI-QUEBEC Study we sought to describe delays to reperfusion therapy for ST-segment elevation myocardial infarction (STEMI) and to identify factors associated with prolonged delays. Methods: We reviewed the charts of all consecutive patients with STEMI admitted to 17 hospitals in the province of Quebec in 2003 to obtain data on the time from presentation to reperfusion therapy. Data were available for 1189 (83.0%) of 1432 patients. Results: The median delay to reperfusion therapy was 32 minutes (first and third quartile [Q1, Q3] 20, 49) for 535 patients who received fibrinolytic therapy, 109 minutes (Q1, Q3 79, 150) for 455 patients who underwent primary percutaneous coronary intervention (PCI) at the initial hospital of presentation and 142 minutes (Q1, Q3 115, 194) for 199 patients who underwent primary PCI after an interhospital transfer. Patients who presented outside daytime working hours, those who received primary PCI and those who required interhospital transfer for primary PCI were less likely to receive reperfusion therapy within current recommended times (odds ratios [ORs] 0.49, 0.56 and 0.15, respectively). Increased age was associated with prolonged delays only among patients who received fibrinolytic therapy (OR for each 10-year increase in age 0.95, 95% credible interval [CrI] 0.93–0.99 for fibrinolytic therapy and 0.99, 95% CrI 0.95–1.05, for primary PCI). Interpretation: In 2003, many patients with STEMI in Quebec were not treated within the recommended times. Delays may be reduced by reorganizing pre-and in-hospital care for patients with STEMI to expedite delivery of reperfusion therapy.

Heterogeneity in platelet cyclooxygenase inhibition by aspirin in coronary artery disease

BACKGROUND Platelets, long believed to be incapable of de novo protein synthesis, may retain their ability to form the cyclooxygenase (COX) enzyme once it has been inactivated by aspirin. This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients. We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration. METHODS Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1, 3, 8, and 24h after observed ingestion of 80-mg enteric-coated aspirin. Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane (Tx) B(2) levels, and functionally by light transmission aggregometry in response to arachidonic acid. COX-independent platelet activity was measured in response to adenosine diphosphate, epinephrine and collagen. RESULTS Plasma TxB(2) levels showed profound inhibition of TxA(2) formation, which was stable throughout 24h, in all but 1 subject. This subject had optimal response to aspirin (inhibition of platelet TxA(2) production within 1h), but recovered the ability to synthesize TxA(2) within 24h of aspirin ingestion. Arachidonic acid-induced platelet aggregation closely mirrored TxB(2) formation in this patient, portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion. COX-independent platelet aggregation triggered TxA(2) production to a similar extent in all patients, likely through signal-dependent protein synthesis. CONCLUSIONS COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration. Further research should consider increasing aspirin dosing frequency to twice daily, to allow sustained inhibition in such subjects.

Cost effectiveness of the sirolimus-eluting stent in high-risk patients in Canada: an analysis from the C-SIRIUS trial.

BackgroundThe cost effectiveness of drug-eluting stents in Canada is debated and deserves further evaluation in high-risk patients.MethodsWe performed an economic analysis from the third-party payer perspective based on the clinical results and resource-utilization data of the C-SIRIUS (The Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients with Long De Novo Lesions in Small Native Coronary Arteries) trial, which examined the safety and efficacy of sirolimus-eluting stents (SES) versus bare metal stents (BMS) in high-risk patients with single long de novo lesions in small coronary arteries. Only inpatient costs were considered, including physician fees. We postulated that the incremental cost required to avoid a repeat revascularization (RR) procedure with BMS versus simple balloon angioplasty (BA) could be considered the willingness to pay (WTP) to avoid restenosis in Canada. We assessed the incremental cost-effectiveness ratio (ICER) of SES compared with BMS in these high-risk patients compared with WTP. Results are expressed in 2003 Canadian dollars.ResultsWith a 7% absolute reduction in the need for RR compared with BA, BMS are associated on average with an ICER of

Genetic determinants of response to aspirin: Appraisal of 4 candidate genes

12 551/RR avoided (RRA) in Canada. In C-SIRIUS, SES further reduced the need for RR at 1 year from 22% to 4% (p = 0.015) compared with BMS. With a 1.5 stent-to-lesion (STL) ratio and an SES retail price of

Impact of Moderate Renal Insufficiency on Restenosis and Adverse Clinical Events After Sirolimus-Eluting and Bare Metal Stent Implantation (from the SIRIUS Trials)

2700 compared with