Clin Res Cardiol (2008)DOI 10.1007/s00392-008-0672-7 CLINICAL TRIAL UPDATES AND HOTLINE SESSIONS j Abstract This article summarizes the results of a number of new Received: 25 April 2008Accepted: 25 April 2008 clinical trials, registries and meta-analyses in the field of cardiovascular medicine. Key presentations made at the annual meeting of the AmericanCollege of Cardiology (ACC), held in Chicago, IL, USA from 29 March tillfirst April 2008 are reported. The ACC meeting was accompanied by theSCAI (Society for Cardiovascular and Angiographic Interventions)Annual Scientific Sessions in Partnership with ACC i2 Summit. The data Y.P. Clever (&) Æ S. RosenkranzM. Bo¨hm Æ B. Scheller were presented by leading experts in the field with relevant positions in Klinik fu¨r Innere Medizin III, Kardiologie, the trials, registries or meta-analyses. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine.
Universita¨tsklinikum des SaarlandesKirrberger Straße66421 Homburg/Saar, GermanyE-Mail: [email protected] j Key words CONTRAST – ARMYDA-RELOAD – BRAVE-3 – TRITON-TIMI 38 – ISAR-REACT 3 – TRANSFER-AMI – SPIRIT II – PEPCAD II – MAIN-COMPARE – ONTARGET – ACCOMPLISH – Joseph-Stelzmann-Str. 950924 Cologne, Germany HYVET – PERISCOPE – ENHANCE – STRADIVARIUS Contrast media induced nephropathy: CONTRAST iso-osmolar contrast medium iodixanol has no ben-eficial effects compared to the low-osmolar contrast There is an ongoing controversy on the impact of iso- medium iomeprol in patients with impaired renal osmolar contrast agents on contrast media induced function undergoing percutaneous coronary inter- nephropathy (CIN). The COntrast Media and Neph- vention (PCI) after appropriate intravenous hydration roToxicity Following Coronary Revascularization by AngioplaSTy (CONTRAST) randomized 324 patients with impaired renal function undergoing PCI to re-ceive either the iso-osmolar contrast medium iodix-anol 320 (VisipaqueÒ) or the low-osmolar contrastmedium iomeprol 350 (ImeronÒ). Around 38% of the Antithrombotic strategies in PCI and acute patients had diabetes, and 78% had complex (B2/C) lesions on angiogram. The authors found no differ-ence in the incidence of CIN: 22.2 versus 27.7% (ns) between the iodixanol and iomeprol groups, respec- tively. Subgroup analysis revealed no advantage of Two trials were focused on a clopidogrel loading dose 672 iodixanol in patients with diabetes.
before PCI. The goal of the ARMYDA-RELOAD trial Clinical Research in Cardiology (2008)Ó Steinkopff Verlag 2008 was to evaluate the safety and efficacy of an additional These results suggest that in patients with STEMI clopidogrel dose prior to PCI. Patients on chronic undergoing PCI following pre-treatment with 600 mg clopidogrel therapy (>10 days) were randomized to of clopidogrel, the additional use of abciximab is not an additional 600 mg clopidogrel dose (n = 285) or associated with a further reduction in infarct size or placebo (n = 283). Among patients with stable angi- na, drug eluting stents (DES) were used in 54% of the preload group and 47% of the placebo group. Withacute coronary syndromes (ACS), DES were used in22% of the preload group and 26% of the placebo group. Among the stable angina population, GP IIb/IIIa inhibitors were used in 5% of the preload group The TRITON-TIMI 38 trial compared the novel thie- and 4% of the placebo group. With ACS, glycoprotein nopyridine prasugrel with clopidogrel in moderate- (GP) IIb/IIIa inhibitors were used in 20% of the to-high-risk ACS patients scheduled to undergo PCI.
preload group and 21% of the placebo group. For the A total of 13,608 subjects were enrolled. Of those, entire study population, the incidence of the primary 6,461 patients received bare-metal stents (BMS) and outcome, MACE, was 7% of the reload group versus 5,743 patients DES. The overall mortality rate for 9% of the placebo group (ns). However among ACS patients with stent thrombosis was 26%. Prasugrel patients, MACE was 7 versus 18% (P = 0.035), reduced stent thrombosis by 50%. The reduction in respectively. There was no increase in bleeding by the stent thrombosis was robust across a broad range of additional clopidogrel dose. Besides the fact that an clinical and angiographic subgroups, including dia- additional loading dose of clopidogrel failed to reduce betes, age, gender, stent length, stent diameter, and MACE at 30 days, subgroup analysis suggest a benefit stent number. However, this reduction in ischemic with an additional loading dose among patients with events was at a cost of increased major bleeding events, especially in patients ‡75 years, ‡60 kg, and with a history of stroke or transient ischemic attack The aim of the BRAVE-3 trial was to assess the impact of the GP IIb/IIIa inhibitor abciximab in In conclusion, prasugrel may be an alternative for patients with ST-elevation myocardial infarction patients undergoing PCI with high risk for stent (STEMI) undergoing PCI after pre-treatment with thrombosis. This should be weighed against its higher clopidogrel. Patients were randomly assigned to ab- ciximab [bolus of 0.25 mg/kg followed by an infusion of 0.125 lg/(kg min) for 12 h] or placebo (additionalunfractionated heparin (UFH) of 70 U/kg, followed byplacebo infusion for 12 h). All patients received a daily dose of 200 mg of aspirin indefinitely. Clopi-dogrel was given as a loading dose of 600 mg, The aim of ISAR-REACT 3 trial was to assess whether followed by 150 mg daily for 3 days, and followed bivalirudin is superior to UFH in terms of ischemic by 75 mg daily for at least 1 month. A total of 800 and hemorrhagic endpoints in PCI after pre-treat- patients were randomized, 401 to the abciximab ment with clopidogrel. Patients with negative bio- arm and 399 to the placebo arm. The median times markers undergoing PCI were randomized to receive from symptom onset to admission were 210 and either UFH (bolus of 140 U/kg, followed by placebo 216 min in the abciximab and control arms, respec- infusion) or bivalirudin [bolus of 0.75 mg/kg, fol- tively, whereas the median door-to-balloon times lowed by infusion of 1.75 mg/(kg h)] during the were 78 and 80 min, respectively. Drug-eluting stents procedure, in addition to 600 mg of clopidogrel and were deployed in about 44% of the patients in both ‡325 mg aspirin at least 2 h prior to the procedure. A arms, whereas bare-metal stents were deployed in total of 4,570 patients were randomized, 2,289 to the about 49% of the patients. TIMI 3 flow was estab- bivalirudin arm, and 2,281 to the UFH arm. The lished in 92% of patients in both arms. Mortality at majority of patients (83%) received DES. The inci- 30 days was 3.2 versus 2.5%, respectively (ns). The dence of death, MI, and urgent target vessel revas- composite endpoint of death, MI, stroke, or urgent cularization (primary endpoint) was 0.1 and 0.2% revascularization was 5.0 versus 3.8%, respectively (ns), 5.8 and 4.8% (ns), and 0.8 and 0.7% (ns), for (ns). The incidence of minor bleeding was non-sig- bivalirudin and UFH, respectively. The secondary nificantly elevated in the abciximab arm compared endpoint of death, MI, and urgent revascularization with the control arm (3.7 vs. 1.8%, P = 0.09), whereas was 5.9% in the bivalirudin arm and 5.0% in the UFH the incidence of thrombocytopenia was significantly arm. The incidence of bleeding was significantly lower with bivalirudin compared with UFH, which may be Y.P. Clever et al.
Clinical trial updates and hotline sessions attributable to the uncommon high dose of heparin treatment with thrombolytics and transfer for rescue used in this study without monitoring of activated PCI only These findings confirm the results of clotting time. In summary, after pre-treated with earlier published trials on early PCI after thrombol- 600 mg of clopidogrel, bivalirudin seems not to be Novel devices and new frontiers in interventional j Early PCI after thrombolysis: TRANSFER-AMI The goal of the TRANSFER-AMI trial was to study the j Second generation drug eluting stent: SPIRIT II impact of early PCI after fibrinolysis in patients withST-elevation myocardial infarction (STEMI). It was The goal of the SPIRIT II study was to evaluate the conducted in a similar design as the Southwest Ger- safety and efficacy of the XIENCEÒ V everolimus- man Interventional Study in Acute Myocardial eluting cobalt chromium coronary stent compared Infarction (SIAM III) []. Patients were randomized with the TAXUSÒ paclitaxel-eluting stent among pa- to a pharmacoinvasive strategy (transfer for PCI tients with de novo coronary lesions. Patients were within 6 h of fibrinolysis) or to standard treatment randomized in a 3:1 ratio to everolimus-eluting stent after fibrinolysis (which included rescue PCI as (n = 223) or paclitaxel-eluting stent (n = 77). A sub- required for ongoing chest pain and <50% resolution set of 152 patients underwent intravascular ultra- of ST-elevation at 60–90 min, or if patients were sound (IVUS) at 6 months and 2 years. The primary hemodynamically unstable). The authors presented endpoint of in-stent late loss in a single lesion per the data of 1,030 patients (522 randomized to the patient at 6 months met the criteria for noninferiority pharmacoinvasive arm and 508 to the standard and superiority for the everolimus-eluting stent group treatment arm). For standard treatment patients who compared with the paclitaxel-eluting stent group did not require rescue PCI, elective cardiac catheter- (0.11 mm for everolimus vs. 0.36 mm for paclitaxel, ization within the first 2 weeks was encouraged. All P < 0.001). This difference was not statistically sig- patients received standard-dose tenecteplase (TNK) nificant at 2 years (0.33 mm for everolimus vs. 0.34 and aspirin 160–325 mg including UFH or enoxapa- for paclitaxel, ns). In-stent percent diameter stenosis rin. Clopidogrel loading was strongly encouraged in was lower in the everolimus group at 6 months (16 vs.
all study patients. Cardiac catheterization was per- 21%, P < 0.001), but not at 2 years (19.2 vs. 18.8%, formed in 97% of patients in the pharmacoinvasive ns). The rate of stent thrombosis was 0.9 and 1.4% in arm, and 82% of patients in the standard treatment the two arms, respectively. Both the stent thrombosis arm. The median time to administration of TNK from episodes in the everolimus arm occurred after 1 year onset of symptoms was 2 h in both arms, whereas the median time from TNK to catheterization was 3 h in the pharmacoinvasive group, and 27 h in the standardtreatment group. Stents were deployed in 98% of thepatients in both arms.
At 30 days follow-up, the incidence of the primary endpoint of death, re-infarction, heart failure, severe Drug eluting stents have become widely accepted and recurrent ischemia, or shock was significantly lower are used for a wide spectrum of clinical indications.
in the pharmacoinvasive arm (10.5%) compared with However, concerns have been raised that DES while the standard management arm (16.5%) (P = 0.001).
being effective may be associated with an increased The incidence of mortality, re-infarction, recurrent incidence of late thrombotic complications. The ischemia, and heart failure was 3.7 and 3.6% (ns), 3.3 treatment of coronary in-stent restenosis (ISR) and 6.0% (P = 0.044), 0.2 and 2.2% (P = 0.02), and remains a challenging problem in many patients de- 2.9 and 5.2% (P = 0.07) in the pharmacoinvasive and spite the advent of DES. The concept of implanting conventional treatment arms, respectively. The inci- DES in ISR involves insertion of a second layer of dence of major bleeding was 4.3 and 4.6%, respec- metal in a native coronary artery. The repeatability of Patients presenting with STEMI to centers without Drug eluting balloon catheters (DEB) represent an timely access to a catheterization lab, a pharmacoin- alternative option for the treatment of coronary and vasive approach consisting of full-dose thrombolytics, peripheral arteries. The DEB delivers a homogenous followed by emergent transfer for cardiac catheteri- drug concentration to the arterial wall, which has zation within 6 h, is safe and efficacious compared to been shown to be an effective substitute for sustained Clinical Research in Cardiology (2008)Ó Steinkopff Verlag 2008 release. So far, preclinical and clinical efficacy has mately 50% of the left main (LM) lesions were ostial only been demonstrated for DEB based on the PAC- or mid-shaft, and 50% were distal bifurcation. The rate of TVR was significantly higher in the PCI group First in-man data with the PACCOCATH balloon compared to the CABG group (13 vs. 3%, P < 0.001).
showed safety and efficacy of this DEB in the treat- However, the 3-year rate of death (8%) and composite ment of ISR [and peripheral artery disease [].
of death, Q-wave MI, or stroke (10%) were similar Results from 12 months of clinical follow-up with the between PCI- and CABG-treated patients. Comparing second generation PACCOCATH balloon SeQuentÒ BMS with CABG and DES with CABG also yielded Please (B. Braun Vascular Systems, Berlin, Germany) higher rates of TVR in the BMS and DES groups, but compared to treatment with the TaxusÒ paclitaxel- the composite of death, Q-wave MI, or stroke was eluting stent in terms of target lesion revasculariza- similar. The overall acute complication rate was 2.7% tion (TLR) and major adverse cardiac events (MACE) in the PCI group, including 0.2% acute vessel closure, were presented. 131 patients with coronary ISR were 0.1% emergent CABG, 0.8% death within 48 h, and randomized to treatment with the DEB or the DES.
0.1% acute stent thrombosis. Stent thrombosis oc- Using an intention to treat analysis, MACE was lower curred in six patients in the PCI group, ranging from in the DEB group (7.8 vs. 16.9%, ns). Analysis of the results with regard to the treatment received dem- This large, long-term study comparing PCI with onstrated a significant benefit of DEB in terms of CABG for unprotected LMCA demonstrates that PCI MACE (4.7 vs. 18.3%, P = 0.02), largely driven by a with stent implantation showed equivalent long-term significant decrease in TLR (3.1 vs. 16.7%, P = 0.02).
Late lumen loss and binary restenosis was signifi- underlines the need for an adequately powered pro- cantly lower in the DEB group in both analyses. In spective randomized trial of the two strategies in contrast to the DES group, in the DEB group com- bined antiplatelet therapy was continued only for 3 months, followed by treatment with aspirin alone.
In patients with coronary in-stent restenosis, treatment with SeQuentÒ Please (DEB based on thePACCOCATH technology) was superior to treatment Medical therapy of cardiovascular diseases with DES in terms of late lumen loss, binary reste- nosis, target lesion revascularization and major ONTARGET (ONgoing Telmisartan Alone and in adverse cardiac events at 12 months [].
Combination with Ramipril Global Endpoint Trial) ONTARGET was designed to measure the effect oframipril (10 mg), telmisartan (80 mg) or a combina- tion of the two on patients over the age of 55 years with coronary heart disease, peripheral artery diseaseor cerebrovascular disease or patients with diabetes Based on historical data, coronary artery bypass with endorgan damage. The HOPE trial demonstrated grafting (CABG) is considered to be the gold standard that the ACE-inhibitor ramipril was able to reduce for treatment of unprotected left main coronary artery cardiovascular death, myocardial infarction, stroke disease (LMCA). Meanwhile for selected patients with and heart failure in high-risk individuals without left unprotected LMCA, PCI has been shown to be similar ventricular dysfunction. Similar effects were observed to CABG in short- and intermediate-term follow-up.
with other ACE-inhibitors However, a significant A recent meta-analysis of non-randomized trials portion of patients were unable to tolerate ACE- comparing DES and CABG was in favor of PCI in inhibitors due to cough hypotension or angioneurotic oedema. The ONTARGET trial asked the question In the MAIN-COMPARE trial, 2240 unprotected whether the angiotensin receptor blocker telmisartan was equivalent to ramipril and whether the combi- (n = 1,102; BMS, n = 318; DES, n = 784) or CABG nation of the two were superior to reduced cardio- (n = 1,138). Treatment strategy was at the discretion vascular endpoints. Investigators from 733 centers of the treating physician or patient preference. In the from 40 countries collaborated in conducting the CABG group, internal mammary graft to the left ONTARGET study, which enrolled 25,620 patients anterior descending artery was used in 98%. Of the over the age of 55 years with the above mentioned 1,102 patients who underwent PCI, 1073 patients were inclusion criteria but without evidence of heart fail- considered eligible for both PCI and CABG. About ure. After a single blind run-in phase, the patients 71% received DES and 29% received BMS. Approxi- were randomized, received ramipril (10 mg a day), Y.P. Clever et al.
Clinical trial updates and hotline sessions telmisartan (80 mg a day) or the combination of the patients with stage 2 hypertension (‡160/100 mmHg), two. The mean duration of follow-up was 55 months.
two-drug combination therapy, usually with a diuretic Telmisartan lowered blood pressure to a slightly greater degree compared to ramipril (0.9 mmHg The ACCOMPLISH trial recruited 11,400 high risk systolic) and the combination lowered it still further patients aged 55 years or older with hypertension (2.4 mmHg systolic). Telmisartan alone or ramipril (defined as systolic blood pressure ‡160 mmHg or alone showed to be equally effective in reducing the current antihypertensive therapy) and evidence of primary outcome of cardiovascular death, stroke, cardiovascular disease or end-organ damage. Patients heart attack or hospitalization for heart failure as well enrolled in the trial were obese, with 60% having dia- as each component of this composite outcome. The betes, and almost all patients were previously treated confidence interval of these estimates were tight and for hypertension. Although more than 70% were trea- clearly met the pre-specified statistical non-inferiority ted with a combination of at least two antihypertensive boundary. Telmisartan was better tolerated than agents, only 37.5% had their blood pressure controlled ramipril, which showed a lower incidence of cough as to the currently recommended target of <140/ well as lower rates of angioneurotic oedema. Due to 90 mmHg at baseline. As per study protocol, all pa- the more pronounced blood pressure reduction, a tients stopped their previous antihypertensive medi- small excess of minor hypotension-related symptoms cation, and—without a wash out period—were randomized to combination therapy with either bena- Despite the further lowering of blood pressure, zepril and amlodipine or benazepril and hydrochloro- combination therapy did not offer any additional thiazide. The trial was stopped early because the benefit but was associated with a higher rate of combination of benazepril with amlodipine was shown hypotension related side effects including syncopy.
to be more effective than the combination of benazepril There was an increase in discontinuation for increased with diuretic. At 36 months, more than 75% of patients potassium levels too. It is concluded that telmisartan is showed significantly improved blood pressure levels equally effective as ramipril, but the combination does that were within the recommended target of <140/ not offer any further clinical benefit and is associated 90 mmHg in both groups. Despite similar effects on with more side effects. Therefore, telmisartan and blood pressure lowering, the combination of ACE ramipril are choices for the treatment of the high inhibitor and CCB was more effective in reducing car- cardiovascular risk patients. The paper was immedi- diovascular morbidity and mortality than ACE inhibi- ately published after the presentation ].
tor plus diuretic. In fact, combination therapy with benazepril plus amlodipine reduced the combinedprimary end point of the study (cardiovascular death,fatal/nonfatal myocardial infarction, fatal/nonfatalstroke, hospitalization for unstable angina, coronary ACCOMPLISH (Avoiding Cardiovascular Events revascularization) by 20%, as compared with the in COMbination Therapy in Patients LIving combination of benazepril plus hydrochlorothiazide ]. These results challenge the current recommen-dations for blood pressure control and will likely lead to The ACCOMPLISH trial was designed to compare the modifications of the guidelines for the treatment of effects of two blood pressure lowering combination hypertension, particularly in terms of starting with a therapies, the ACE inhibitor benazepril plus the cal- one-drug strategy and the use of diuretics in combi- cium channel blocker (CCB) amlodipine versus benazepril plus diuretic (hydrochlorothiazide), on major fatal and nonfatal cardiovascular events (fatal/nonfatal myocardial infarction, fatal/nonfatal stroke,cardiovascular death, hospitalization for unstable j HYVET (HYpertension in the Very Elderly Trial) angina, coronary revascularization) ].
Hypertension is an established risk factor for car- Despite the clear overall benefit of reducing blood diovascular events. The current recommendations for pressure in hypertensive patients for the prevention the treatment of hypertension include thiazide-type of stroke and other vascular events, it is not clear diuretics as the integral component of antihyperten- whether antihypertensive treatment in patients over sive therapy [, According to JNC7, the treatment the age of 80 is also beneficial. A meta-analysis sug- of stage 1 hypertension includes the use of thiazide- gested that the reduction in the risk of stroke may type diuretics for most patients, with additional be offset by possible adverse events in the elderly consideration given to ACE inhibitors, angiotensin- population []. Consistently, the pilot phase of receptor blockers, beta blockers, and CCBs. In HYVET also showed that the reduced risk of stroke Clinical Research in Cardiology (2008)Ó Steinkopff Verlag 2008 may be out-weighted by a possible increase in death effects of diabetes medications beyond their glucose from any cause ]. The lack of definitive data on the advisability of treating hypertension in older patients PERISCOPE was designed to compare the effects of is reflected in European and US guidelines.
the insulin sensitizer pioglitazone and the sulfonylurea The HYVET study was designed to evaluate the glimepiride on the progression of coronary artery dis- relative benefits and risks of antihypertensive treat- ease (CAD) as assessed by intravascular ultrasound ment in patients 80 years of age and older. 3,845 pa- (IVUS). About 543 patients with type 2 diabetes were tients ‡80 years with a sustained systolic blood randomized to receive either glimepiride (1–4 mg) or pressure ‡160 mmHg were enrolled and randomized to pioglitazone (15–45 mg). IVUS was performed at receive either the diuretic indapamide (sustained re- baseline and at 18 months (at study completion, lease 1.5 mg) or placebo. The ACE inhibitor perin- n = 360). As expected, both drugs lowered glycated dopril (2 or 4 mg) or placebo could be added as hemoglobin (HbA1c) and fasting insulin levels, al- necessary in order to achieve a target blood pressure of though these effects were more procounced in the 150/80 mmHg. While scheduled to be completed in pioglitazone group. Pioglitazone also led to significant 2009, the trial was prematurely stopped, owing to the improvements of triglicerides ()15.3 vs. +3.3%; significant benefit of active therapy with regard to P < 0.001) and HDL cholesterol (+16.0 vs. +4.1%; reductions in stroke and all-cause mortality. At two P < 0.001) compared to glimepiride. The IVUS studies years of treatment, there was a difference in blood revealed that pioglitazone – but not glimepi- pressure lowering (15.0 vs. 6.1 mmHg) between the ride—prevented the progression of coronary athero- groups. At that time point, target blood pressure (150/ sclerosis. The main outcome measure, mean percent 80 mmHg) was reached in 48% of the treatment group atheroma volume (PAV), decreased by 0.16% in the and in 20% of the placebo group. In an intention-to- pioglitazone group but increased by 0.73% in the treat analysis, the primary end-point of the study (fatal glimepiride group (P = 0.002). In addition, there were or non-fatal stroke) was reduced by 30% in the active also significant differences in secondary IVUS end- treatment group, but this finding did not reach nominal points such as atheroma thickness ()0.011 vs.
significance (P = 0.06). Treatment was, however, +0.011 mm; P = 0.006) and atheroma volume ()5.5 vs.
associated with significant reductions in all-cause )1.5 mm3; P = 0.06). Although the IVUS data must be mortality (by 21%), the rate of death from stroke (by interpreted with caution as they only represent surro- 39%), and the rate of heart failure (by 64%). Further- gate markers of cardiovascular events, they are in line more, a trend was found for a reduction in the rate of with data from the PROactive study which showed a death from cardiovascular causes (by 23%). Active 10% trend towards a decrease of all macrovascular treatment was also associated with fewer adverse side events (primary end point; ns) and a statistically sig- effects (358 vs. 448 events; P < 0.001). Hence, the re- nificant decrease of 16% of the composite endpoint sults from HYVET provide evidence that antihyper- death, myocardial infarction, and stroke (secondary tensive therapy based on indapamide, with or without endpoint; P < 0.05) by pioglitazone ]. These studies perindopril, in the very elderly, aimed to achieve a collectively suggest that pioglitazone may modify cor- target blood pressure of 150/80 mmHg, is beneficial, as onary atherosclerosis and the risk of cardiovascular it is associated with reduced risks of fatal stroke, death events. While hypoglycaemia and angina were more from any cause, and heart failure. Furthermore, the common with glimepiride treatment, edema, weight results of the study support a target blood pressure of gain, and bone fractures occurred more frequently with 150/80 mmHg in this population, since the target was pioglitazone treatment. The latter, occurring in 3% of reached in nearly 50% of patients in the active-treat- pioglitazone-treated patients, was a surprising finding ment group Whether further reduction is more that causes some concern. Nevertheless, PERISCOPE beneficial needs to be established in future trials.
was the first diabetes study that has shown to slow the PERISCOPE (Pioglitazone Effect on Regression ofIntravascular Sonographic Coronary Obstruction and High-Dose Simvastatin vs. Simvastatin Aloneon the Atherosclerotic Process in Patients with Thiazolidinediones (TZDs) or glitazones, activators of Heterozygous Familial Hypercholesterolemia) the nuclear hormone transcription factor PPARc, areoral antidiabetic agents that reduce glucose levels HMG-CoA reductase inhibitors (statins) have been primarily by increasing insulin sensitivity in periph- shown to reduce cardiovascular event rates, mainly by eral tissues Few studies have compared the their lipid-lowering effects and possibly by additional Y.P. Clever et al.
Clinical trial updates and hotline sessions it should be acknowledged that ENHANCE measured absorption inhibitor, leads to further reductions of a surrogate end-point. Therefore, it cannot yet be LDL cholesterol when added to statin treatment.
concluded that further lowering of LDL cholesterol However, the effect of ezetimibe on the progression of with ezetimibe does not reduce hard clinical end atherosclerosis and on the rate of cardiovascular points [It will still be interesting to see whether studies that are specifically designed to determine The ENHANCE trial aimed to investigate whether a whether or not ezetimibe reduces clinical events, such combination of ezetimibe with simvastatin would re- as the ongoing IMPROVE-IT trial, will be able to duce the progression of atherosclerosis in patients demonstrate any benefit in improving cardiovascular (HeFH) compared with simvastatin alone. The pri- mary goal of the trial was to compare the meanchange in the intima-media thickness (IMT) mea-sured at three sites in the carotid arteries between patients with HeFH treated with ezetimibe/simvasta- tin (10/80 mg) versus patients treated with high-dose Administration of Rimonabant—the IVUS Study) simvastatin (80 mg) alone, over a period of 2 years.
About 720 patients were randomized to receive either Abdominal obesity is associated with specific meta- ezetimibe/simvastatin or simvastatin alone. The bolic abnormalities that increase the risk of coronary baseline characteristics of the two groups in terms of artery disease (CAD). Rimonabant, a cannabinoid LDL cholesterol levels, previous statin treatment, and type 1 receptor antagonist, enhances weight loss and carotid IMT measurements at baseline were similar.
improves obesity-related metabolic abnormalities. It The combination of ezetimibe and simvastatin was was approved in Europe (EMEA)—but not the US more effective in reducing LDL cholesterol levels (FDA)—for weight loss in obese patients. Rimonabant compared to simvastatin alone (56% reduction vs.
was not approved by the FDA primarily because of 39% reduction; P < 0.01). The primary outcome safety concerns regarding psychiatric adverse events.
measure, change from baseline to study endpoint for STRADIVARIUS aimed to investigate whether mean carotid IMT, was not different between groups rimonabant could reduce the progression of athero- (0.0058 ± 0.0037 mm in the simvastatin arm versus sclerosis in obese patients. 839 patients with abdom- 0.0111 ± 0.0038 mm in the simvastatin/ezetimibe inal obesity (defined as waist circumference >102 cm arm; ns). Similarly, new plaque formation (defined as for men and >88 cm for women) and two additional IMT >1.3 mm) was not different between groups 9/ factors of the metabolic syndrome or current smoking 320 (2.8%) in the simvastatin arm versus 15/322 were randomized to receive either rimonabant (20 mg (4.7%) in the simvastatin/ezetimibe arm; ns). No daily) or matching placebo. The patients underwent significant changes were observed between groups for a close metabolic follow-up, and intravascular ultra- the IMT of the common carotid, carotid bulb, internal sound (IVUS) was performed at baseline and at carotid, femoral, or the average of the mean carotid 18 months (at study completion, n = 676). The pri- and femoral IMT values. There was also no difference mary efficacy parameter was change in percent ath- in the incidence of cardiovascular mortality, nonfatal eroma volume (PAV), and the secondary efficacy myocardial infarction, nonfatal stroke, and need for parameter was change in normalized total atheroma revascularization, although the trial was not powered volume (TAV). Consistent with previous studies, to study clinical outcomes. Furthermore, the inci- rimonabant caused a significant reduction in body dence of adverse events was similar. Hence, EN- weight ()4.3 vs. )0.5 kg) and waist circumference HANCE shows that while the addition of ezetimibe to ()4.5 vs. )1.0 cm), and furthermore improved HDL simvastatin led to the expected changes in LDL cho- cholesterol levels (+22.4 vs. +6.9%), serum triglycer- lesterol levels, it did not reduce any of the IMT ides ()20.5 vs. )6.2%), C-reactive protein (CRP) lev- els ()1.3 vs. )0.9 mg/l) and glycated hemoglobin Both carotid IMT and LDL cholesterol levels have (HbA1c) (0.11 vs. 0.40%), compared to placebo (all been demonstrated to accurately predict the risk of P < 0.001). Despite these positive outcomes in labo- incident cardiovascular events in numerous studies.
ratory values and clinical features, there was no dif- Thus, the results of ENHANCE seem paradoxical.
ference between the groups in the primary end point: Despite a further lowering of LDL cholesterol, the The change in PAV was +0.25% in the rimonabant combination of ezetimibe with simvastatin was not group versus +0.51% in the placebo group (P = 0.22).
associated with a reduction of carotid IMT compared The secondary endpoint of normalized TAV did to simvastatin alone. Although the results strongly however improve in the rimonabant group ()2.2 vs.
argue against an anti-atherogenic effect of ezetimibe, +0.88 mm3, P = 0.03). Given that the primary end Clinical Research in Cardiology (2008)Ó Steinkopff Verlag 2008 point of atherosclerosis was negative, despite the rimonabant failed to show any benefit on progression positive metabolic changes, the results indicate that of atherosclerosis in an IVUS study, but led to higher there may be no cardiovascular benefit with rimona- rates of psychiatric and other side effects compared with placebo. Nevertheless, caution should be taken A major concern with rimonabant is the rate of about the use of IVUS findings as surrogate markers side effects. Obesity is associated with a significant of patient outcomes, since IVUS results have yet to be psychiatric comorbidity. This is reflected by the high definitely linked to lower rates of death or myocardial prevalence of anxiety and depression (28.4%) in the infarction. Hence, additional studies will be needed to placebo group of STRADIVARIUS. Even so, the rate assess the role of rimonabant in the treatment of of psychiatric adverse effects was significantly higher obese patients with CAD and metabolic risk factors.
in the rimonabant group (43.4%; P < 0.001). In addition, there was an almost threefold higher risk of Underlying Development Assessed by Intima-Media gastrointestinal tract side effects (e.g., nausea 14.9 vs.
Thickness in Patients on Rimonabant) and CRE- 5.5%; P < 0.001) and a tripling of the risk of erectile SCENDO (Comprehensive Rimonabant Evaluation dysfunction (3.3 vs. 0.7%; P = 0.03) by rimonabant.
Study of Cardiovascular End Points and Outcomes), a In particular, the dramatically high rate of psychiatric long-term cardiovascular outcomes study, are cur- side effects raises concerns with this drug Taken together, in patients with abdominal obesity and additional factors of the metabolic syndrome 1. Beckett NS, Peters R, Fletcher AE et al; 6. DiSciascio G, Patti G, Colonna G et al 11. Kastelein JJ, Akdim F, Stroes Es et al (2008) For the ENHANCE investigators.
clopidogrel therapy. Results of the anti- 12. Kastrati A, Neumann FJ, Mehilli J et al platelet therapy for reduction of myocar- meeting. Late breaking clinical trials.
treatment with 600 mg of clopidogrel.
(2003) Results of the pilot study for the hypertension in the Very Elderly Trial.
management of arterial hypertension.
tion: are the results controversial? Clin plasty and Stenting After Fibrinolysis to 9. Gueyffier F, Bulpitt C, Boissel JP et al meeting. Late breaking clinical trials.
Dahlo¨f B, Pitt B, Velazquez E, on behalf meeting. Late breaking clinical trials.
tients living with systolic hypertension.
Y.P. Clever et al.
Clinical trial updates and hotline sessions 15. Nissen SE, Nicholls SJ, Wolski K et al tors. Comparison of pioglitazone vs.
sus the TaxusÒ stent in the treatment of 16. Nissen SE, Nicholls SJ, Wolski K et al ing clinical trials. Chicago, 29 March–1 meeting. Late breaking clinical trials.
25. Wessely R, Koppara T, Kastrati A et al stent restenosis with a paclitaxel-coated 21. Staels B, Fruchart JC (2005) Therapeu- 22. Tepe G, Zeller T, Albrecht T et al (2008) restenosis during angioplasty of the leg.
meeting. Late breaking clinical trials.
tients at high risk for vascular events. N (2008) Intensive oral antiplatelet ther-apy for reduction of ischaemic eventsincluding stent thrombosis in patientswith acute coronary syndromes treatedwith percutaneous coronary interven-tion and stenting in the TRITON-TIMI38 trial: a subanalysis of a randomisedtrial. Lancet 371:1353–1363


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Winter school ‘New skills and occupations in Europe: Challenges and possibilities’ 25-27 November 2013 CEPS- Place du Congres, 1000 Brussels Website Programme Application form Practical information (will be published soon) Financial information for participants Contact: mailto:[email protected] General information The winter school off

Regression Course – Additional Notes I & IIThese consolidate the earlier separate sets of additional notes – I & IIBalanced vs Unbalanced Data – What is the Effect?This section illustrates, in a very simple case, confounding effects that may arise when data are unbal-anced. It demonstrates, also, how the estimate for a term may change when a further term is includedin the model.

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