Summary of the Most Important Studies Presented During the ESC Congress 2008
D. Sakellariou, G. Andrikopoulos, September 8, 2008
The annual Congress of the European Society of Cardiology was held in Munich from August 30 to September 3, 2008. We present a summary of the most interesting results of late-breaking important trials which were presented at the meeting.
In a post hoc analysis of the ATHENA trial, one of the largest antiarrhythmic drug trials ever conducted, with 4628 randomised patients, the antiarrhythmic agent dronedarone, was associated with a 34% drop (p=0.027) in adjusted risk of stroke compared with placebo over a follow up averaging 21 months. ATHENA had already shown a 24% decline (p<0.001) in time to first cardiovascular (CV) hospitalisation or any-cause death, which was its primary end point, as well as cuts in risk of CV mortality (29%, p=0.034), CV hospitalisation (25%, p<0.001), and arrhythmic death (45%, p=0.01) associated with dronedarone. So dronedarone seems to be a potential safe alternative to amiodarone.
This study is the first large-scale, multicentre, randomised, double-blind controlled trial to assess whether CRT plus optimal medical therapy (CRT ON) can attenuate heart failure (HF) progression compared to optimal medical therapy alone (CRT OFF), in patients with NYHA I or II HF, QRS-duration ≥120 ms and LV ejection fraction ≤40%. During the ESC 2008 congress the study investigators presented the results of the 18 month follow up in European countries, while during the ACC 2008 scientific sessions they presented the results of the 12 months follow up. In the 262 European patients there was a progressive reduction in LVESVI (-27 versus -7 ml/m2, p<0.0001) and LVEDVi (-28 versus -6 ml/m2, p<0.0001) over 18 months in the CRT ON compared to OFF groups. Mean LVEF increased by 7.6% in CFT ON versus 2.4% in CRT OFF, p<0.0001. The HF clinical composite response endpoint indicated that 15% of the studied patients worsened in the CRT ON arm compared to 29% in the CRT OFF arm (p=0.007). Although there was no difference in mortality between treatment assignments, the time to first HF hospitalisation was significantly reduced in the CRT ON compared to OFF group (CRT ON=3.9% and CRT OFF=11.2%, hazard ratio 0.34, p=0.03). The clinical implications of this study are quite important because they may be used to expand the indications for CRT in the wider population of heart failure patients without overt symptoms (NYHA I and II).
This study was designed to assess lifestyle, risk-factor, and therapeutic management of individuals at high risk of developing cardiovascular disease. Twelve countries participated in this survey. The investigators studied the medical records of 5687 individuals and conducted interviews in more than 75% of these high-risk patients. High-risk patients were defined as men and women <80 years old without a history of coronary or other atherosclerotic disease who had been started on one or more of the following: antihypertensive therapy, lipid-lowering drugs, and/or diabetes therapies. The findings of this study were disappointing, as these patients are not being managed effectively, and more than 80% had never received any advice or direction about the importance of following a heart-healthy lifestyle program. Specifically, 16% of patients were smokers, with nearly 90% of patients continuing to smoke at the time of the interview. Almost 50% of patients were overweight, and almost 80% had blood-pressure, triglyceride, and LDL-cholesterol levels exceeding the recommended European targets. Among diabetic patients, only 27% had normal fasting glucose levels and 53% had HbA1c levels <7.0 mg/dl.
In a subanalysis of this study, which showed that telmisartan was equal to ramipril in 25.260 hypertensive patients >55 years old with coronary heart disease or diabetes plus additional risk factors, the patients were divided into four quartiles based upon blood pressure, regardless of which study arm they had been randomised to. The analysis showed that only the very highest quartile of BP (systolic BP >154 mmHg) had a significantly higher risk of the primary end point: cardiovascular death, stroke, MI, or heart-failure hospitalisation (p<0.001).
This large real-world registry compared three types of DES (the Cypher, the Taxus Express, the Taxus Liberté and the Endeavor) which were implanted since December 31, 2007. During this time period, 35,478 stents were used, of which 8231 (23.2%) were used in diabetics. The Cypher was the most commonly used stent in diabetic patients (2616 pts), followed by the Taxus Liberté (2553), the Taxus Express (2182), and the Endeavor (881). In the 3 years of follow-up, there were no significant differences in restenosis rates between the two Taxus stents and the Cypher in diabetic patients. But when the Endeavor stents were added to the analysis, the relative risk of restenosis for diabetics was twice as high in the Endeavor as it was with the other stents. A similar analysis conducted in nondiabetic patients also pointed to higher rates of restenosis for the Endeavor, but not to the same degree. In an intriguing, albeit unrelated, observation, restenosis rates were also 32% higher for the Taxus Express than for the Taxus Liberté and 24% higher for the Taxus Express vs the Cypher.
In this exploratory study, 234 STEMI patients due to undergo primary PCI for their first MI were randomised to receive either 400 mg of FX06, a new small peptide compound for reperfusion injury, (n=114) or placebo (n=120) intravenously at the start of the PCI procedure and 10 minutes later, which was generally when reperfusion was established. Infarct size as measured by MRI after five days was the primary outcome, and the same measure after four months was a secondary outcome. Other endpoints included biomarkers at four months and major adverse clinical events (MACE). After five days there was no difference in the primary endpoint between the groups (p=0.207). After four months, the resulting scar mass was 37% less in those who received FX06 (not statistically significant difference).
The objective of this study was to evaluate the effect of long-term, intensive cholesterol lowering on clinical and echocardiographic outcomes in subjects with aortic stenosis (AS). The primary study endpoint was major cardiovascular events, a composite consisting of death from cardiovascular causes, aortic valve replacement, congestive heart failure (CHF) resulting from the progression of AS, nonfatal myocardial infarction (MI), hospitalisation for unstable angina, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or non-haemorrhagic stroke. The study population included 1873 subjects with asymptomatic, echocardiographically confirmed mild-to-moderate aortic valve stenosis and no other condition with indication for lipid lowering therapy. After a diet run-in period of 4 weeks, subjects were randomly assigned to receive a combination of 40 mg simvastatin + 10 mg ezetimibe (n=944) or placebo (n=929). Subjects were followed for a minimum of 4 years; the median follow-up period was 52.2 months. There was no difference between the simvastatin/ezetimibe and placebo groups in the primary endpoint (hazard ratio [HR] 0.96; 95% CI, 0.83 to 1.12; p=0.59) or for the secondary outcome measures associated with aortic valve disease events (HR 0.97; 95% CI 0.83 to 1.14; p=0.73). In contrast, significantly, fewer subjects in the combination group experienced ischaemic cardiovascular events versus those in the placebo group (148 [15.7%] vs 187 [20.1%]; HR 0.78, 95% CI 0.63 to 0.97; p=0.02). An unexpected finding of the study was the significant difference in the incidence of cancer between treatment and placebo groups. Cancer was diagnosed in 11.1% of subjects receiving combination treatment versus 7.5% of subjects in the placebo group (p=0.01). However, an independent interim analysis of data from Oxford University based on all ongoing large scale studies with ezetimibe that were published in the New England Journal of Medicine showed that the overall incidence of new cancer is the same with that of the placebo group. The incidence of other serious adverse events was similar in the two groups.
In this study 1715 patients who had had an acute coronary syndrome within the previous 7 days were enrolled. Subjects were randomised to placebo (n=427), or apixaban, an oral factor Xa inhibitor, in a dose ranging from 5 to 20 mg per day. The primary safety outcome was major bleeding or clinically relevant non-major (CRNM) bleeding. The addition of apixaban to standard antiplatelet therapy for 6 months after onset of ACS resulted both in dose-dependent increases in bleeding and in a trend towards a reduction in clinically important ischaemic events. Specifically, bleeding at both apixaban dosages was higher compared with placebo (2.5 mg twice a day: HR 1.78; 95% CI, 0.91 to 3.48; p=0.09, and 10 mg once a day: HR 2.45; 95% CI, 1.31 to 4.61; p=0.005). For the combined secondary efficacy endpoint outcome of cardiovascular death, MI, severe recurrent ischaemia, or ischaemic stroke, there was a trend toward efficacy versus placebo (2.5 mg twice a day: HR 0.73; 95% CI, 0.44 to 1.19; p=0.21 and 10 mg once a day: HR 0.61; 95% CI, 0.35 to 1.04; p=0.07) but the difference did not reach statistical significance.
This study was a multicentre, randomised trial for the comparison of intracoronary infusion of bone marrow-derived unselected mononuclear cells (MNC) and selected CD34+CXCR4+ cells in 200 patients with acute myocardial infarction and reduced LVEF ≤40%. The primary endpoint was change in LV ejection fraction (LVEF) and volumes measured by MRI before and 6 months after the procedure. In patients receiving both selected and unselected bone marrow cells, LVEF increased significantly by 3% in comparison to baseline values. This increase, however, was not significantly higher in comparison to the control group. At 6 months clinical follow up, the major cardiovascular event rate was low, and there was no difference between the groups. In conclusion, treatment with intracoronary infusion of BMC did not lead to significant improvement of LVEF and LV volumes in comparison to the control group; however, there was a trend towards significant improvement of LVEF in patients with severely depressed baseline LVEF.
In this study 263 patients with stable or low-risk unstable coronary artery disease who underwent elective coronary angioplasty were evaluated. The patients were poor responders to aspirin and/or clopidogrel, based on a point-of-care assay. Patients were randomly assigned in a double blind manner to receive either high-dose bolus (HDB) tirofiban or placebo on top of standard aspirin and clopidogrel therapy. The primary endpoint was the occurrence of periprocedural myocardial infarction, as defined by an increase in Troponin I or T greater than 3 times the upper limit of normal within 48 hours. This occurred in 20.4 percent of patients treated with HDB tirofiban, compared to 35.1 percent of patient treated with placebo. This resulted in a significant reduction of major adverse cardiovascular events within 30 days in the HDB tirofiban group compared to the placebo group (21.2 percent versus 36.6 percent, respectively; p=0.0065). The incidence of bleeding was low and did not differ between the two groups.
EUROPA Heart Rate study
This sub-study examined the role of elevated baseline heart rate on outcome in patients with stable coronary artery disease. Of the 12,205 patients enrolled, 3134 had heart rate ≥75 bpm. This elevated baseline heart rate was associated with 21% (p<0.05), 24% (p<0.05), and 51% (p=0.013) increases in relative risk for total mortality, cardiovascular mortality, and hospitalisation for heart failure over 4.2 years of follow up. This subgroup of patients had greater relative risk for the composite end point of hospitalisation for heart failure and/or cardiovascular mortality (23%, p=0.025). These results suggest that resting heart rate is a powerful predictor of mortality and hospitalisation for heart failure in patients with stable coronary artery disease.
This was a multicentre, prospective, randomised, open label trial that randomised 1376 patients with HF and LVEF <35% with a history of AF to rhythm control vs rate control. Over a follow-up period of 37 months, rhythm control did not improve patient outcomes as compared to a rate control strategy. Sinus rhythm could be documented at repeated assessments in 75-80% of patients in the rhythm-control group, while in the rate-control group, heart rate targets were achieved in more than 80% of patients during follow up. However, 58% of the patients of the rhythm control group had at least one recurrence of AF during follow up, demonstrating that antiarrhythmic drug therapy is surely suboptimal.
The trial was conducted at 62 sites in Europe and 23 sites in the United States. Patients had either left main stenosis and/or three-vessel CAD with the intent to revascularise all 3 vascular territories. The investigators relied on a cardiologist and surgeon consensus to determine whether each subject was eligible for both coronary interventions. Limited exclusion criteria included previous interventions, acute MI with creatine phosphokinase (CPK)-myocardial band >2X or concomitant cardiac surgery. The aim of the study was to compare the outcome between percutaneous coronary intervention with TAXUS stenting and coronary artery bypass graft (CABG). One thousand eight hundred (1800) patients were randomised. Approximately 28% had diabetes, 33% prior MI, and 29% recent unstable angina. The average number of lesions was 4.4 with 66% qualifying on the basis of three-vessel disease only, 3% with left main only, and 31% both left main and three-vessel disease. The primary endpoint was the rate of MACCE (Major Cardiovascular or Cerebrovascular Event Rate) as defined by all-cause death, cerebrovascular accident (CVA), documented MI, or any repeated revascularisation (PCI and/or CABG) at 12 months, occurred in more patients undergoing PCI than CABG (17.8% vs 12.1%; p=0.0015). There was a significantly higher rate of revascularisation in the PCI group (13.7% vs 5.9%; p<0.0001) but a significantly higher rate of CVA in the CABG group (2.2% vs 0.6%; p=0.003). The composite rates of all-cause death, CVA, and MI were nearly identical (7.6% for PCI vs 7.7% for CABG; p=0.98). Individual rates of death, MI, and thrombosed vessel (bypass graft vs stented vessel) at 12 months were each similar in both cohorts.
In this study, 1,707 patients undergoing PCI were randomly assigned to receive a biolimus stent (n=857) or a sirolimus stent (n=850). In a factorial design, one in four patients was also randomly selected for angiographic follow-up at 9 months. Biolimus is a highly lipophilic, semi-synthetic sirolimus analogue that is immersed into a biodegradable polymer and applied only to the vessel side of the stent, thereby reducing the amount of drug released into the circulation. The primary endpoint was the composite of cardiac death, MI, or clinically-indicated target vessel revascularisation (TVR) at 9 months. In those selected for angiographic evaluation, the primary endpoint was in-stent percent diameter stenosis as assessed by a blinded core laboratory. Nine months after PCI, a similar proportion of patients with biolimus-eluting stents and sirolimus-eluting stents reached the primary endpoint (9.2% vs 10.5%; RR=0.88; 95% CI 0.64 to 1.19; p=0.003 for non-inferiority). Regarding individual safety and efficacy outcomes at 9 months, patients in the biolimus and sirolimus groups had similar rates of death (2.6% vs 2.8%; p=0.74), cardiac death (1.6% vs 2.5%; p=0.22), MI (5.7% vs 4.6%; p=0.30), or clinically indicated TRV (4.4% vs 5.5%; p=0.29) (p values for superiority). In conclusion, the new generation of drug-eluting stents coated with biolimus demonstrated similar safety and efficacy through 9 months as compared to sirolimus stents.
DECREASE III trial
This was a randomised, double-blind, placebo controlled study conducted to assess the cardioprotective effect of sustained release fluvastatin 80 mg in addition to beta-blocker therapy in vascular surgery patients. The primary outcome measure of the study was the occurrence of myocardial ischaemia through 30 days as assessed by continuous ECG monitoring and serial or troponin T measurement in the first 72 postoperative hours, and 12-lead ECG until the end of follow-up. The secondary efficacy endpoint was the composite of cardiovascular death and nonfatal MI within 30 days after surgery. Safety endpoints were elevations in creatine kinase (CK) and AST/ALT, myopathy, and rhabdomyolysis. Four hundred and ninety-seven (497) patients were enrolled and randomly assigned to receive either extended-release fluvastatin (80 mg daily; n=250) or matching placebo (n=247) beginning 30 days prior to surgery and continuing for at least 30 days post surgery. CK, ALT, and AST were measured 1, 3, 7, and 30 days after surgery. Significantly fewer subjects receiving fluvastatin reached the primary study endpoint of myocardial ischaemia within 30 days of the initial vascular surgical procedure. A total of 27/250 [10.9%] fluvastatin subjects were diagnosed with myocardial ischaemia versus 47/247 [18.9%] placebo patients (OR 0.53; 95% CI 0.32 to 0.88; p=0.016). Fluvastatin therapy was associated with a 52% relative risk reduction in the incidence of the combined secondary endpoint of cardiovascular death or MI (OR 0.48; 95% CI 0.24 to 0.95; p=0.039).These results showed that extended release fluvastatin therapy in addition to beta-blockers is associated with significantly improved perioperative cardiac outcomes in high-risk patients undergoing elective vascular surgery.
In this randomised, double-blind, placebo-controlled, parallel-group trial 10,197 patients with coronary artery disease and a left ventricular ejection fraction of less than 40% were enrolled. 5479 patients received 5 mg ivabradine, a new agent which specifically inhibits the If current in the sinoatrial node to lower heart rate, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. Median follow-up was 19 months. Ivabradine reduced heart rate by 6 bpm (baseline heart rate 71.6 bpm) at 12 months, corrected for placebo. Most (87%) patients were receiving β-blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, p=0.94). 1233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22.8%) controls (p=0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, p=0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, p=0.001) and coronary revascularisation (0.70, p=0.016). In conclusion, reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.
CARDia was a randomised trial specifically comparing coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) in 510 patients with diabetes and multivessel disease. Preliminary results of the CARDia trial at one year show no apparent difference between CABG and PCI in terms of the composite endpoints of death, non fatal MI and non fatal stroke (10.2% vs. 11.6%, p=0.63). Comparison of the individual endpoints of CABG vs. PCI was as follows: death (3.3% vs. 3.2%, p=0.83), non fatal MI (5.7% vs. 8.4%, p= 0.25) and non fatal stroke (2.5% vs. 0.4%, p=0.09). Repeat revascularisation was higher in the PCI group, as expected, with a rate of 9.9% vs. 2.0% for CABG. Comparing CABG and a subgroup of 179 PCI patients who received drug-eluting Cypher stents rather than bare metal stents, the composite endpoint of death, non fatal MI and non fatal stroke was 10.2% vs. 10.1% (p=0.98) again showing no difference in this composite endpoint.
GISSI HF study
The GISSI-HF project is a large-scale, randomised, double-blind study designed to investigate the effects of omega-3 fatty acids and statin therapy on mortality and morbidity in patients with symptomatic heart failure. Patients with chronic heart failure of New York Heart Association class II-IV, irrespective of cause and left ventricular ejection fraction were enrolled and randomly assigned to n-3 PUFA 1 g daily (n=3494) or placebo (n=3481). Patients were followed up for a median of 3.9 years. Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. 955 (27%) patients died from any cause in the n-3 PUFA group and 1014 (29%) in the placebo group (adjusted hazard ratio [HR] 0.91, p=0.041). 1981 (57%) patients in the n-3 PUFA group and 2053 (59%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 0.92, p=0.009). These results showed a small (8% reduction of risk) beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure.
In the rosuvastatin arm of the study, 2285 patients were randomly assigned to rosuvastatin 10 mg daily or placebo (2289) and followed up for 3.9 years with the same end points. 657 (29%) patients died from any cause in the rosuvastatin group and 644 (28%) in the placebo group (adjusted hazard ratio [HR] 1.00, p=0.943). 1305 (57%) patients in the rosuvastatin group and 1283 (56%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 1.01, p=0.903). As a result, rosuvastatin 10 mg daily did not affect clinical outcomes in patients with chronic heart failure of any cause.
In this study, 5296 patients were enrolled and randomly received telmisartan 80 mg/day (n=2954) or placebo (n=2972) in order to assess whether telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage. The median duration of follow-up was 56 months. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study. 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio [HR] 0.92, p=0.216). One of the secondary outcomes—a composite of cardiovascular death, myocardial infarction, or stroke—occurred in 384 (13%) patients on telmisartan compared with 440 (14.8%) on placebo (HR 0.87, p=0.048). 894 (30.3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33%) on placebo (relative risk 0.92, p=0.025). Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke.
TIME CHF study
In this study 499 patients with systolic HF (ejection fraction <45%) were randomised to an NT-BNP-guided or a symptom-guided strategy treatment. The primary endpoint was survival free of all-cause hospitalisations up to 18 months and quality of life. Secondary endpoints were survival and HF hospitalisation-free survival. Compared to standard therapy, intensified treatment did not improve primary endpoint (hazard ratio [HR] 0.92, p=0.46), but did improve the more disease-specific endpoint of survival free of HF hospitalisations (HR=0.66, p=0.008). Intensified therapy reduced total mortality (HR=0.38, p=0.01) and improved survival free of HF hospitalisations (HR=0.41, p=0.002) in younger patients, but not in those ≥75years old. In addition, quality of life improved less by intensified versus standard therapy in older patients despite similar reductions in symptoms and BNP levels. As the investigators concluded, intensified HF therapy did not improve overall outcome compared to standard treatment. However, it improved survival free of HF hospitalisations overall and it reduced mortality in patients <75 years of age, without similar benefits in older patients.
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