News from ACC 2009
April 2, 2009. Summaries by D. Sakellariou
In this randomised trial 352 patients with NSTE-ACS were randomised either to a primary PCI strategy or to catheterisation/PCI on the next day. NSTE-ACS was defined by the presence of at least two of the following: ischemic symptoms, ST-T abnormalities in ≥2 leads, or a positive troponin measurement. Patients were required to have a TIMI score ≥3 to be eligible for inclusion in the study. The mean age of the patients was 66 ± 12 years. PCI was performed with triple antiplatelet therapy in both study groups. A radial access for PCI was used in 84% of patients, and a drug-eluting stent was used in 52%. Coronary artery bypass grafting (CABG) was performed in 11% of the patients. The primary endpoint was myocardial infarction defined by troponin release. The key secondary endpoint was the composite of death, myocardial infarction, (using CK-MB to denote MI), and urgent revascularisation at one month. The median time from randomisation to sheath insertion was 1.2 hours in the immediate group, and 20.5 hours in the delayed group (p<0.0001).
There was no difference for the primary endpoint between the two groups. The median peak value of troponin was 2.0 (interquartile range 0.3–7.16) for the immediate group and 1.7 (interquartile range 0.3–7.2) in the delayed group(p: non-significant). The key secondary endpoint did not differ between the two groups. The total hospital stay was shorter by one day in the immediate group.
AGIR 2 STUDY
This multi-centre randomised trial from France enrolled 320 patients with heart attack symptoms within the previous six hours who were preparing for transport to a cardiac catheterisation laboratory for primary percutaneous coronary intervention (PCI). Patients were randomly assigned to receive a high-dose tirofiban infusion in the ambulance or in the catheterisation laboratory. All patients also received a pre-hospital loading dose of the antiplatelet medications clopidogrel and aspirin and the blood thinner heparin. In the pre-hospital group, tirofiban was administered 48 minutes earlier than in the cath lab group. The proportion of patients who had TIMI-2 or TIMI-3 flow in the target artery was 44.2% in the pre-hospital group and 39.7% in the cath lab group. There was also no significant difference between the two groups in TIMI-3 flow after PCI (91.7% and 92.7%, respectively) or in restoration of blood and oxygen to the heart tissue, as gauged by marked improvement in the electrocardiogram one hour after the start of the coronary intervention (52.6% and 55.4%, respectively). The peak levels of cardiac enzymes released during a heart attack were similar in the two groups, as was the rate of major bleeding. The authors concluded that, in the initial angiographic images of the heart-attack related artery, the likelihood of moderate-to-brisk blood flow was equally good whether high-dose tirofiban was given in the ambulance or in the cath lab.
EARLY ACS STUDY
This trial was a randomised, double-blind, controlled study of early eptifibatide vs. provisional eptifibatide during PCI use with standard background antithrombin therapy. A total of 9492 patients were enrolled, all of whom were scheduled to undergo an invasive strategy 12 to 96 hours after starting the study drug. The primary efficacy endpoint for EARLY ACS was composite all-cause death, myocardial infarction, recurrent ischaemia requiring urgent revascularisation, or thrombotic bailout during the first 96 hours. The secondary endpoint was death or myocardial infarction through 30 days. Safety endpoints included bleeding, transfusions, stroke and serious adverse events. For neither efficacy endpoint was the strategy of early eptifibatide use in all high-risk patients better than the delayed, provisional use of eptifibatide prior to PCI. Furthermore, early eptifibatide initiation was associated with more bleeding.
ARMYDA RECAPTURE TRIAL
The aim of this study was to determine the effectiveness of atorvastatin in the reduction of myocardial infarction in patients chronically treated with statins with both stable angina and acute coronary syndromes. The study randomised 352 patients (mean age 66 ± 10 years) with stable angina (54%) or non ST-elevation acute coronary syndrome (46%) on chronic statin therapy to atorvastatin reload (80 mg 12 hours before PCI, with a further 40 mg pre-procedural dose, (n=177) or to placebo (n=175). All patients received 40 mg/day atorvastatin thereafter. The primary study endpoint was the incidence of major adverse cardiac events (MACE: cardiac death, myocardial infarction or unplanned revascularisation) at 30 days. There was a significant reduction of MACE for a relative risk reduction of 48%. In addition, there was a lower incidence of post-procedural CK-MB and troponin-I elevation in the atorvastatin arm (13% versus 23%, p=0.023, for CK-MB and 36% versus 47%, p=0.032, for troponin-I, respectively).
In the AURORA trial—a large-scale, international, double-blind, placebo-controlled study—patients aged 50-80 years with end-stage renal disease who had been receiving dialysis for at least three months (mean duration 3.5 years) were enrolled in 280 centres in 25 countries. A total of 2,776 patients were randomised to receive rosuvastatin (10 mg daily) or a placebo in order to determine whether initiating a statin during maintenance dialysis influenced cardiovascular-related events or death. The combined primary endpoint was death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. Secondary endpoints included death from all causes and individual cardiac and vascular events. Dialysis patients who were already taking statins were not included in the present trial. The mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg/dL (2.6 mmol/L). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively, p=0.59). Rosuvastatin had no effect on individual components of the primary endpoint. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years, p=0.51). The investigators concluded that, in patients undergoing haemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
This randomised, controlled study examined the effects of the DASH diet, alone or in combination with a weight-reduction programme, on lowering BP and other key CV risks (e.g. left ventricular mass, arterial stiffness, autonomic function, and glucose and cholesterol levels). The study randomised 144 patients with pre-hypertension or stage I hypertension (BP 130-160/80-99 mmHg) to one of three groups: 1) DASH diet alone, in which patients were given nutritional counselling without exercise or caloric restriction; 2) DASH diet plus weight management training including supervised exercise and a behavioural modification program; or 3) usual care. All study participants were overweight or obese (body mass index of 25 to 40 kg/m2), not currently engaged in any exercise and not using anti-hypertensive medicines. Patients who followed the DASH diet in addition to an exercise and weight loss routine had a 14 mmHg drop in systolic BP, compared to a 5 mmHg drop among those on the DASH diet alone and a 1 mmHg fall with usual care. Diastolic BP was reduced by an average of 11 mmHg, 9 mmHg and 6 mmHg, respectively. Patients randomised to the DASH diet plus weight management lost an average of 19 pounds, compared to a loss of 0.6 pounds in those on the DASH diet alone and a gain of roughly two pounds in those only receiving usual care.
GENOUS STEMI TRIAL
In this randomised trial 100 consecutive patients with an ST-elevation myocardial infarction (STEMI) were studied. Equal numbers of patients were randomly assigned to undergo stenting with the Genous EPC (endothelial progenitor cells) capture stent or a chromium-cobalt stent. During follow up, researchers evaluated the patients clinically as well as with angiographic imaging and intravascular ultrasound. They found that at 30 days the combined rate of major adverse cardiac events (MACE)—defined as heart attack, cardiovascular death, and repeat treatment of the target lesion—was comparable in the two groups. However, at 6 months there was a significantly higher MACE rate among patients treated with the Genous stent when compared with those treated with the chromium-cobalt stent (24% vs.10%; p=0.03). Patients treated with the Genous stent also had a statistically higher rate of repeat procedures in the originally targeted lesion (14% vs. 4%; p=0.04).
Intravascular ultrasound showed larger amounts of tissue overgrowth, the most common cause of restenosis, inside the Genous stent, although the difference was not statistically significant. In addition, there were three cases of late stent thrombosis in patients treated with the Genous stent (6%), but none in patients treated with the chromium-cobalt stent.
HEINZ NIXDORF RECALL STUDY (5 year results)
In this study 4,487 randomly selected subjects without known coronary disease (age from 45 to 75 years) participated. Patients were placed into risk categories on the basis of standard cardiovascular risk factors, as defined by the National Cholesterol Education Program (NCEP). Electron-beam CT was used to measure the coronary calcium score. Of the 4,137 study participants with complete follow-up data (5 years), 93 suffered cardiac death or non-fatal heart attack, including 28 women. When coronary calcium scores in the highest one-fourth were compared to those in the lowest one-fourth, the relative risk of a cardiac event was 3.16 (p=0.009) for women and 11.09 for men (p<0.0001). Receiver operating characteristic (ROC) curves were constructed, in which true-positive and false-positive results are calculated and plotted in relation to each other. The area under the curve for the NCEP risk categories was 0.667, while the AUC for coronary calcium scoring was 0.740, and the AUC for a combination of NCEP risk categories and coronary calcium scoring was 0.754. In another analysis that included both NCEP risk categories and coronary calcium score, the odds of a heart attack or cardiac death among study participants in the highest NCEP risk category, as compared to the odds in the lowest risk category, was 3.19 (p<0.0001). Coronary calcium scoring did an even better job differentiating risk, with an odds ratio of 4.26 when the highest one-quarter of coronary calcium scores was compared to the lowest (p<0.0001).
JUPITER TRIAL (venous thromboembolism)
During the ACC meeting the results of the Jupiter trial were presented (which was first announced at the AHA Congress in November 2008) in the arm of protection of venous thromboembolism (VTE). The trial recruited 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of <130 mg/dL and high-sensitivity C-reactive protein (hsCRP) levels ≥2.0 mg/L, randomly assigning them to rosuvastatin, 20 mg/day, or placebo. The median age of study participants was 66 years, and 38% were obese. During follow-up, 34 participants in the rosuvastatin group and 60 in the placebo group developed symptomatic VTE. That means a 43% reduction (hazard ratio, 0.57; p=0.007). Similar reductions in risk were observed in people who had certain triggers for VTE, including cancer or recent hospitalisation, surgery, or trauma (provoked VTE), and in those who did not have any of these triggers (unprovoked VTE). Risk reductions were seen for both deep vein thrombosis and for pulmonary embolism.
NAPLES II STUDY
In this study 668 patients scheduled for elective PCI who were not on statin therapy were randomly assigned to atorvastatin 80 mg (n=338) or no atorvastatin (n=330). The primary endpoint was the incidence of periprocedural MI, as assessed by analysis of creatine kinase myocardial enzyme (CK-MB) and cardiac troponin-I before, 6 and 12 hours after the intervention. Periprocedural MI was defined as a CK-MB elevation greater than three times the upper limit of normal (ULN), alone or associated with chest pain or ST-segment or T-wave abnormalities. The incidence of periprocedural MI was 9.5% in the atorvastatin group and 15.8% in the control group (p=0.014). The incidence of troponin elevation greater than three times ULN was 26.6% in the atorvastatin group and 39.1% in the control group (p<0.001).
THE OMEGA TRIAL
This multi-centre randomised trial from Germany assessed the effect of omega-3 fatty acid supplementation on one-year mortality in patients with heart attack. The study involved 3,827 patients. Three to 14 days after having a heart attack, patients were randomly assigned to one year of treatment with highly purified omega-3 fatty acids or placebo, in addition to the best possible medical care. Almost 94% of patients had coronary angiography at the time of the heart attack, and nearly 78% underwent percutaneous coronary intervention to restore blood flow through the blocked coronary artery. In about 8%, "clot-busting" medications were used as the primary treatment. Upon discharge from the hospital, almost 94% of patients were prescribed beta-blockers, 83% ACE inhibitors, 94% statins, 95% aspirin and 88% clopidogrel, an anti-clotting medication. During a follow up that averaged just over one year, 4.1% of patients died, 3.9% had another non-fatal heart attack, 1.7% had a non-fatal stroke, and 1.5% experienced sudden cardiac death. There were no significant differences in clinical outcomes between patients assigned to omega-3 fatty acids and those assigned to placebo.
This study was designed to evaluate the safety and best dose of intravenous vasodilator relaxin in patients with acute heart failure and normal or elevated blood pressure. In this multi-centre study a total of 234 patients were recruited. All patients had shortness of breath even while resting and showed congestion on a chest X-ray. Patients were randomly assigned to receive a placebo or intravenous relaxin at doses of 10, 30, 100, or 250 mcg/kg/day for two days. The 30-mcg/kg dose of relaxin (relaxin-30) turned out to be the most effective. More patients (41%) reported moderate or marked improvements in dyspnoea at six, 12 and 24 hours when treated with relaxin-30, as compared to 23% of patients assigned to placebo (p=0.04). Relief remained significantly greater in the relaxin-30 group at day 14. Researchers also noted trends toward greater fluid and weight loss, less need for intravenous diuretics, and less deterioration of heart failure in the hospital. When all of the doses of relaxin were compared with placebo, hospital stay was one to two days shorter, on average.
After 60 days, 3% of patients in the relaxin-30 group had been hospitalised for heart failure or died of cardiovascular causes, as compared to 17%in the placebo group (p=0.06), over an 80% reduction. During an average follow-up of 4.5 months, no patients in the relaxin-30 group died of cardiovascular causes, as compared with 14% of those in the placebo group (p=0.046).
The PRIMA study compared the effectiveness of guiding heart failure therapy according to clinical signs and symptoms or through the use of individually selected biomarker targets. A total of 437 patients who had been admitted for heart failure were enrolled in this multi-centre study from the Netherlands. Of these, 345 patients in whom NT-proBNP levels decreased during hospitalisation were randomly assigned to ongoing therapy guided by clinical observations or by NT-proBNP measurements. Another 92 patients in whom NT-proBNP levels failed to decrease during hospitalisation were not included in the randomisation but were monitored during follow up. The individual NT-proBNP target for each patient was set at the lowest NT-proBNP level observed during the first two weeks after treatment for acute heart failure. During follow up, if NT-proBNP levels increased beyond the individualized target, patients received more intense medical therapy. The vast majority of patients who received NT-proBNP-guided care achieved the individually set target.
All patients were followed up for a minimum of 12 months. A preliminary analysis demonstrated a small but non-significant increase in the numbers of days alive outside the hospital among patients in the NT-proBNP-guided group. Similarly, there was a small but non-significant reduction in mortality and rates of hospital admission in the NT-proBNP group.
PROTECT AF TRIAL
For the PROTECT AF study, 707 patients with non-valvular atrial fibrillation were randomly assigned to closure of the left atrial appendage (LAA) with the WATCHMAN device (463 patients), followed by discontinuation of warfarin, or to long-term treatment with warfarin (244 patients). WATCHMAN is a fabric-covered expandable nitinol cage that blocks blood clots that typically form in the LAA. The study found in over 900 patient-years of follow up that the combined rate of stroke (ischaemic and haemorrhagic) and cardiovascular death—the primary measures of effectiveness—was 3.4 per 100 patient-years in the device group vs. 5.0 per 100 patient-years in the warfarin group, a reduction of 32% (relative risk [RR] 0.68).
As for the safety of the device, the researchers observed more procedure-related complications in patients treated with the device (8.7 vs. 4.2 per 100 patient-years; RR 2.08). Most complications were related to device implantation. However, after successful implantation of the WATCHMAN and discontinuation of warfarin therapy, complication rates were significantly lower with device therapy (1.7 vs. 4.2 per 100 patient-years; RR, 0.40). The researchers concluded that the WATCHMAN is an effective alternative to warfarin therapy for preventing stroke in patients with atrial fibrillation.
This study was designed to compare surgical ventricular reconstruction (SVR) in addition to coronary artery bypass graft (CABG) surgery with the CABG procedure alone. The study enrolled 1000 patients with symptomatic heart failure, an anterior wall scar and a left ventricular ejection fraction <0.35. For the quality of life substudy, investigators collected a battery of instruments including the Kansas City Cardiomyopathy Questionnaire (KCCQ), which evaluates the effects of heart failure symptoms on quality of life. Both treatment groups significantly improved their KCCQ scores compared with a preoperative assessment, and these observed improvements in disease-specific health status occurred rapidly and were sustained throughout three years of follow up. However, quality of life scores did not differ between the two treatment groups at baseline or at any follow-up interval. Similarly, depressive symptoms decreased significantly postoperatively in both treatment groups but were not different between each group at any point during follow up. Additionally, 4% of preoperative patients had New York Heart Association Class I symptoms and 15% had Class IV symptoms, while postoperatively 40% of the survivors were Class I and 2% were Class IV, demonstrating an overall marked improvement in heart function for both groups.
This prospective randomised trial enrolled 270 consecutive patients who had undergone CABG a mean of 12 years previously (range 4 to 26 years). All underwent coronary-SVG angiography for symptoms of acute coronary syndrome (myocardial infarction or unstable angina) or stable angina. Of these, 57 patients (21%) were found to have at least one moderate SVG lesion (defined as 30% to 60% diameter stenosis) not responsible for the patient's clinical syndrome. They were randomised to receive stenting with a paclitaxel-eluting stent (n=30) or no stenting (n=27), and all were on optimal medical therapy. All patients had an IVUS evaluation of the SVG. Major adverse cardiac events (MACE), including death, myocardial infarction, and target vessel revascularisation, were evaluated at 1-, 6- and 12-month increments. Angiographic and IVUS evaluations were repeated at 12-month increments. At 12 months, significant disease progression leading to a severe lesion or SVG occlusion occurred in 22% of the medically treated group, despite mean LDL cholesterol levels <80 mg/dL, compared to 0% of patients who received a paclitaxel-eluting stent (p=0.014). The 12-month cumulative incidence of MACE related to the target SVG was 19% in the medically treated group versus 3% in the paclitaxel-eluting stent group (p=0.091).
The Indian Polycap study (TIPS) was designed to investigate the tolerability of the polypill and test whether it leads to meaningful changes in cardiovascular risk factors. The study enrolled 2,053 participants. During the three-month study, researchers compared the impact of the polypill and eight other pharmacological therapies on BP, blood cholesterol levels and heart rate, among other measures. The combination pill, which includes low doses of thiazide (12.5 mg/day), atenolol (50 mg/day), ramipril (5 mg/day), simvastatin (20 mg/day) and aspirin (100 mg/day), significantly reduces LDL cholesterol, BP and platelet aggregability. Participants were randomised to the Polycap (n=400) group or to one of eight other study arms, each with about 200 individuals, which included aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two BP lowering drugs, three BP lowering drugs alone, and an arm with three BP lowering drugs plus aspirin. The mean age of the participants was 54 years, 32% had diabetes, mean baseline BP was 134/85 mmHg, mean cholesterol was 180 mg/dl, HDL 44 mg/dl, and LDL 117 mg/dl. There were several exclusion criteria. The polycap was well tolerated and there was no evidence of problems with increasing number of active components in the pill. Compared to groups not receiving BP lowering agents, the polycap reduced systolic BP by 7.4 mmHg and diastolic BP by 5.6 mmHg; this was similar to when 3 BP lowering drugs were used, with or without aspirin. Polycap reduced LDL by 0.70 mmol/L, which was slightly less than the reduction with simvastatin used alone (0.83 mmol/L; p<0.04); both were greater than groups without simvastatin (p<0.001). The reductions in heart rate with polycap (7.0 beats/min) and other arms using atenolol (7.0 beats/min) were similar; and both were significantly greater than that in arms without atenolol (p<0.001).
This trial investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. After the follow-up period (median 3.6 years), major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; p=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; p<0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; p=NS). Major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; p<0.001). The researchers concluded that the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major haemorrhage.
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