News from ACC 2008
April 8, 2008. Summaries by D. Sakellariou, G. Andrikopoulos.
The 57th annual meeting of the American College of Cardiology (ACC), which was for the first time combined with the annual meeting of the Society for Cardiac Angiography and Interventions (SCAI), was held in Chicago from March 29 to April 1 2008. We present a summary of the more interesting results of late-breaking important trials which were presented at the meeting.
Coronary artery disease and risk factors
The ENHANCE study. In this double-blind, randomised, 24-month trial the effects of daily therapy with 80 mg of simvastatin, either with placebo or with 10 mg of ezetimibe, were compared in 720 patients with familial hypercholesterolaemia. The primary endpoint was the change in the mean carotid-artery intima-media thickness, as an index of the progression of atherosclerosis. At the end of the follow-up period the mean change in the carotid-artery intima-media thickness, was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (p=0.29), although the mean LDL cholesterol level was significantly lower in the combination therapy group (141.3 ± 52.6 mg /dl vs. 192.7 ±60.3 mg/dl, p<0.01) as were the CRP and triglycerides. The investigators conclude that in patients with familial hypercholesterolaemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in the progression of atheromatosis as compared with simvastatin alone. The trial results were published simultaneously in the New England Journal of Medicine.
The ACCOMPLISH study. This study (Avoiding Cardiovascular Events Through COMbination Therapy in Patients LIving with Systolic Hypertension) is a multi-centre randomised trial which determined cardiovascular outcomes using single pill, fixed-dose combination therapy for the treatment of high-risk hypertensive patients. The trial was terminated early. The investigators compared the combination of an ACE inhibitor and calcium channel blocker (ace/ccb) with the combination of an ACE inhibitor and hydrochlorothiazide (ace/hctz). Patients treated with ace/ccb had 20% fewer events (cardiovascular death, heart attacks, strokes, hospitalisations for unstable angina and need for coronary heart procedures). The investigators conclude that "the ACCOMPLISH trial demonstrates the superiority of an ace/ccb pill fixed-dose combination treatment strategy for reducing cardiovascular morbidity and mortality and provides evidence to modify future hypertension guidelines."
The HYVET trial. This randomised double-blind placebo-controlled study (The Hypertension in the Very Elderly Trial) involved 3,845 hypertensive patients aged 80 or older (mean age at baseline of 84 ±3 years). Entry criteria included a systolic blood pressure of 160-199 mmHg. The mean entry blood pressure was 173/91 ± 9/8 mmHg. Active treatment was indapamide (SR) 1.5 mg with the addition of perindopril 2-4 mg, in tablet form once a day as required, to reach a target blood pressure of 150/80 mmHg. The primary end-point was all-strokes. The average follow-up was just over two years, by which time 20% of the placebo subjects and 48% of those taking medication had achieved the target blood pressure of 150/80 mmHg. The trial was stopped early in July 2007 in view of a significant reduction in the primary endpoint and total mortality: a 21% (p=0.02) reduction in the total mortality rate and a 30% reduction in the rate of all-strokes (p=0.06). The fatal strokes were reduced by 39% (p=0.05) and the fatal and non-fatal heart failures by 64% (p<0.001). In addition, there was a reduction of 34% (p<0.001) in cardiovascular events. "These results will have important implications for the generation of future guidelines and mean that very elderly individuals with sustained systolic blood pressures of 160 mmHg or more should now be appropriately assessed and treated in accordance with the new findings," concluded the lead investigator. The HYVET trial results were published simultaneously in the New England Journal of Medicine.
The MEND-CABG II study. This phase three trial of MC-1, a naturally occurring metabolite of vitamin B6, was carried out at 130 centres in the United States, Canada and Germany. The participants were 3,023 high-risk patients undergoing CABG who were randomised to MC-1 250 mg per day, or to placebo, given before bypass surgery and then continued for 30 days post-bypass. The purpose of the study was to determine the efficacy of MC-1 in reducing myocardial injury following cardiac surgery. The investigators determined cardiovascular death or myocardial infarction, using a definition of myocardial infarction of CKMB 100 ng/mL, or approximately 20 times the upper limit of normal, during and immediately after CABG surgery. The incidence of heart attacks during CABG surgery, defined as an elevation of the enzyme CKMB 5, 10, or even 20 times the upper limit of normal, ranges between 10% and 30 percent. The results, from the MEND-CABG II Trial, did not meet their primary endpoint and showed that patients undergoing High-Risk CABG do not benefit from MC-1 over placebo.
The ONTARGET study. This multi-centre double-blind randomised study was designed to measure the effect of doses of ramipril, telmisartan or a combination of the two on patients over the age of 55 years with coronary heart disease or diabetes. The study enrolled 25,620 patients from 40 countries, whose age was over 55 years and who had coronary heart disease or diabetes, plus additional risk factors, but without evidence of heart failure. The patients were randomised to receive ramipril 10 mg a day, telmisartan 80 mg a day, or a combination of the two. The mean duration of follow up of the study was 55 months. Telmisartan lowered blood pressure to a slightly greater extent compared to ramipril (1 mmHg lower systolic), and the combination lowered it still further (2.4 mmHg lower systolic). Telmisartan alone, or ramipril alone, was found to be equally effective in reducing the primary outcome of cardiovascular death, stroke, heart attack or hospitalisation for heart failure, as well as each component of this composite outcome. Telmisartan was better tolerated than ramipril, with the main difference being lower rates of cough and angioneurotic oedema. Despite the further lowering of blood pressure, combination therapy surprisingly did not offer any additional benefit but was associated with a higher rate of hypotension-related side effects, including syncope. There was also higher rate of discontinuation for high potassium levels. The investigators conclude that "telmisartan is an effective and safe alternative to ramipril. The lack of additional benefit with combination therapy, but with some concerns over safety, emphasises that combination therapy with an ACE inhibitor and an angiotensin receptor blocker at full doses is not only of little additional benefit, but can be associated with significant adverse effects." The ONTARGET study was published simultaneously in the New England Journal of Medicine.
The HFHC study. The Heart Failure Home Care trial was a multi-centre, randomised and controlled trial designed to assess the impact of a home-based heart failure monitoring system on healthcare costs for heart failure patients. It compared sophisticated monitoring of heart failure patients with an interactive program (HFMS) versus standard heart failure monitoring with enhanced education in Medicare-eligible patients. The study endpoints included cardiovascular death or re-hospitalisation for heart failure, length of hospital stay, total patient cost and cost to Medicare at six months of enrolment. A total of 315 patients were randomised: 160 to the HFMS and 155 to standard heart failure care (SC). There was no significant statistical difference between the groups with regard to six-month cardiac mortality, re-hospitalisations for heart failure, or length of hospital stay. Of the patients enrolled, 292 had their Medicare data available; the information from the claims data was used to determine the cost to Medicare as well as the societal costs for those services covered by Medicare. The six month mean total societal costs were estimated to be $20,190 and $15,966 for the HFMS and the SC groups, respectively, while the six-month mean Medicare costs were estimated to be $17,837 and $13,886, respectively. The lead investigator concluded that, "The results of our study demonstrate that enhanced patient education and follow-up is as successful as a home monitoring device with an interactive program and is less costly for patients who are elderly, either women or non-Caucasian males and receive the care from a community-based primary care practitioner."
The HORIZON-HF study. In this study the action of istaroxime, a novel agent with both inotropic and lusitropic properties, was examined in patients with acute heart failure symptoms. One hundred and twenty patients participated in the study. Patients admitted to hospital with acute heart failure symptoms and after being given initial therapy to stabilise their condition were randomised to a six-hour infusion of placebo (n=31) or to 3 different doses of istaroxime as follows: 0.5 μg/kg/min (n=29); 1.0 μg/kg/min (n=30); or 1.5 μg/kg/min (n=30). All doses of istaroxime lowered pulmonary capillary wedge pressure, and the highest dose decreased left ventricular end-diastolic volume (the heart size at the end of a pumping cycle), increased E-wave deceleration time (a measurement of the heart's relaxation ability), and increased cardiac index (the heart's pumping ability) compared with placebo. These changes were associated with increases in systolic blood pressure and decreases in heart rate. As the lead author expained, "It appears that this agent will increase both the pumping effect and the vacuum effect of the heart. Importantly, in contrast to other agents, it will actually increase the blood pressure when it is needed. It potentially fills a gap that currently exists in the management of acute heart failure, since all other available agents will not increase but have a tendency to decrease blood pressure."
The MOMENTUM trial. The Enhanced Treatment of HF Unresponsive to Medical Therapy trial was a multi-centre study sponsored by the Orqis® Medical Cancion® System. The aim of the study was to compare haemodynamic and clinical effects of continuous aortic flow augmentation (CAFA) plus medical therapy, versus medical therapy alone. In total, 168 extremely ill patients hospitalised with worsening heart failure, who were unresponsive to conventional medical treatment, were enrolled in the study. One hundred and nine patients were randomised to the CAFA device and 59 to the medication-only arm. All patients had impaired renal function or a substantial diuretic requirement in spite of intravenous inotrope or vasodilator treatment. The investigators report that CAFA was able to be achieved for up to 96 hours using a percutaneous arterial-to-arterial circuit with an extracorporeal, magnetic, centrifugal pump. Technical success, as defined as at least 24 hours of pump flow, was achieved in 93% of CAFA-treated patients.
The PROTECT trial. In this study the role of rolofylline, a new adenosine A1-receptor blocker, in the improvement of dyspnoea and renal dysfunction will be investigated in patients with acute heart failure. It is an ongoing trial that should be completed in early 2009. In the pilot study, which was presented in ACC 08, 305 patients who were hospitalised for acute decompensated heart failure and associated renal dysfunction were randomised to placebo, or to 10, 20 or 30 mg of intravenous rolofylline. They were assigned to one of three outcome categories: "Success," as evidenced by improved dyspnoea; "Failure," as evidenced by worsening heart failure, worsening renal function, heart failure readmission or death; or "Unchanged," as determined by neither success or failure. The study also looked at the change in renal function over 14 days after treatment, 60-day mortality, and hospital readmission for worsening heart failure. Rolofylline in a dosage of 30 mg was associated with a 44% increase in "Success" and a 40% decrease in treatment "Failure". It was also associated with a trend towards reduction in the composite endpoint of 60-day mortality or readmission for cardiovascular or renal cause.
Arrhythmias and sudden cardiac death
The CARISMA study. The aim of this multi-centre observational prospective study was to assess the incidence and prognostic significance of arrhythmias using an insertable loop recorder (ILR) that has the capability of monitoring the heartbeat continuously for two years and determined that patients who survive a heart attack experience many episodes of what are mostly asymptomatic brady- and tachyarrhythmias. The study screened 1393 patients with an ejection fraction (EF) <40% soon after an acute myocardial infarction (three to 21 days post-event). Of these patients, 312 (22%) consented to participate and 297 patients had an ILR implanted within 21 days of acute myocardial infarction. As a result of the study, 24 patients (8%) received treatment with a pacemaker or implantable defibrillator. A substantial number of serious and potentially treatable cardiac arrhythmias were recorded by the ILR during the first two years of follow up. Significant arrhythmias were documented in 137 patients, asymptomatic in 86%. The study analysis found a substantial number of these arrhythmias: one third of the patients experienced new onset atrial fibrillation; one fifth of the patients developed severe bradyarrhythmias; and one tenth of the patients exhibited ventricular tachyarrhythmias. Some of the arrhythmias were significant predictors of cardiac death: in particular, slow heart rhythm, high degree atrioventricular (AV) block and non-sustained ventricular tachycardia (VT), which could be addressed with either pacemaker or defibrillator (ICD) therapy. High-degree AV block was the most powerful predictor of cardiac death. "The loop recorder turned out to be a strong diagnostic tool to record abnormal heart rhythms, and should be considered in future studies as a clinical tool to better manage patients," concluded the lead investigator.
The HAT study. The Home Automated External Defibrillator Trial was conducted at 178 centres in 7 countries. Seven thousand stable patients with a history of anterior-wall MI who were not candidates for an implantable cardioverter-defibrillator were assigned to control response (calling emergency services and performing CPR) or automated external defibrillator (AED) with control response. The primary endpoint was death from any cause. Secondary outcomes were sudden death, death from tachyarrhythmias, and use of the AED. Patients reported that median time alone at home was 1.5 hours per day, and median time away from home was 4.0 hours per day. Of the whole cohort, 3506 were assigned to the control and 3495 to the home AED group. Median duration of follow-up was 37.3 months. Four hundred and fifty patients died, 6.5% in the control and 6.4% in the home AED group (hazard ratio 0.97; p=0.77, not significant). The mean annual mortality rate was 2.1% in the control and 2.0% in the home AED group. 37.6% of deaths were caused by tachyarrhythmias and 21.3% by heart failure or nonarrhythmic cardiac causes. In addition, 37.8% of deaths were caused by non-cardiac causes. Overall, 4 (28.6%) of 14 patients with ventricular fibrillation who received an AED shock were long-term survivors. The authors suggested that the reasons for not observing an effect of AED on cardiac deaths may be related to the overall low event rate, the training of rescuers, the high proportion of unwitnessed events, and underuse of AEDs in emergencies, rather than lack of device efficacy.
The REVERSE study (REsynchronisation reVErses Remodeling in Systolic left vEntricular dysfunction) is a year-long, multi-centre, randomised, double-blind controlled trial to assess whether CRT plus optimal medical therapy (CRT ON) can manage the progression of heart failure compared to optimal medical therapy alone (CRT OFF). A total of 610 pts were randomised in 73 centres in the US, Canada and Europe. Eligible patients had NYHA Class II heart failure or I with previous symptoms, QRS-duration ≥ 120 ms and LV ejection fraction ≤ 40 percent. Patients had to be on optimal drug therapy. The primary endpoint of the study was the HF clinical composite response (all-cause mortality, HF hospitalisations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in a double-blind manner). The secondary endpoint, left ventricle end-systolic volume index (LVESVi), was also evaluated after 12 months. In the CRT ON group (419 patients) 54% of patients improved the primary endpoint at the end of the 12 month follow up period, compared to 40% improvement with CRT OFF. In addition, a significant reduction of LVESVi was observed (p: 0.001) in the CRT ON group. Not surprisingly, the study found that quality of life and six-minute hall walk distance did not improve significantly in this patient population, suggesting that while specific factors may have improved, the overall patient experience may not have changed dramatically. This indicates that CRT in mildly symptomatic heart failure patients not only reverses LV modelling, but also influences morbidity. Since heart failure-related hospitalisations are an indicator of mortality, it is possible that CRT over a longer period of observation might lower mortality in patients with mild heart failure, and in spite of optimal medical therapy, these patients should be considered for CRT to modify or reverse disease progression as the investigators explained.
The TRENDS Study is a prospective, observational study evaluating the relationship between device-detected AF and risk of thromboembolic events (TEs). According to the investigators, the newer implantable medical devices are extremely sensitive and can comprehensively detect events in the heart that have never been seen before. The goal is to determine how to take this information and use it to give patients the best care. A total of 2813 patients were enrolled in the study and 2486 had device data available for analysis. Inclusion criteria were implantation of a cardiac rhythm device capable of monitoring atrial tachycardia (AT)/AF burden and ≥1 stroke risk factor (heart failure, hypertension, age ≥65y, diabetes, or prior stroke). AT/AF burden was defined as the longest total duration of AT/AF in hours on any given day during a 30-day rolling window before the first TE or end of follow-up. Time-varying burden for each window was divided into 3 groups: zero burden, and burden below (low burden: <5.5 h on each day/window), or above (high burden: ≥5.5 h on at least 1 day/window) the median value for all non-zero windows. During an average follow-up of 1.4 years device data were retrieved every three months. In total, 12% of windows had high burden, 12% had low burden, and 76% had zero burden. Forty TEs were included in the analysis. The TE rate for the zero AT/AF burden group was 1.1% per year compared to 1.7% per year for any AT/AF burden; subdivided as high burden (2.4% per year) and low burden (1.1% per year). Compared to zero burden, the hazard ratios in the low and high burden groups were 0.98 (p=0.97) and 2.20 (p=0.06), respectively. The results suggest that device-detected AT/AF burden greater than 5.5 hours on any day during the preceding 30 days may double the risk for thromboembolism independent of known risk factors and antithrombotic therapy.
The PERISCOPE trial. In this prospective, randomised, multi-centre, double-blind trial, 543 patients with type 2 diabetes underwent coronary IVUS and then were randomised to receive either glimepiride (1-4 mg) or pioglitazone (15-45 mg) for 18 months, after which time IVUS studies were repeated. The primary endpoint was percentage atheroma volume (PAV) based on IVUS in the longest and least angulated epicardial coronary artery. According to the study investigators, mean% atheroma volume decreased by 0.16% in pioglitazone-treated subjects but increased by 0.73% in glimepiride-treated patients (p: 0.002). Haemoglobin A1c was slightly lower in the pioglitazone than in the glimepiride group (6.9% vs. 7.0%). Mean HDL cholesterol increased by 5.7 mg/dL in the pioglitazone and 0.9 mg/dL in the glimepiride group (p<0.001). Triglyceride levels decreased by 16.3 mg/dL in the pioglitazone and increased by 3.3 mg/dL in the glimepiride group. Median fasting insulin levels decreased by 5.0 μU/mL in the pioglitazone and increased by 1.33 μU/mL in the glimepiride group (p<0.001). Systolic blood pressure increased in both groups, but the median increase was smaller for the pioglitazone group (0.1 vs. 2.3 mmHg, p=0.03). Pioglitazone was associated with a significant increase in weight of 3.6 vs. 1.6 kg in the glimepiride group (p<0.001). Major adverse cardiovascular events were similar in both groups. Thus, the use of pioglitazone vs. glimepiride is associated with a lower rate of progression of coronary atherosclerosis as measured by IVUS in patients with type 2 diabetes and coronary artery disease and a better lipid profile. The study was published simultaneously in the Journal of the American Medical Association (JAMA).
The VICTORY trial. In this multi-centre randomised double-blind placebo-controlled study, conducted at eight centres in Canada and Spain with 193 participants, researchers investigated the benefit and safety of rosiglitazone in preventing atherosclerosis progression in patients with type 2 diabetes one to 10 years after CABG surgery. The primary end point was the change in plaque volume (12 month vs. baseline) in a ≥40 mm segment in one vein graft as measured by intravascular ultrasound (IVUS). There was no significant change in plaque volume after 12 months. A significant reduction of CRP and PAI1 (p:0.007 and p:0.01, respectively) and an improvement in HDL level (p<0.0001) were observed in the patients treated with rosiglitazone. The investigators conclude that rosiglitazone in post CABG patients demonstrates a neutral effect on atherosclerosis at 12 months, a significant improvement in glucose-insulin homeostasis, and a significant benefit in terms of lipid, pro-thrombotic and inflammatory parameters.
The STRADIVARIUS trial. In this study 839 patients at 112 centres in North America, Europe and Australia were randomised to receive either rimonabant at a dose of 20 mg or placebo. The progression of disease was measured by intravascular ultrasound, which was performed at baseline and after 18 months. The primary endpoint was the change in% atheroma volume and the secondary end point was the total atheroma volume. After 18 months the primary endpoint did not show a statistically significant difference (p: 0.22) although the total atheroma volume was significantly decreased (p: 0.03). Moreover, patients treated with rimonabant lost about 4.3 Kg and 4.5 cm in waist circumference. HDL cholesterol rose by 22.4%, triglycerides decreased by 20.5%, and CRP levels decreased by 50.3%. There was a statistically significant increase in psychiatric and gastrointestinal adverse effects, particularly anxiety, depression and nausea, in patients randomised to rimonabant. "Although the current study did not achieve a statistically significant effect for the primary efficacy measure, the favourable results for the secondary endpoint suggest that this approach to the treatment of abdominal obesity holds promise for patients with abdominal obesity and heart disease," said the lead investigator. The study was published simultaneously in the Journal of the American Medical Association (JAMA).
The BRAVE III trial. The BRAVE-3 study is the first to test the influence of high-dose clopidogrel on the value of abciximab exclusively in patients with ST-elevation myocardial infarction (STEMI). Eight hundred patients with STEMI who were undergoing PCI were recruited in the study. All patients were pre-treated with 600 mg of clopidogrel and then randomly assigned to receive intravenous abciximab or a placebo during the procedure. The study was designed primarily to compare how the two treatment strategies affected the final amount of heart attack damage, as gauged by blood flow in the heart muscle on a nuclear scan 5 to 10 days later. The researchers found no difference between the two groups: the damage involved 10% of the left ventricle, on average, in the abciximab group and 9% of the left ventricle in the placebo group. In addition, the 30-day combined rates of death, heart attack, stroke and urgent repeat coronary procedures were similar in the two groups (5% and 3.8 percent, respectively). "For patients with acute ST-elevation myocardial infarction undergoing primary coronary intervention after pre-treatment with a 600 mg loading dose of clopidogrel, the additional use of abciximab is not associated with any measurable benefit after 30 days," concluded the principal investigator of the study.
The CREATE study. In this study the efficacy and the clinical outcome of a novel drug-eluting stent coated with a biodegradable polymer, the sirolimus-eluting Excel stent, was examined. A total of 2,077 patients from 59 medical centres in four countries were recruited. All had stenting with the Excel stent. Of these, 369 (17.8%) underwent primary stenting within 24 hours of having a heart attack. After stenting, all patients were prescribed both clopidogrel and aspirin for six months to inhibit the action of platelets in the blood. On average, patients continued to take clopidogrel for 199 days. After 12 months, the overall rate of major cardiovascular complications was 2.77%, including cardiac death in 23 patients (1.12%), heart attack in 8 patients (0.39%), and repeat coronary procedure in 32 patients (1.55%). Death from any cause occurred in 34 patients (1.64%), including 11 non-cardiac deaths. Overall, thrombotic complications occurred in 16 patients (0.78%), including six definite cases, five probable cases and five possible cases. Of these, three thrombotic complications (0.15%) occurred after discontinuation of clopidogrel. The researchers concluded that the Excel stent is associated with a low incidence of cardiovascular complications, and that six months of dual-antiplatelet therapy appears to be feasible and safe.
The GENESIS trial. This trial was terminated early because of the high rate of revascularisation proceedings needed in patients treated with a pimecrolimus stent. Two hundred and forty eight patients were enrolled in the study. Patients were randomly assigned to stenting with the Corio stent, which delivers pimecrolimus, the SymBio stent, which delivers both pimecrolimus and paclitaxel, or the paclitaxel-coated CoStar stent. After nearly six months of follow up, shrinkage of the arterial opening inside the stent (in-stent late loss) was greatest with the pimecrolimus-eluting Corio stent (1.40 mm), mid-range with the dual-drug SymBio stent (0.96 mm), and least with the paclitaxel-eluting CoStar stent (0.58 mm), but none of the differences between stents was statistically significant. Other angiographic findings followed the same pattern, including minimal lumen diameter,% diameter stenosis and restenosis rate, as did the findings of intravascular ultrasound at six months. At six months, 39% of patients treated with the Corio stent experienced a major adverse cardiac event (MACE), including a 35% rate of repeat procedure in the target artery. With the SymBio stent, those rates were both 14.4%, and with the CoStar stent, they were both 2.0%. The difference in MACE rates between the CoStar stent and both of the pimecrolimus stents was highly statistically significant (p<0.0001). The rate of stent thrombosis at six months was 2.0% with the Corio stent, 1.0% with the SymBio stent and 0% with the CoStar stent.
MAIN COMPARE study. The Revascularisation for Unprotected Left MAIN Coronary Artery Stenosis: COMparison of Percutaneous Coronary Angioplasty Versus Surgical REvascularization (MAIN-COMPARE) study was held in Korea, where left main artery stenting is far more common than in the USA and Europe. The study analysed data from 2,240 patients with unprotected left main coronary artery disease treated at 12 medical centres in Korea. Of these, 318 were treated with bare metal stents, 784 were treated with drug-eluting stents, and 1,138 underwent bypass surgery. During three years of follow up, patients treated with bare metal stents were nearly 11 times as likely to need a repeat procedure to reopen the target vessel when compared to those who underwent bypass surgery. However, the rates of death (hazard ratio: 1.04) and the combined rates of death, heart attack and stroke (hazard ratio: 0.86) were similar in the two groups. Patients treated with drug-eluting stents were nearly six times as likely to need a repeat procedure during three years of follow-up, but the rates of death (hazard ratio 1.36) and the combined rates of death, heart attack and stroke (hazard ratio: 1.40) were statistically similar, although there was a trend toward higher event rates with drug-eluting stents.
The ON TIME 2 trial. The Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 trial, was a multi-centre, randomised, double-blind study which attempted to evaluate the benefits of pre-hospital initiation of high-dose tirofiban in patients with ST elevation myocardial infarction (STEMI). For this reason, 984 patients with STEMI who were also scheduled for primary PCI were enrolled. The patients were randomized 1:1 to receive treatment in the ambulance with 25 μg/kg bolus and 0.15 μg/kg/min maintenance infusion of tirofiban or with placebo, and all patients also received a 600 mg loading dose of clopidogrel. Patients who received tirofiban had significantly better ST resolution (i.e. their electrocardiogram returned to normal) one hour after they underwent primary PCI compared with the group who did not receive tirofiban. The tirofiban-treated group also had fewer deaths and recurrent heart attack, and less need for urgent target vessel revascularisation or thrombotic bailout at 30 days post-PCI. "Treatment for acute myocardial infarction [or heart attack] should start in the ambulance, i.e. as early as possible," said the lead author of the study.
The TRANSFER-AMI study. The Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI) tried to answer to the question whether PCI is safe and effective after giving clot-busters for heart attack. One thousand and sixty (1060) patients with STEMI were enrolled. All patients initially sought treatment at a hospital without PCI capability and were treated with tenecteplase, a clot-busting drug. Patients were then randomly assigned to urgent transfer for PCI within six hours, or to standard therapy, consisting of observation for 60 to 90 minutes, with transfer for PCI only in the case of continuing chest pain or other evidence of treatment failure. The study will evaluate 30-day combined rates of death, repeat heart attack, recurring ischaemia, heart failure and shock in the two groups of patients. This primary end point occurred in almost 16.6% of the standard-therapy-treated patients and in 10.6% of the urgent PCI group (p: 0.0013). However, there was no difference between the two groups in the bleeding events. Thus, the strategy of transferring ST-segment elevation myocardial infarction (STEMI) patients for percutaneous coronary intervention (PCI) within six hours of receiving thrombolysis at a non-PCI centre is superior to the more standard wait-and-see strategy.
The TRITON TIMI 38 study. For the main TRITON-TIMI 38 study, researchers recruited 13,608 patients with ACS who needed stenting from 707 medical centres in 30 countries. Patients were randomly assigned to antiplatelet therapy consisting of either a 300-mg loading dose of clopidogrel before the procedure, followed by a maintenance dose of 75 mg daily for one year, or to a loading dose of 60 mg of prasugrel, followed by 10 mg daily for one year. Of the 12,844 patients who ultimately were treated with at least one coronary stent, 6,461 patients received only bare-metal stents (BMS), and 5,743 patients received only drug-eluting stents (DES). Overall, prasugrel reduced both early stent thrombosis—within 30 days of stenting—when compared with clopidogrel (0.64% vs. 1.56%, hazard ratio 0.41, p<0.001), and late stent thrombosis—more than 30 days after stenting—(0.49% vs. 0.82%, hazard ratio 0.60, p=0.035). For BMS, the respective rates of stent thrombosis with prasugrel and clopidogrel were 1.3% vs. 2.4%, hazard ratio 0.52, p=0.009, and for DES, 0.8% vs. 2.3 percent, hazard ratio 0.36, p<0.001. Prasugrel's advantage remained highly statistically significant across a broad array of patient and procedural characteristics.
The TAPAS study. The Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS) study examined the safety and efficacy of thrombus aspiration during PCI after a STEMI. 1,071 patients with STEMI were randomly assigned, 535 to PCI supported by the Export aspiration catheter and 536 to PCI using conventional techniques. To assess the quality of myocardial perfusion, the researchers documented myocardial blush grade. A myocardial blush grade of 0 or 1 indicates that little or no X-ray dye has reached from the surface artery into the heart muscle, a sign that the microcirculation is blocked. A myocardial blush grade of 3 indicates that X-ray dye has reached deep into the heart muscle, a sign of good blood flow through the microcirculation. A myocardial blush grade of 2 falls in between. Analysis of the elevated ST-segment on the electrocardiogram—specifically, its return to a normal baseline—was also used to gauge the quality of blood flow to the heart muscle. During angiography, researchers observed a blush grade of 0 or 1 in 17% of patients treated with the aid of the aspiration catheter and in 26% of patients treated with conventional PCI (p<0.001). At 30 days, clinical outcomes were strongly related to the degree of myocardial reperfusion. The rate of death in patients with a myocardial blush grade of 0/1, 2 and 3 was 5.2%, 2.9% and 1.0%, respectively (p=0.003). The combined rates of repeat heart attack, repeat procedure in the target artery and death in patients with a myocardial blush grade of 0/1, 2 and 3 were 14.1%, 8.8% and 4.2%, respectively (p<0.001). At one-year follow up, mortality was significantly lower in patients treated with the aspiration catheter (p=0.04), as was a combination of death and heart attack. A similar, highly significant relationship was observed between myocardial blush grade and death, or a combination of death and repeat heart attack (p=0.001).
The SPIRIT II study. This study compared two kinds of drug-eluting stents (TAXUS and XIENCE V). Three hundred patients who needed stenting of up to two new coronary lesions were recruited. Patients were randomly assigned to treatment with the XIENCE V (everolimus-eluting stent) or the TAXUS (paclitaxel-eluting stent). The study primarily set out to document any differences in the amount of arterial tissue that grew into the stents at six months (in-stent late loss). As previously reported, the results were significantly better for the XIENCE V stent when compared to the Taxus stent. At one-year follow-up, the combined rates of major adverse cardiac events (MACE), consisting of cardiac death, heart attack and repeat procedure to treat the target lesion, were also significantly better in the XIENCE V group. Now, new data from a late-stage evaluation report that, although the XIENCE V stent continues to show a trend toward improved clinical outcomes compared to the Taxus stent at two years, the differences between the two stents were no longer statistically significant. The overall MACE rate at two years was 40% lower in patients treated with the XIENCE V stent (6.6% vs. 11.0% in the Taxus group). Repeat procedures to treat the target lesion were performed in 3.8% and 6.8% of patients, respectively, a 44% reduction favoring the XIENCE V stent. Similarly, the rates of heart attack were 2.8% and 5.5 percent, respectively, a 49% reduction, and the rates of cardiac death were 0.5% and 1.4 percent, respectively, a 64% reduction. There was no difference in the rates of blood clotting inside the stent, or stent thrombosis, at two years. In the 117 patients who had follow-up angiography at two years, there was no significant difference in the rates of re-narrowing of at least 50% (binary restenosis) within the stents (2.1% with the XIENCE V stent vs. 2.9% with the Taxus stent). In-stent late loss was virtually identical (0.33 mm vs. 0.34 mm, on average, respectively).
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