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News from AHA 2008

November 8-12, 2008. Summaries by Socrates Pastromas and George Andrikopoulos.

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Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin

This trial seems to be a landmark in primary prevention, as it showed that rosuvastatin, nowadays a widely used lipid lowering drug, significantly reduced cardiovascular morbidity and mortality in patients considered to be at low cardiovascular risk, based on the Framingham risk score, and who had no clear indication to receive statin treatment according to currently published guidelines. More specifically, JUPITER enrolled 17,802 apparently healthy men (≥50 years) and women (≥60 years) from 1315 centres in 26 different countries, without cardiovascular disease or diabetes, but with LDL cholesterol < 130 mg/dl and hsCRP ≥2.0 mg. These individuals were randomised to rosuvastatin 20 mg or placebo. The primary endpoint included major cardiovascular events (a composite of non-fatal myocardial infarction, non-fatal stroke, unstable angina, revascularisation or cardiovascular death). The secondary endpoints included the primary endpoints plus death from any cause. After a median follow up of 1.9 years a significant difference in major events between two groups was reported (142 major cardiovascular events in the rosuvastatin group and 251 in the placebo group, HR for rosuvastatin 0.56, p<0.00001) and subsequently the trial was stopped prematurely by the safety monitoring board. Throughout the study population, rosuvastatin treatment reduced LDL cholesterol by 50% and hsCRP by 37%. Cardiovascular events including MI (HR 0.46), stroke (HR 0.52), revascularisation/unstable angina (HR 0.53), non-fatal MI, non-fatal stroke, or CV death (HR 0.53), and death from any cause (HR 0.80) were significantly reduced. It must be noted that the beneficial effects of rosuvastatin treatment were consistent in all subgroups, regardless of clinical condition, sex, racial or ethnic characteristics. The total numbers of reported serious adverse events were similar in the rosuvastatin and placebo groups (1352 and 1377, respectively; p=0.60). However, there was a higher incidence of physician-reported diabetes in the rosuvastatin group (3.0% vs. 2.4%, p=0.01), as well as higher median glycated haemoglobin at 2 years with rosuvastatin (5.9% vs. 5.8%, p=0.001); the median fasting glucose at 2 years was similar in the two groups (98 vs. 98 mg/dl, p=0.12). In conclusion, JUPITER illustrated beneficial effects after rosuvastatin treatment in healthy subjects with apparent low cardiovascular risk who were not candidates for statin treatment. Indeed, the exact influence of this important trial on formulation of the future guidelines and recommendations is not yet clear, and more data and study analyses are surely awaited. However, there is little doubt that the JUPITER trial did reveal that there is a hidden risk in some of our patients that are considered to be at relatively low risk, and this residual risk can be, at least partly, confronted by statin treatment.

JPAD Trial

Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes

The JPAD Trial evaluated the efficacy of daily low-dose aspirin in the primary prevention of cardiovascular events in patients with type 2 diabetes. The trial enrolled 2539 Japanese patients aged 30-85 years with type 2 diabetes and without atherosclerotic or cardiac disease. They were randomised to low-dose aspirin (81 or 100 mg/day) or no aspirin and followed up for a median of 4.37 years. Primary endpoints were atherosclerotic events, including fatal or non-fatal ischaemic heart disease, fatal or non-fatal stroke, and peripheral arterial disease. Secondary endpoints included each primary endpoint and combinations of primary endpoints as well as death from any cause. During the follow-up period there was a significant reduction of fatal coronary and cerebrovascular events (0.08% vs. 0.8%, p=0.0037), but there were no significant differences in the incidence of non-fatal myocardial infarction (1.0% vs. 0.7%, p=0.5), unstable angina 0.3% vs. 0.8%, p=0.13), stable angina (1.0% vs. 0.9%, p=0.82), non-fatal ischaemic strokes (1.7% vs. 1.9%, p=0.80), non-fatal haemorrhagic strokes (0.4% vs. 0.2%, p=0.48), transient ischaemic attack (TIA) (0.4% vs. 0.6%, p=0.42), or all-cause mortality (2.7% vs. 3.0%, p=0.67). It must be noted that in a subgroup analysis low-dose aspirin was associated with a significant reduction in atherosclerotic events in subjects aged ≥65 years old versus younger patients (6.3% vs. 9.2%, p=0.047). Twelve episodes of gastrointestinal bleeding were reported in the aspirin arm, compared with 4 in the other arm of the study cohort. Moreover, other bleeding such as haematuria and nosebleed were more commonly associated with aspirin therapy. All the above indicate that aspirin 81 or 100 mg daily has no favourable effect in the total reduction of atherosclerotic events in patients with type-2 diabetes. The results of this prospective trial do not encourage low-dose aspirin treatment for primary prevention of cardiovascular events in the overall population of patients with type 2 diabetes, with the exception of those aged 65 years and over.


Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

The SEARCH Trial is a late-breaking trial that involved 12,064 subjects with a recent episode of myocardial infarction, aged 40 to 80 years, with a mean follow up of 6.7 years. The aim of the study was to evaluate the safety and efficacy of aggressive statin therapy with 80 mg of simvastatin compared with 20 mg of simvastatin, as well as homocysteine reduction with folic acid plus vitamin B12, compared with placebo. These patients were randomised to folic acid and vitamin B12 (6033), to placebo vitamins (6031), to simvastatin 80 mg (6031), and to simvastatin 20 mg (6033). All groups had similar baseline characteristics. About 33% had a history of prior revascularisation, 7% had a history of cerebrovascular disease, 11% had diabetes, and 42% had hypertension. The mean low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels were 97, 39, and 168 mg/dl, respectively. The mean baseline homocysteine level was 13.5 µmol/L. The results of the LDL lowering group showed that an additional 0.35 mmol/L (14 mg/dL or 14%) drop in LDL could be achieved by giving higher versus lower dose statin. Despite homocysteine levels being reduced by an average of 3.8 µmol/L over a mean of 6.7 years of follow up in the vitamin supplementation versus placebo group, about 25.5% of patients had a major vascular event. A similar number of patients (24.7%) in the placebo group experienced this primary outcome measure, thus resulting in an overall risk ratio (RR) of 1.04. Moreover, there was no difference between the high-dose and low-dose simvastatin groups in the incidence of major vascular events (24.5% vs. 25.7%, p>0.05). Similarly, there was no difference in the incidence of all-cause mortality (16.0% vs. 16.1%, p>0.05), cardiac mortality (7.4% vs. 7.3%, p>0.05), or strokes (4.2% vs. 4.6%, p>0.05). There was a significant higher incidence of myopathy in patients receiving 80 mg simvastatin compared with the 10 mg daily dosage group. In the group of patients receiving folic acid plus B12 a 28% reduction in homocysteine levels was noticed, but there was no difference between this group and the placebo group in the incidence of major vascular events. Additionally, there was no significant difference in the incidence of non-fatal myocardial infarction (7.1% vs. 7.1%, p>0.05), coronary revascularisation (9.8% vs. 9.8%, p>0.05), cardiac death (7.7% vs. 7.0%, p>0.05), all-cause mortality (16.3% vs. 15.8%, p>0.05), or stroke (4.5% vs. 4.4%, p>0.05). The results of this study suggest that there is no significant beneficial effect in patients with coronary artery disease after a reduction in homocysteine levels with folic acid and B12 treatment. Moreover, the SEARCH trial does not support the current evidence that high-dose statin therapy is more efficient in secondary prevention after a myocardial infarction.


Irbesartan in Heart Failure With Preserved Ejection Fraction Study

This trial focused on heart failure patients with a preserved ejection fraction (also known as diastolic heart failure) and examined the effect of irbesartan on major cardiovascular events. A total of 4128 patients were enrolled and randomised, receiving 75 mg daily irbesartan (2067) or placebo (2061). The dose of irbesartan was titrated during the follow-up period and the maximum dose was finally 300 mg daily. Baseline characteristics were similar in the two groups and the majority of patients suffered from hypertensive heart failure (64%) or from ischaemic cardiomyopathy (25%). The baseline ejection fraction was at least 45% and most of the participants had New York Association (NYHA) class III symptoms (77%) with a recent hospitalisation (44%). The study's primary endpoint was death or hospitalisation for heart failure, myocardial infarction or arrhythmia. During a mean follow up of 49.5 months, there was no significant difference between the two arms in the incidence of the primary endpoint of all cause mortality or hospitalisation for cardiovascular disease (HR 36% vs. 37%). Quality of life improved in both groups at the end of 6 months, without any inter-group difference. Consequently, irbesartan failed to improve the outcomes of patients with heart failure with preserved ejection fraction, apart from which serious hyperkalaemia ( K+ >6 mmol/l) was observed in some of these patients.


Effect of Exercise Training on Health-Related Quality of Life in Patients With Chronic Heart Failure

This is the largest study ever to address the effect of exercise on mortality and hospitalisation in patients with heart failure (HF). The study enrolled 2331 adults with New York Heart Association Class II-IV HF, a left ventricular (LV) ejection fraction ≤35%, receiving optimal medical therapy, and able to undergo an exercise training programme safely. The cohort was randomised into two groups having normal physical activity at home or a structured exercise training programme. The exercise protocol was based on the cardiac rehabilitation model with increasing workout intensity and duration. For the first 36 weeks patients exercised under supervision for 30 minutes three times per week. Subsequently they performed exercise at home for 40 minutes five times a week. The primary endpoint was a composite of all-cause death and hospitalisations. The secondary endpoints included cardiovascular death, heart failure hospitalisations, and quality of life (QOL) after 2.5 years of follow up. No significant difference in the primary endpoint was reported between the two groups (HR 0.93, p=0.13). However, the exercise protocol was associated with an 11% reduction in cardiovascular death (p=0.03) and a 15% reduction in HF hospitalisation (p=0.03) compared to the standard exercise model. Additionally, exercise training was associated with a significant improvement in the Kansas City Cardiomyopathy Questionnaire (p=0.005) during the first 3 months. According to the investigators, the HF ACTION Trial indicates a beneficial effect of the exercise training model in patients with left ventricular dysfunction receiving optimal medical treatment.


Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine in Subjects with Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 46

The ATLAS - TIMI 46 trial was a phase II trial designed to identify tolerable and effective doses of rivaroxaban, an oral direct factor Xa inhibitor, in the treatment of patients with acute coronary syndromes. Nowadays, oral anticoagulant treatment is considered to be indispensable in this cohort. The study design included three groups of recently diagnosed patients with acute coronary syndromes. A total of 3491 patients were enrolled, 761 to aspirin alone, and 2730 to aspirin and clopidogrel for 6 months. Of these, 1160 patients received placebo, 1166 received rivaroxaban daily, and 1156 received rivaroxaban twice daily. Investigators administrated rivaroxaban at a dose of 5 mg, followed by 10 mg, and then 20 mg, in either single or divided doses. All groups had similar baseline characteristics and about one half of the participants had an ST-elevation myocardial infarction. The primary endpoint was composite, including the incidence of death, myocardial infarction, stroke or recurrent ischaemia requiring revascularisation, and it was reported less frequently in the rivaroxaban arm compared with placebo, although this was not statistically significant (5.6% vs. 7.0%, hazard ratio [HR] 0.79, p=0.10). However, there was a statistically significant reduction in the secondary endpoint of death, MI, or stroke in the rivaroxaban arm compared with placebo (3.9% vs. 5.5%, HR 0.69, 95% CI 0.50-0.96, p=0.028). As regards the safety of the rivaroxaban, data showed that bleeding rates were higher as doses were increased compared to placebo. Furthermore, bleeding was higher in the group receiving dual antiplatelet therapy in comparison to aspirin for all doses of rivaroxaban and the need for medical evaluation was more frequent at higher rivaroxaban doses. In conclusion, the results of the ATLAS-TIMI 46 trial indicate that rivaroxaban has beneficial effects compared with placebo for triple therapy in patients presenting with acute coronary syndromes, but is associated with a higher risk of significant bleeding. A phase III trial using doses of rivaroxaban 2.5 and 5 mg twice daily will begin recruitment next month (13,500–16,000 patients) with a composite primary endpoint of cardiovascular death, myocardial infarction and stroke.


Timing of Intervention in Patients With Acute Coronary Syndromes

In the current literature, there is debate about the potential beneficial effects of early invasive therapy in patients presenting with non-ST–elevation myocardial infarction (NSTE-ACS). The TIMACS trial was performed at 100 centres in 17 countries and enrolled 3031 patients with unstable angina or NSTE-ACS. They were randomised either to an early invasive strategy (coronary angiography as soon as possible, followed by PCI or CABG within 24 hours) or a delayed strategy (coronary angiography any time >36 hours followed by PCI or CABG). Ischaemic ECG changes were noted in about 80% of the patients, and about 77% of the patients had elevated biomarkers (NSTEMI). About 20% of the participants had a prior myocardial infarction and 27% of them had diabetes. The median times to coronary angiography in the early and delayed arms were 14 and 50 hours, respectively. PCI was conducted more often in the early invasive group (59.6% vs. 55%), with a median time of 16 vs. 52 hours. The primary results from this trial were not encouraging for an early invasive strategy, as no significant difference in primary endpoints (death, myocardial infarction and stroke) was observed between the early invasive and delayed invasive arms (9.7% vs. 11.4%, HR= 0.85, p=0.15). On the other hand, the secondary endpoint of death, myocardial infarction or refractory ischaemia was significantly lower in the patients who underwent early invasive therapy (6% vs. 13.1%, HR 0.72, p=0.0002), probably because of a reduction in the episodes of recurrent ischaemia. In the high risk for adverse events subgroup, as determined by GRACE score >140, there was a significant reduction in the incidence of the primary endpoint in the early invasive group compared with the delayed invasive group (14.1% vs. 21.6%, HR 0.65, p=0.005). In addition, major bleeding rates were similar between the two groups. These results indicate that early invasive therapy after NSTE-ACS does not have an advantage compared to delayed invasive therapy in the above mentioned composite endpoints. However, a significant reduction was seen in the incidence of refractory ischaemia in patients who underwent early catheterisation.

BICC Trial

Beta-Interferon in Chronic Viral Cardiomyopathy

In this trial, the efficacy of interferon beta-1b (IFNβ-1b) in patients with dilated cardiomyopathy (DCM) was evaluated. Virus infection is considered to be a main cause of DCM in these patients and molecular diagnostic techniques (polymerase chain reaction) are now available to estimate viral reactivity and the possibility of adverse outcomes. BICC is the first trial to estimate the treatment effect of IFNβ-1b versus placebo using biopsy. A total of 143 patients, most of them with NYHA II symptoms, were randomised to 24 weeks' treatment with one of two doses of IFNβ-1b (4 x 106 or 8 x 106 IU every other day) or placebo. Myocardial biopsies were taken before and approximately 12 weeks after the treatment phase ended. Follow up was continued for a further 12 weeks after the second biopsy was taken. The composite clinical endpoint of patient global assessment at 24 weeks was significantly lower in the IFNβ-1b group compared with placebo (p<0.039). The primary endpoint was viral load reduction or elimination and a significant reduction was observed in both IFNβ-1b groups versus placebo (32% vs. 17%, odds ratio 2.33, p=0.048). Moreover, NYHA improvement was significantly better in the IFNβ-1b group compared with placebo at 12 weeks (p=0.013). However, there was no difference between the efficacies of the two different doses of IFNβ-1b. There were no significant rates of adverse events or cardiac concerns in any group, although adverse events were more common in the active treatment groups.


Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Type 2 Diabetes Patients With Cardiovascular History

This is a multi-centre, double-blind, randomised, controlled trial of rosiglitazone (8 mg/day) versus glipizide (15 mg/day) in patients with diabetes type 2 (233 and 239 patients, respectively) and an indication for coronary angiography or PCI. Patients were excluded if they had prior coronary artery bypass surgery, structural heart disease, renal disease, liver disease, or uncontrolled hypertension. All subjects underwent coronary angiography with IVUS assessment of a 40 mm segment of a non-intervened artery with 10-50% stenosis. About 462 subjects had a repeat IVUS after 18 months of therapy and were included in the efficacy analysis. The primary endpoint was a significant change in atheroma volume, which fell by 0.21% in the rosiglitazone group and rose by 0.43% in the glipizide group. Neither change was significant versus baseline and the treatment difference was -0.64%, which was not significant (p=0.12). Rosiglitazone treatment resulted in a statistically significant reduction in total atheroma volume (p=0.04), but no significant difference in atheroma volume in the most diseased segment. Moreover, there was no statistically significant difference in clinical events between two groups.


Tailored clopidogrel dosing cuts stent thrombosis after PCI

This trial sought to assess the usefulness of an index (vasodilator-associated stimulated phosphoprotein: VASP) as regards platelet reactivity and subsequent stent thrombosis in non-emergent PCI. It is known that there is a large inter-individual variability in the response to clopidogrel, even with very large loading doses. Recently, a platelet assay, known as the VASP index, has been developed. A VASP index ≥50% is considered the optimum threshold for identifying clopidogrel-resistant patients who are at increased risk of thrombosis. A cohort of 429 patients, with similar baseline characteristics and a VASP index ≥50%, after an initial loading dose of aspirin 160 mg and clopidogrel 600 mg, were randomised, 214 to the VASP-guided group and 215 to the placebo group. In the first group, 70% of patients had a VASP index <50% after two loading doses of clopidogrel. Nevertheless, 8% of patients remained above this threshold even after four loading doses, equivalent to 2400 mg of clopidogrel, suggesting a clopidogrel resistance phenomenon. The primary endpoint was definite stent thrombosis at 30 days post PCI. This was significantly reduced in the VASP-guided group as compared with controls (0.47% vs. 4.7%, p=0.01). It should be noted that all stent thromboses occurred in the first 7 days. There was no difference in bleeding rates between two groups. These results indicate that the VASP index can be useful in the stratification risk of patients with abnormalities in their response to clopidogrel treatment. Subsequently, a significant reduction in major cardiac events, stent thrombosis and major bleeding episodes is associated with the use of VASP index.


Physicians Health Study II

The PHS II trial was designed to assess the role of vitamin C and E supplementation in the prevention of cardiovascular events in low-risk male physicians. A cohort of 14,641 healthy males were randomised, 3656 to active vitamins E and C, 3659 to active vitamin E and placebo vitamin C, 3673 to placebo vitamin E and active vitamin C, and 3653 to placebo vitamins C and E. Baseline characteristics were broadly similar in the four groups. Compliance was about 72% at 8 years. After a mean follow up of 8 years, there were 1245 confirmed major cardiovascular events, of which an almost equal number occurred in the vitamin-E versus placebo-treated patients (620 vs. 625, HR=1.01) and in the vitamin-C versus placebo-treated patients (619 vs. 626, HR=0.99). The results of the PHS II trial indicate that neither vitamin C nor vitamin E supplementation is associated with a reduction in major cardiovascular outcomes, as compared with placebo, although vitamin E may be associated with a slightly higher incidence of haemorrhagic stroke, compared with placebo.

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