Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial.

BACKGROUND: Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. METHODS: We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat. FINDINGS: 310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction. INTERPRETATION: Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.

Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration.

OBJECTIVES: We sought to determine whether abnormal myocardial blood flow (MBF) responses to the cold pressor test (CPT) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants. BACKGROUND: There is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide, leading to impaired vasodilator function. It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors. METHODS: Fifty patients with normal coronary angiograms were studied. The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline (placebo), as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily. RESULTS: In hypertensive patients, the change in MBF (DeltaMBF) was not modified significantly by short-term vitamin C administration challenges (0.20 +/- 0.20 ml/g/min; p = NS) but was significantly increased after three months and two years of treatment with vitamin C versus baseline (0.58 +/- 0.27 and 0.63 +/- 0.17 vs. 0.14 +/- 0.18 ml/g/min; both p < or = 0.001). In smokers, DeltaMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment (0.52 +/- 0.10, 0.54 +/- 0.13, 0.50 +/- 0.07 vs. -0.08 +/- 0.10 ml/g/min; all p < or = 0.001). In hypercholesterolemic patients, no improvement in DeltaMBF during CPT was observed after short- and long-term vitamin C treatment (0.05 +/- 0.14, 0.08 +/- 0.18, 0.02 +/- 0.19 vs. 0.08 +/- 0.16 ml/g/min; p = NS). The CPT-induced DeltaMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects (p < or = 0.001). CONCLUSIONS: The present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors, which highlights the quite complex nature underlying abnormal coronary vasomotion.

Prognostic value of abnormal vasoreactivity of epicardial coronary arteries to sympathetic stimulation in patients with normal coronary angiograms.

OBJECTIVE: We aimed to evaluate prospectively whether patients with normal coronary angiogram but abnormal epicardial vasoreactivity to cold pressor test (CPT) are at increased risk for cardiovascular events. METHODS AND RESULTS: Vasoreactivity in response to CPT and dilation of epicardial arteries to intracoronary application of nitroglycerin were assessed quantitatively (percent change of luminal area, DeltaLA%) in 130 patients with normal coronary angiograms. Cardiovascular events (cardiovascular death, acute coronary syndrome, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, or peripheral revascularization) were assessed as clinical outcome parameters over a mean follow-up period of 45+/-9 months. Based on their vascular responses to CPT, patients were assigned into the following 3 groups: group 1, patients with normal vasodilator response (DeltaLA >0%; n=37); group 2, patients with moderate vasoconstrictor response (DeltaLA between 0% and -15%; n=42); and group 3, patients with severe vasoconstrictor response (DeltaLA < or =-15%; n=51). Although patients from groups 2 and 3 had significantly increased vasoconstrictor response to CPT (group 2, DeltaLA -6+/-3% and group 3, DeltaLA -24+/-6% versus group 1, DeltaLA 11+/-9%; P< or =0.0001), they showed normal endothelial-independent epicardial vasodilation to intracoronary application of nitroglycerin similar to patients from group 1 (DeltaLA 39+/-16% and 34+/-14% versus 41+/-14%; P=NS, respectively). During follow-up, none of the patients from group 1 developed cardiac events. However, 7 cardiovascular events occurred in group 2 and 30 occurred in group 3 in 4 and 22 patients, respectively (P< or =0.0001, univariate by log-rank test). After adjustment for known risk factors for coronary artery disease, impaired epicardial coronary vasoreactivity to CPT remained significantly associated with the risk of developing cardiovascular events (P=0.040, multivariate by Cox regression model). CONCLUSIONS: In patients with normal coronary angiogram, abnormal vasoreactivity of epicardial coronary arteries in response to sympathetic stimulation is associated with the risk of developing cardiovascular events.

Therapeutic advances in heart failure.

Annual mortality from congestive heart failure ranges from 15% to 60%, depending on the severity of the left ventricular damage and underlying disease. Most controlled trials have been too small to detect any beneficial effect on survival from the newer vasodilator and inotropic drugs. However, the results of two recent studies strongly suggest that some vasodilator drugs improve prognosis. In one study, a hydralazine-nitrate combination reduced 2-year mortality by 34%, while in another study, enalapril, in addition to diuretics, digitalis, and directly acting vasodilators, reduced 1-year mortality by 31%. Thus far no large studies have been published with the new phosphodiesterase-inhibiting agents. Although preliminary reports of large-scale trials did not demonstrate changes in survival rate, they have been shown to improve well-being in class III-IV congestive heart failure patients.

[Effect of vitamin C on platelet aggregation in smokers and nonsmokers]. / Wirkung von Vitamin C auf die Thrombozytenaggregation bei Rauchern und Nichtrauchern.

BACKGROUND: Epidemiologic studies suggest a protective effect of regular intake of vitamin C and vitamin E as antioxidant in the manifestation of coronary heart disease. Cigarette smoke contains a large amount of radicals and reactive oxygen-derived substances enhancing aggregation of platelets. We investigated the effect of vitamin C as an important antioxidant in human plasma on the aggregation of human platelets in smokers and nonsmokers. TEST PERSONS AND METHOD: Overall 40 persons (mean age: 28 +/- 9 years) were randomized. The groups of chronic smokers (21 +/- 9 "packyears") and nonsmokers consisted of 20 persons, respectively. In each group ten persons were treated with intravenous infusion of 3 g vitamin C or 100 ml 0.9% saline solution (placebo). The maximal aggregation was measured with an aggregometer after 0, 3, 6, and 24 hours with collagen concentrations of 0.5 microgram/ml and 1.0 microgram/ml, respectively. RESULTS: In smokers with vitamin C application the group comparison by Wilcoxon's rank test demonstrated a significant decrease of platelet aggregation after 6 hours for both collagen concentrations (0.5 microgram/ml and 1.0 microgram/ml) compared to the placebo group (p < or = 0.05), whereas nonsmokers with vitamin C application revealed a significant decrease of platelet aggregation after 3 and 6 hours for both collagen concentrations (0.5 microgram/ml and 1.0 microgram/ml) compared to the placebo group (p < or = 0.03). The comparison between smokers and nonsmokers regarding the effect of vitamin C on platelet aggregation for both collagen concentrations demonstrated no significant difference (3 hours: p = 0.84 and p = 0.97; 6 hours: p = 0.81 and p = 0.59; and 24 hours p = 0.57 and p = 0.06, not significant, respectively). CONCLUSION: These findings suggest that vitamin C exerts an unknown inhibitory effect on collagen-induced platelets aggregation. These observations may represent a further protective effect of vitamin C in the development of coronary heart disease.

Real-time assessment of acute myocardial ischaemia by an intra-thoracic 6-lead ECG: evaluation of a new diagnostic option in the implantable defibrillator.

AIM: In the presence of coronary artery disease, implantable cardioverter-defibrillators (ICD) are used effectively for treating life-threatening tachyarrhythmias. Continuous monitoring of myocardial ischaemia would provide a new diagnostic option in future ICD generations. METHODS AND RESULTS: In 22 selected patients undergoing coronary angioplasty, percutaneous transluminal coronary angioplasty (PTCA), three electrodes, similar to those used in the ICD, were inserted aiming to create six intra-thoracic ECG (IT-ECG) leads according to Einthoven and Goldberger. In total, 27 PTCA were conducted. The diagnostic efficacy for ischaemia assessment was compared with the surface ECG. The IT-ECG proved to be more sensitive than conventional ECG in early and overall ischaemia assessment. At 30 s of coronary artery occlusion, ischaemic ST-segment alterations (> or =0.25 mV) were present in the IT-ECG 2.3 times more often (23 vs. 10/27 PTCA attempts, P<0.01) and at 90 s 1.4 times more often compared with conventional ECG leads (18 vs. 26/27, P<0.05). Intra-thoracic Einthoven 2 (SVC+RVA vs. ICD-housing) and Goldberger 3 (SVC+ICD-housing vs. RVA) had the highest sensitivity (88/85%). Using > or =4 IT-ECG, ischaemia monitoring was independent of severity and site of origin. IT-ECG signals showed double ST-T signal amplitude (4.19+/-0.6 vs. 2.15+/-0.3 mV, ratio: 1.95, P<0.01) at a QRS/ST amplitude ratio similar in the two ECG techniques. CONCLUSION: This study provides strong evidence that the ICD-based IT 6-lead ECG would provide a new and efficient means of assessing a patient's daily ischaemic burden.