Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.

BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.

Long-term impact of secondary preventive treatments in patients with stable angina.

We assessed the independent effects of beta blockers, calcium antagonists, lipid-lowering drugs, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), anti-platelet drugs, vitamin K antagonists, percutaneous coronary intervention (PCI) and coronary artery by-pass grafting (CABG) on mortality and on the composite endpoint of death, myocardial infarction, stroke or heart failure in patients with stable angina pectoris. We estimated the effects of the interventions used at baseline by multivariate Cox regression and during follow-up by G-estimation in 7,665 patients followed for a mean of 5 years in the ACTION trial. Adjusted hazard ratios (95% confidence intervals) comparing all cause mortality among users during follow-up to non-users were 1.01 (0.91, 1.09) for beta blockade, 0.82 (0.75, 0.89) for ACEIs or ARBs, 0.93 (0.87, 0.98) for calcium antagonists, 0.54 (0.49, 0.62) for lipid-lowering drugs, 0.49 (0.42, 0.53) for anti-platelet drugs, 0.74 (0.69, 0.78) for PCI, and 0.91 (0.82, 0.98) for CABG. Effects on the composite endpoint were less marked. This observational study confirms that ACEIs or ARBs, lipid-lowering and anti-platelet drugs as used in the everyday management of stable angina have independent secondary preventive effects. Calcium antagonists, PCI and CABG also appear to improve outcome.

Effect of Crizanlizumab, a P-Selectin Inhibitor, in COVID-19: A Placebo-Controlled, Randomized Trial.

COVID-19 is characterized by vascular inflammation and thrombosis, including elevations in P-selectin, a mediator of inflammation released by endothelial cells. We tested the effect of P-selectin inhibition on biomarkers of thrombosis and inflammation in patients with COVID-19. Hospitalized patients with moderate COVID-19 were randomly assigned to receive either placebo or crizanlizumab, a P-selectin inhibitor, in a double-blind fashion. Crizanlizumab reduced P-selectin levels by 89%. Crizanlizumab increased D-dimer levels by 77% and decreased prothrombin fragment. There were no significant differences between crizanlizumab and placebo for clinical endpoints. Crizanlizumab was well tolerated. Crizanlizumab may induce thrombolysis in the setting of COVID-19. (Crizanlizumab for Treating COVID-19 Vasculopathy [CRITICAL]; NCT04435184).

Quality management of a large randomized double-blind multi-centre trial: the ACTION experience.

The ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study was an independent, investigator-initiated, multi-national trial comparing nifedipine GITS to placebo in 7665 patients with stable angina pectoris. The trial was sponsored by the manufacturer of the medication concerned. 291 centers in 19 countries participated. Results have been published. We defined quality management (QM) as all activities directed at ensuring data integrity and consistency; and ensuring appropriate trial conduct, including pro-active prevention of deviations from protocol. We describe the QM framework that was adopted for the ACTION trial and the key tools that were used. In the protocol, particular attention was paid to explicit definition of tasks and responsibilities of all participants, and to unequivocal operational definitions of terms such as 'randomized', 'follow-up', etc. that could be applied by investigators, on-site monitors and during data processing at the coordinating centre. A comprehensive clinical trial and study management system based on simultaneous display of scanned documents and data base content had a central role. We describe in detail how compliance with good clinical practice was ensured, how the intention-to-treat principle was implemented, how compliance with study medication and completeness of follow-up was achieved, how double blinding was maintained throughout the study structure, and how patient safety was protected. The protocol ruled out participation in any other study at the same time by ACTION participants. Our experience showed that the reasons for this are not always understood by investigators. Unequivocal operational definitions of the procedural concepts that characterize randomized clinical trials should not only be the basis of QM, but also of reporting results.

Uric acid and other renal function parameters in patients with stable angina pectoris participating in the ACTION trial: impact of nifedipine GITS (gastro-intestinal therapeutic system) and relation to outcome.

BACKGROUND: Little data is available concerning the prognostic implications of renal function abnormalities, their evolution over time and the effects of nifedipine on such abnormalities in patients with stable angina pectoris. METHODS: The previously published ACTION trial compared long-acting nifedipine GITS 60 mg once daily to placebo among 7,665 patients. Standard laboratory tests including creatinine and uric acid were assessed at baseline, after 6 months, 2 and 4 years, and at the end of follow-up. We assessed the impact of nifedipine on markers of renal dysfunction and determined whether evidence of renal failure alters the impact of nifedipine on the clinical outcome of patients with stable angina. RESULTS: Uric acid was not while creatinine level and estimated creatinine clearance were potent conditionally independent predictors of total mortality and of cardiovascular clinical events. Relative to placebo, nifedipine reduced 6-month uric acid levels by 3% (P < 0.001) of the baseline value. This difference was maintained during long-term follow-up, was present both in normotensives and in hypertensives, and was not explained by differences in diuretic therapy or allopurinol use. Nifedipine had no effect on the occurrence of clinical renal failure. Relative to placebo, the effects of nifedipine on cardiovascular death or myocardial infarction [hazard ratio (HR) = 1.01, 95% confidence interval (CI) 0.88-1.17], any stroke or transient ischaemic attack (HR = 0.73, 95% CI 0.60-0.88), new overt heart failure (HR = 0.72, 95% CI 0.55-0.95), and the need for any coronary procedure (HR = 0.81, 95% CI 0.75-0.88) were consistent across strata of markers of renal dysfunction. CONCLUSIONS: We conclude that, in patients with stable angina, nifedipine reduces uric acid levels and does not affect other markers of renal dysfunction. Renal dysfunction does not alter the effects of nifedipine on clinical outcome.

Blood pressure reduction in stable angina by nifedipine was related to stroke and heart failure reduction but not to coronary interventions.

BACKGROUND AND OBJECTIVE: Whether blood pressure (BP) reduction is a necessary prerequisite for cardiovascular risk reduction or an epiphenomenon has not been definitively established. We used an innovative analytic method to address this question. METHODS: For 7,287 participants in a stable angina trial comparing long-acting nifedipine to placebo, we estimated the BP response after 2 weeks of treatment corrected for regression-to-the mean, and then related the latter and assigned treatment to subsequent cardiovascular outcomes. RESULTS: Subsequent stroke and heart failure was strongly related to 2-week corrected systolic BP response, but coronary angiography and bypass surgery was not. Adjustment for the 2-week corrected systolic BP response changed nifedipine effect estimates (relative to placebo) for subsequent stroke from 28% (P=0.04) to 21% (P=0.13) risk reduction, and for heart failure from 30% (P=0.02) to 21% (P=0.11) risk reduction; but did not alter the effect estimates for coronary angiography (27% reduction, P<0.001), and coronary bypass surgery (22% reduction, P=0.002). CONCLUSION: The stroke and heart failure risk reduction by nifedipine GITS in patients with stable angina can be attributed partly to its BP lowering effect, whereas effects on coronary procedures are likely to be related almost entirely to its antianginal effects.

Resource utilization implications of treatment were able to be assessed from appropriately reported clinical trial data.

BACKGROUND AND OBJECTIVE: Published clinical trial data rarely allow assessment of the health care resource utilization implications of treatment. We give an example of how these can be assessed given appropriate tabulation of data. METHODS: Data from a trial comparing long-acting nifedipine gastrointestinal therapeutic system to placebo in 7,665 patients with stable angina pectoris was analyzed. RESULTS: Relative to placebo, nifedipine significantly increased mean cardiovascular (CV) event-free survival by 41 days but had no effect on mean survival. Per 100 years of follow-up, 78.1 patient-years of double-blind nifedipine administration reduced use of another calcium antagonist, an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, a diuretic and a cardiac glycoside by 1.54, 3.73, 2.63, 2.23, and 0.64 years, respectively, whereas 0.21 less hospitalization for overt heart failure, 0.47 less hospitalization for any stroke or transient ischemic attack, 0.8 less coronary angiogram, 0.38 less coronary bypass procedure, and 0.13 additional orthopedic procedure was required. Combining resource utilization with cost data for one particular hospital showed that one additional year of CV event-free survival costs an average additional euro 3,036 in the setting considered. CONCLUSION: Appropriately tabulated clinical trial data allows clinicians to judge the resource utilization implications and economic effect of treatment decisions.

The development of heart failure in patients with stable angina pectoris.

BACKGROUND: To describe the clinical characteristics of patients with stable angina pectoris who develop heart failure and the events preceding its onset. METHODS AND RESULTS: Of 7665 patients with stable angina in the ACTION trial, which compared long-acting nifedipine to placebo, 207 (2.7%) developed heart failure (HF) during a mean follow-up of 4.9 years. Those who developed HF were significantly (P<0.05) older, more often had diabetes, had a more extensive history of cardiovascular disease, lower ejection fractions, a higher serum creatinine and glucose, a lower haemoglobin, and were more often on blood pressure lowering drugs. A cardiac event or an intervention (n=155), a significant non-cardiac infection (n=19) or poor control of hypertension (n=12) preceded the development of HF in 186/207 cases (90%). There was no obvious precipitating factor in the remaining 21 patients (10%). Myocardial infarction increased the risk of the development of new HF within one week more than 100-fold. Nifedipine reduced the incidence of HF by 29% (P=0.015). CONCLUSIONS: The development of heart failure is uncommon in patients with stable angina, and even less so in the absence of an obvious precipitating factor.

Diagnostic criteria and adjudication process both determine published event-rates: the ACTION trial experience.

OBJECTIVE: Few trials report event-adjudication procedures in detail. Using data from the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study, we compared the impact on event-rates of an adjudication strategy based on systematic screening of all reported serious adverse events (SAEs) with a strategy based on investigator diagnoses. The final diagnosis was always made by a critical events committee (CEC) using standard criteria. METHODS: ACTION randomized 7665 patients with stable angina to either nifedipine or placebo. Pre-specified events included acute or procedural myocardial infarction (MI), refractory angina, heart failure and debilitating stroke. Clinically related SAEs including in-hospital procedures were combined into episodes independent from the investigator diagnoses entered on SAE reports. All fatal episodes and those episodes suggestive of pre-specified events were adjudicated by the CEC. RESULTS: During follow-up, 17,081 episodes were reported in 5312 patients. The SAE descriptions ruled out the occurrence of a pre-specified event in 28%. The remaining 72% were adjudicated by the CEC and 616 cases of MI, 361 of refractory angina, 275 of heart failure and 190 of debilitating stroke were diagnosed (total=1442). Had adjudication by the CEC been limited to the 3924 episodes (2397 patients) that were fatal or for which the investigator had reported any of the diagnoses mentioned, 98 cases of MI, 35 of refractory angina, 81 of heart failure and 14 of debilitating stroke would have been missed (total=228). CONCLUSION: Both the diagnostic criteria used and the adjudication process determine event-rates and conclusions about treatment effects in clinical trials. Published trial reports should always state if event-adjudication was independent of the diagnoses of investigators, and if all events of interest were adjudicated or only the first one.

Tracking coronary calcification and atherosclerotic lesions in patients with stable angina pectoris undergoing nifedipine therapy.

AIMS: The objective of the Coronary Calcification (CC) study was to determine in patients with chronic symptomatic coronary artery disease, if, in addition to standard therapy, nifedipine GITS, relative to placebo, would arrest or slow down the progression of calcium or the development of new atherosclerotic lesions in the coronary arteries. METHODS AND RESULTS: The CC study was part of the ACTION trial. Multi-slice computerized tomography was used to measure and track the progression of CC. Five hundred and eighteen patients were included in this study. The changes in calcium score from baseline every 24 months, over a period of between 4.5 and 6 years, were similar in the nifedipine and placebo treatment groups (p = 0.8). Compared to placebo, more patients in the nifedipine group (71 vs. 60%) were free of new calcified atherosclerotic lesions during follow-up(p = 0.095). CONCLUSION: Nifedipine GITS was not effective in slowing down the progression of calcium in advanced atherosclerotic plaques in patients with stable angina pectoris. Although statistically not significant, Nifedipine demonstrated a trend in slowing down the development of new atherosclerotic lesions.

Postoperative Ocular Inflammation: A Single Subconjunctival Injection of XG-102 Compared to Dexamethasone Drops in a Randomized Trial.

PURPOSE: To evaluate the efficacy and safety of XG-102 (brimapitide) compared to dexamethasone eye drops in the treatment of postoperative ocular inflammation. DESIGN: Multicenter, randomized, parallel group, double-masked, noninferiority clinical trial. METHODS: Patients who underwent anterior and posterior segments combined surgery or glaucoma surgery or complex posterior segment surgery were eligible to participate. Patients were administered a single subconjunctival injection of 250 µL XG-102 90 µg (n = 47) or 900 µg (n = 48) or placebo (n = 50) at the end of ocular surgery. Subconjunctival injection for each group (XG-102 90 µg, XG-102 900 µg, or placebo) was followed by eye drops instilled 4 times per day for 21 days with placebo, placebo, or dexamethasone solution, respectively. The primary outcome measure was anterior chamber cell grades at day 28 comparing XG-102 900 µg with dexamethasone. RESULTS: The anterior cell grades for both XG-102 groups were noninferior to dexamethasone (-0.054 anterior cell grade [95% confidence interval -0.350-0.242]; P < .001 for noninferiority) for XG-102 900 µg and -0.086 anterior cell grade (95% confidence interval -0.214-0.385; P = .003 for noninferiority) for XG-102 90 µg. Rescue medication was introduced for 10 (21%), 7 (15%), and 2 (4%) patients allocated to the XG-102 90 µg, XG-102 900 µg, and dexamethasone groups, respectively. The difference between XG-102 90 µg and dexamethasone was statistically significant (P = .013). The number of patients for whom adverse events were reported and the nature of the events reported was similar between the 3 treatment groups. CONCLUSIONS: A single subconjunctival injection of XG-102 at the end of ocular surgery is noninferior to dexamethasone eye drops in the treatment of postoperative ocular inflammation.

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial.

OBJECTIVE: To examine the effects of nifedipine GITS on clinical outcome in patients with concurrent stable angina and hypertension. METHODS: Data from the double-blind placebo-controlled ACTION trial was stratified for hypertension (blood pressure > or = 140/90 mmHg), at baseline. RESULTS: A total of 52% of 7665 ACTION patients were hypertensive. Some 80% were on a beta blocker; hypertensives were more often treated with other blood pressure-lowering drugs. Mean baseline blood pressure was 122/74 mmHg among normotensives and 151/85 mmHg among hypertensives. Follow-up blood pressures were reduced by nifedipine (P < 0.001) on the average by 3.9/2.4 and 6.6/3.5 mmHg among normotensives and hypertensives, respectively. Nifedipine GITS significantly (P < 0.05) reduced the combined incidence of all-cause mortality, myocardial infarction, refractory angina, heart failure, stroke and peripheral revascularization by 13% in hypertensives only. Nifedipine significantly reduced the incidence of any stroke or transient ischemic attack by almost 30% in both subgroups and the need for coronary angiography by 21% in normotensives and 16% in hypertensives. Among hypertensives, the incidence of new overt heart failure was significantly reduced by 38% and of debilitating stroke by 33%. Among normotensives, the need for coronary bypass grafting was significantly reduced by 32%. Nifedipine did not affect all-cause death, cardiovascular death and myocardial infarction in either normo- or hypertensives, but increased the need for peripheral revascularization. CONCLUSION: The salutary effects of the addition of nifedipine GITS to the basic regimen of patients with concurrent stable symptomatic coronary artery disease and hypertension emphasize the need for blood pressure control.

Telemedicine in heart failure: pre-specified and exploratory subgroup analyses from the TIM-HF trial.

BACKGROUND: Meta-analyses have suggested that remote telemedical management (RTM) positively affects clinical outcomes in chronic HF patients. The results of two recent randomised RTM trials do not corroborate these results. We aim to report prospectively defined and exploratory subgroup analyses for the TIM-HF trial and to identify a patient profile that could potentially benefit from RTM for further investigation in randomised clinical trials. METHODS: In TIM-HF, 710 stable chronic HF patients, in NYHA class II or III with a history of HF decompensation within 2 years previously or a LVEF ≤ 25% were randomly assigned (1:1) to RTM or usual care. The primary outcome was total death and secondary outcomes included days lost due to death or HF hospitalisation and a composite of cardiovascular death and HF hospitalisation. Twelve subgroups were prospectively defined and patient profiling was investigated for the subgroup with a prior history of HF decompensation, an LVEF ≥ 25% and a PHQ-9 score<10. RESULTS: The subgroup treatment effects were significant for total mortality for the PHQ-9 subgroup only (p for interaction<0.027). For the outcome 'number of days lost due to hospitalisation for HF or death', the subgroup treatment effects were significant (p for interaction<0.05) for patients with a prior HF decompensation or an ICD implant or a PHQ score of <10 and for the patient-profiling subgroup. CONCLUSIONS: Telemedicine management may not be appropriate for all HF patients. Future research needs to investigate which HF population may benefit from this intervention.

Correlates of coronary angiography in patients with stable angina and geographical differences in its utilisation: the ACTION experience.

BACKGROUND: Utilisation of coronary angiography (CAG) varies between different countries. For patients with stable angina, the present study aimed to assess whether such differences could be explained by differences in patient characteristics, and whether these differences were related to outcome. METHODS: Using data from the ACTION trial, which compared long-acting nifedipine GITS with placebo in 7665 patients with stable angina from 19 countries, we determined by country the ratio of the observed (O) and the expected (E, based on multivariate models) number of patients who had a history of CAG before entry, or underwent CAG during a mean follow-up of 5 years. Similarly, we determined corresponding O/E ratios for the combined occurrence of any death, myocardial infarction (MI) or debilitating stroke (DS) during follow-up. RESULTS: O/E ratios for a history of CAG before entry ranged from 0.68 [95% confidence interval (CI) 0.60-0.77) for Sweden to 1.43 (95%CI 1.36-1.44) for Belgium, and were significantly correlated (p=0.04) to the corresponding O/E ratios for CAG during follow-up. The combined O/E ratio for CAG either before entry or during follow-up was not correlated (p=0.7) to the O/E for death, MI or DS, which ranged from 0.38 (95%CI undetermined) for Austria to 1.34 (95%CI 0.80-1.89) for France. CONCLUSIONS: The degree to which CAG is utilised in patients with stable angina varies between countries but is not related to the occurrence of death, MI or stroke. This supports the notion that percutaneous coronary intervention does not reduce the risk of events.

Gender differences in cardiac remodeling and clinical outcomes in chronic stable angina pectoris (from the ACTION Trial).

Our objective was to determine the gender differences in the relation between the echocardiographic parameters of cardiac remodeling and clinical outcomes in patients with chronic stable angina. The baseline ejection fraction (EF), end-diastolic volume, and end-systolic volume were assessed in 7,016 patients in the study "A Coronary disease Trial Investigating Outcomes with Nifedipine gastrointestinal therapeutic system" (ACTION). All-cause and cardiac mortality and incident heart failure were determined after a median of 5.0 years. Cox proportional hazard models were fit to determine the effect of gender on the relation between the echocardiographic parameters and clinical outcomes (interaction p <0.10). The association between the EF and mortality differed significantly between men and women, with women demonstrating a marked increase in risk as the EF decreased, compared to men (interaction p = 0.03, adjusted p = 0.07). Also, a significant interaction by gender was seen for the association between the end-systolic volume and the risk of heart failure (interaction p = 0.01, adjusted p = 0.05). In conclusion, the relation between EF and mortality differed according to gender in patients with chronic coronary disease, with women having a greater risk of adverse outcomes as the EF decreased. Similar findings were observed with the end-systolic and end-diastolic volumes and the risk of heart failure. These findings may reflect inherent gender-based differences in ischemic heart disease and cardiac remodeling and might help to identify women at high risk.

Clinical course of isolated stable angina due to coronary heart disease.

AIMS: To describe the clinical course of patients with stable angina due to coronary heart disease without a history of cardiovascular (CV) events or revascularization (isolated angina). METHODS AND RESULTS: Of 7,665 patients in a trial comparing long-acting nifedipine with placebo, 2170 (28%) had isolated angina. During a mean follow-up of 4.9 years, 147 of these died (1.4/100 patient-years), while 761 (8.7/100 patient-years) either died, or had a cardiac event or procedure. The first event was death in 82, myocardial infarction or heart failure in 112, coronary revascularization in 171, and chest pain requiring hospitalization in 396. Six hundred and twelve patients (6.8/100 patient-years) underwent coronary angiography (CAG), followed by revascularization in 371. Sixty-eight of 262 deaths or major cardiac events were preceded by chest pain requiring hospitalization or revascularization. Event-rates after CAG were higher than before. The stroke rate was 0.7/100 patient-years (75 patients). CONCLUSION: Patients with stable isolated angina have low rates of death and major cardiac events, but relatively high rates of chest pain requiring hospitalization despite contemporary management. Since the majority of deaths and major CV clinical events are not preceded by clear warning symptoms, the main clinical implication is that measures to prevent such events must target all patients.

Predictive value of local and core laboratory echocardiographic assessment of cardiac function in patients with chronic stable angina: The ACTION study.

AIMS: To evaluate the relationship between echocardiographic cardiac function and outcome in patients with stable symptomatic angina. METHODS: Baseline echo left ventricular ejection fraction and volume data measured in a central laboratory was available for 7016 patients (92% of the total) participating in the ACTION trial (A Coronary disease Trial Investigating Outcome with Nifedipine GITS). Ejection fraction was also measured by investigators. Evaluation of the different echocardiographic variables was based on adjusted hazard ratios comparing the unfavourable limit of the 90% range of the variable concerned to the favourable limit. RESULTS: The centrally measured ejection fraction was the most powerful predictor of all-cause death (adjusted hazard ratio=2.5), myocardial infarction, any stroke or transient ischaemic attack and overt heart failure (adjusted hazard ratio=4.5). The addition of either end systolic volume or end diastolic volume to ejection fraction did not materially affect the power of prediction. Compared to the central ejection fraction measurement, the investigator-measured ejection fraction was a less powerful predictor for all outcomes considered. CONCLUSION: Routine echocardiography carefully analysed by standardised methods provides useful prognostic information in patients with stable angina, including for total mortality.

Safety of nifedipine GITS in stable angina: the ACTION trial.

AIM: We describe the safety profile of nifedipine GITS as assessed from adverse events reported in the ACTION trial in which 7,665 patients with stable, symptomatic coronary artery disease were randomly assigned nifedipine GITS or placebo and followed for a mean of 4.9 years. METHODS: All adverse events were coded using the COSTART coding dictionary. The incidence rate for each event was calculated as the number of patients with the event concerned divided by the total time 'at risk'. Hazard ratios comparing nifedipine with placebo and their 95% confidence intervals were obtained by Cox proportional-hazards analysis. RESULTS: As reported previously, nifedipine significantly reduced the incidence of cardiovascular events and procedures [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.83-0.95]. Apart from the known side effects of nifedipine, which include peripheral oedema, vasodilatation, hypotension, asthenia, constipation, leg cramps, non-specific respiratory complaints, impotence and polyuria, and which were reported more frequently in patients assigned nifedipine, the incidence rates of most other adverse events were similar. There were no differences in the occurrence of gastrointestinal haemorrhage, myocardial infarction and suicide. The rate of occurrence of death or new cancer excluding non-melanoma skin cancer for patients with no history of cancer at baseline was 2.53/100 patient years for patients assigned nifedipine and 2.37/100 patient years for patients assigned placebo (HR 1.06, 95% CI 0.93-1.22). CONCLUSION: Overall nifedipine GITS was well tolerated by patients with stable symptomatic angina.

Incidence and outcome of atrial fibrillation in stable symptomatic coronary disease.

OBJECTIVES: Evaluate the prevalence, incidence and impact on prognosis of existing and new onset atrial fibrillation (AF) in patients with stable, symptomatic coronary artery disease. DESIGN: Data from the 7 665 participants included in the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) trial was used. RESULTS: Over a mean follow-up of 4.9 years, the incidence of recurrent AF in patients with AF at baseline (4.1%) was 13.5/100 patient-years and 1.64/100 patient-years for patients without baseline AF. Patients with AF at baseline had increased mortality and new overt heart failure. New onset AF was associated with increased morbidity and mortality and in particular soon after onset. [adjusted 30-day relative risk for mortality 23, 95% CI 14-36; for debilitating stroke 37, 95% CI 18-77; and for heart failure 54, 95% CI 32-93]. The incidence of AF was not affected by treatment with nifedipine GITS. CONCLUSION: The presence of AF in patients with stable symptomatic CAD is an independent risk factor and in particular in the first 30 days for subsequent mortality and morbidity.

Quantitative analysis of catch-up saccades during sustained pursuit.

During visual tracking of a moving stimulus, primates orient their visual axis by combining two very different types of eye movements, smooth pursuit and saccades. The purpose of this paper was to investigate quantitatively the catch-up saccades occurring during sustained pursuit. We used a ramp-step-ramp paradigm to evoke catch-up saccades during sustained pursuit. In general, catch-up saccades followed the unexpected steps in position and velocity of the target. We observed catch-up saccades in the same direction as the smooth eye movement (forward saccades) as well as in the opposite direction (reverse saccades). We made a comparison of the main sequences of forward saccades, reverse saccades, and control saccades made to stationary targets. They were all three significantly different from each other and were fully compatible with the hypothesis that the smooth pursuit component is added to the saccadic component during catch-up saccades. A multiple linear regression analysis was performed on the saccadic component to find the parameters determining the amplitude of catch-up saccades. We found that both position error and retinal slip are taken into account in catch-up saccade programming to predict the future trajectory of the moving target. We also demonstrated that the saccadic system needs a minimum period of approximately 90 ms for taking into account changes in target trajectory. Finally, we reported a saturation (above 15 degrees /s) in the contribution of retinal slip to the amplitude of catch-up saccades.