Informative noncompliance in endpoint trials

Noncompliance with study medications is an important issue in the design of endpoint clinical trials. Including noncompliant patient data in an intention-to-treat analysis could seriously decrease study power. Standard methods for calculating sample size account for noncompliance, but all assume that noncompliance is noninformative, i.e., that the risk of discontinuation is independent of the risk of experiencing a study endpoint. Using data from several published clinical trials (OPTIMAAL, LIFE, RENAAL, SOLVD-Prevention and SOLVD-Treatment), we demonstrate that this assumption is often untrue, and we discuss the effect of informative noncompliance on power and sample size

Spontaneous recanalization of a completely occluded saphenous vein graft two months following acute myocardial infarction with persistent one year patency

Acute myocardial infarction resulting from saphenous vein graft occlusion occurs not infrequently in patients who have undergone coronary artery bypass graft surgery. In this case report, we present a novel case of spontaneous recanalization of a thrombotic graft occlusion in a patient who presented with a subacute myocardial infarction. The patient was treated medically with aspirin as the only anti-platelet agent. Interestingly, he presented 2 months later with new onset angina. Coronary angiography demonstrated complete resolution of thrombus but a severe focal stenosis in the distal anastomoses. Following drug eluting stent placement, a favorable clinical course has ensued and patency confirmed on follow up angiography at 1 year

A randomised controlled trial to evaluate and optimize the use of antiplatelet agents in the perioperative management in patients undergoing general and abdominal surgery- the APAP trial (ISRCTN45810007)

<p>Abstract</p> <p>Background</p> <p>Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery.</p> <p>Methods/Design</p> <p>This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed.</p> <p>Discussion</p> <p>This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery.</p> <p>Trial registration</p> <p>The trial is registered with Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN45810007">ISRCTN45810007</a>.</p

Determinants of pre-hospital pharmacological intervention and its association with outcome in acute myocardial infarction

BACKGROUND: The aim of this study was a) To identify predictors of the use of aspirin in the pre-hospital setting in acute myocardial infarction (AMI) and b) To analyze whether the use of any of the recommended medications was associated with outcome. METHODS: All patients with a final diagnosis of AMI, transported by the Emergency Medical Services (EMS) and admitted to the coronary care unit at Sahlgrenska University Hospital in Gothenburg, Sweden, in 2009–2011, were included. RESULTS: 1,726 patients were included. 58 % received aspirin by the EMS. Ischemic heart disease (IHD) was suspected in 84 %. Among patients who did not receive aspirin IHD was still suspected in 67 %. Among patients in whom IHD was suspected, and who were not on chronic treatment with aspirin the following predicted its pre-hospital use: a) age (odds ratio 0.98; 95 % confidence interval (CI) 0.96–0.99); b) a history of myocardial infarction (2.21; 1.21–4.04); c) priority given by EMS (8.07; 5.42–12.02); d) ST-elevation on ECG on admission to hospital (2.22; 1.50–3.29); e) oxygen saturation > 90 % (3.37; 1.81–6.27). After adjusting for confounders among patients who were not on chronic aspirin, only nitroglycerin of the recommended medications was associated with a reduced risk of death within 1 year (hazard ratio 0.40; 95 % CI 0.23–0.70). CONCLUSIONS: Less than six out of ten patients with AMI received pre-hospital aspirin. Five clinical factors were independently associated with the pre-hospital administration of aspirin. This suggests that the decision to treat is multifactorial, and it highlights the lack of accurate diagnostic tools in the pre-hospital environment. Nitroglycerin was independently associated with a reduced risk of death, suggesting that we select the use for a low-risk cohort. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13049-015-0188-x) contains supplementary material, which is available to authorized users

Pre-hospital ECG for acute coronary syndrome in urban India: A cost-effectiveness analysis

<p>Abstract</p> <p>Background</p> <p>Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective.</p> <p>Methods</p> <p>We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained.</p> <p>Results</p> <p>Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and$1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations.</p> <p>Conclusions</p> <p>While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.</p

Differences in access to coronary care unit among patients with acute myocardial infarction in Rome: old, ill, and poor people hold the burden of inefficiency

BACKGROUND: Direct admission to Coronary Care Unit (CCU) on hospital arrival can be considered as a good proxy for adequate management in patients with acute myocardial infarction (AMI), as it has been associated with better prognosis. We analyzed a cohort of patients with AMI hospitalized in Rome (Italy) in 1997–2000 to assess the proportion directly admitted to CCU and to investigate the effect of patient characteristics such as gender, age, illness severity on admission, and socio-economic status (SES) on CCU admission practices. METHODS: Using discharge data, we analyzed a cohort of 9127 AMI patients. Illness severity on admission was determined using the Deyo's adaptation of the Charlson's comorbidity index, and each patient was assigned to one to four SES groups (level I referring to the highest SES) defined by a socioeconomic index, derived by the characteristics of the census tract of residence. The effect of gender, age, illness severity and SES, on risk of non-admission to CCU was investigated using a logistic regression model (OR, CI 95%). RESULTS: Only 53.9% of patients were directly admitted to CCU, and access to optimal care was more frequently offered to younger patients (OR = 0.35; 95%CI = 0.25–0.48 when comparing 85+ to >=50 years), those with less severe illness (OR = 0.48; 95%CI = 0.37–0.61 when comparing Charlson index 3+ to 0) and the socially advantaged (OR = 0.81; 95%CI = 0.66–0.99 when comparing low to high SES). CONCLUSION: In Rome, Italy, standard optimal coronary care is underprovided. It seems to be granted preferentially to the better off, even after controversial clinical criteria, such as age and severity of illness, are taken into account

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial

Background: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.Methods: STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously.Results: The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity.Conclusion: It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials