Arne Ring

Complete Versus Lesion-Only Primary PCI: The Randomized Cardiovascular MR CvLPRIT Substudy

Background Complete revascularization may improve outcomes compared with an infarct-related artery (IRA)-only strategy in patients being treated with primary percutaneous coronary intervention (PPCI) who have multivessel disease presenting with ST-segment elevation myocardial infarction (STEMI). However, there is concern that non-IRA PCI may cause additional non-IRA myocardial infarction (MI). Objectives This study sought to determine whether in-hospital complete revascularization was associated with increased total infarct size compared with an IRA-only strategy. Methods This multicenter prospective, randomized, open-label, blinded endpoint clinical trial evaluated STEMI patients with multivessel disease having PPCI within 12 h of symptom onset. Patients were randomized to either IRA-only PCI or complete in-hospital revascularization. Contrast-enhanced cardiovascular magnetic resonance (CMR) was performed following PPCI (median day 3) and stress CMR at 9 months. The pre-specified primary endpoint was infarct size on pre-discharge CMR. The study had 80% power to detect a 4% difference in infarct size with 100 patients per group. Results Of the 296 patients in the main trial, 205 participated in the CMR substudy, and 203 patients (98 complete revascularization and 105 IRA-only) completed the pre-discharge CMR. The groups were well-matched. Total infarct size (median, interquartile range) was similar to IRA-only revascularization: 13.5% (6.2% to 21.9%) versus complete revascularization, 12.6% (7.2% to 22.6%) of left ventricular mass, p = 0.57 (95% confidence interval for difference in geometric means 0.82 to 1.41). The complete revascularization group had an increase in non-IRA MI on the pre-discharge CMR (22 of 98 vs. 11 of 105, p = 0.02). There was no difference in total infarct size or ischemic burden between treatment groups at follow-up CMR. Conclusions Multivessel PCI in the setting of STEMI leads to a small increase in CMR-detected non-IRA MI, but total infarct size was not significantly different from an IRA-only revascularization strategy. (Complete Versus Lesion-Only Primary PCI Pilot Study [CvLPRIT]; ISRCTN70913605)

A randomised controlled trial of six weeks of home enteral nutrition versus standard care after oesophagectomy or total gastrectomy for cancer: report on a pilot and feasibility study

BackgroundPoor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients.MethodsPatients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences.ResultsFifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI −0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI −1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process.ConclusionsThis study demonstrated that home enteral feeding by jejunostomy was feasible, safe and acceptable to patients and their carers. Whether home enteral feeding as ’usual practice’ is a cost-effective therapy would require confirmation in an appropriately powered, multi-centre study.Trial registrationUK Clinical Research Network ID 12447 (main trial, first registered 30 May 2012); UK Clinical Research Network ID 13361 (qualitative substudy, first registered 30 May 2012); ClinicalTrials.gov NCT01870817 (first registered 28 May 2013)

Evaluation of a tailored intervention to improve management of overweight and obesity in primary care: study protocol of a cluster randomised controlled trial

BackgroundIn the UK around 22% of men and 24% of women are obese, and there are varying but worrying levels in other European countries. Obesity is a chronic condition that carries an important health risk. National guidelines, for use in England, on the management of people who are overweight or obese have been published by the National Institute for Health and Clinical Excellence (NICE, 2006). NICE recommendations for primary care teams are: determine the degree of overweight and obesity; assess lifestyle, comorbidities and willingness to change; offer multicomponent management of overweight and obesity; referral to external services when appropriate. This study investigates a tailored intervention to improve the implementation of these recommendations by primary care teams.Methods/DesignThe study is a cluster randomised controlled trial. Primary care teams will be recruited from the East Midlands of England, and randomised into two study arms: 1) the study group, in which primary care teams are offered a set of tailored interventions to help implement the NICE guidelines for overweight and obesity; or 2) the control group in which primary care teams continue to practice usual care. The primary outcome is the proportion of overweight or obese patients for whom the primary care team adheres to the NICE guidelines. Secondary outcomes include the proportion of patients with a record of lifestyle assessment, referral to external weight loss services, the proportion of obese patients who lose weight during the intervention period, and the mean weight change over the same period.DiscussionAlthough often recommended, the methods of tailoring implementation interventions to account for the determinants of practice are not well developed. This study is part of a programme of studies seeking to develop the methods of tailored implementation.Trial registrationCurrent Controlled Trials ISRCTN07457585. Registered 09/08/2013. Randomisation commenced 30/08/2013.

Cluster randomised trial of a tailored intervention to improve the management of overweight and obesity in primary care in England.

BackgroundTailoring is a frequent component of approaches for implementing clinical practice guidelines, although evidence on how to maximise the effectiveness of tailoring is limited. In England, overweight and obesity are common, and national guidelines have been produced by the National Institute for Health and Care Excellence. However, the guidelines are not routinely followed in primary care.MethodsA tailored implementation intervention was developed following an analysis of the determinants of practice influencing the implementation of the guidelines on obesity and the selection of strategies to address the determinants. General practices in the East Midlands of England were invited to take part in a cluster randomised controlled trial of the intervention. The primary outcome measure was the proportion of overweight or obese patients offered a weight loss intervention. Secondary outcomes were the proportions of patients with (1) a BMI or waist circumference recorded, (2) record of lifestyle assessment, (3) referred to weight loss services, and (4) any change in weight during the study period. We also assessed the mean weight change over the study period. Follow-up was for 9xa0months after the intervention. A process evaluation was undertaken, involving interviews of samples of participating health professionals.ResultsThere were 16 general practices in the control group, and 12 in the intervention group. At follow-up, 15.08xa0% in the control group and 13.19xa0% in the intervention group had been offered a weight loss intervention, odds ratio (OR) 1.16, 95xa0% confidence interval (CI) (0.72, 1.89). BMI/waist circumference measurement 42.71xa0% control, 39.56xa0% intervention, OR 1.15 (CI 0.89, 1.48), referral to weight loss services 5.10xa0% control, 3.67xa0% intervention, OR 1.45 (CI 0.81, 2.63), weight management in the practice 9.59xa0% control, 8.73xa0% intervention, OR 1.09 (CI 0.55, 2.15), lifestyle assessment 23.05xa0% control, 23.86xa0% intervention, OR 0.98 (CI 0.76, 1.26), weight loss of at least 1xa0kg 42.22xa0% control, 41.65xa0% intervention, OR 0.98 (CI 0.87, 1.09). Health professionals reported the interventions as increasing their confidence in managing obesity and providing them with practical resources.ConclusionsThe tailored intervention did not improve the implementation of the guidelines on obesity, despite systematic approaches to the identification of the determinants of practice. The methods of tailoring require further development to ensure that interventions target those determinants that most influence implementation.Trial registrationISRCTN07457585

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI-1 study

AIMS Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. METHODS We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. RESULTS Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, Cmax 189.4 ng ml−1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. CONCLUSIONS Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.

Indirect bioequivalence assessment using network meta-analyses

AimsFor market approval, new drug formulations (test) must demonstrate bioequivalence (BE) to at least one approved formulation (reference). If several formulations of a drug are already on the market, one might have to show BE to more than one reference formulation. Similarly, if several test formulations have shown BE to a reference formulation, it will be of interest whether the test formulations are bioequivalent to each other.MethodsAn enhanced statistical model to assess BE indirectly through a network meta-analysis is provided. Statistical properties of a parallel and a bridging approach are derived, in particular the relative statistical efficiency of the two approaches. The analysis is illustrated using individual subject data from two 3×3 crossover trials of metformin formulations, which have one of the formulations in common.ResultsThe parallel estimate of relative bioavailability is confounded with between-trial differences, while the bridging estimate is not. The standard errors of the formulation differences using the bridging approach are smaller than the standard errors using the parallel approach if the within-subject correlation in each trial of the network is larger than 0.5. This is the condition for a crossover trial to be more efficient than a parallel trial, and thus is usually fulfilled in pharmacokinetic crossover trials.ConclusionsIndirect BE assessment offers the opportunity to efficiently determine the relative bioavailability of drug formulations that have not been studied in the same randomized BE trial. The methodology developed here allows estimating formulation differences across a larger network.

Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study

BackgroundThe CvLPRIT study showed a trend for improved clinical outcomes in the complete revascularisation (CR) group in those treated with an immediate, as opposed to staged in-hospital approach in patients with multivessel coronary disease undergoing primary percutaneous intervention (PPCI). We aimed to assess infarct size and left ventricular function in patients undergoing immediate compared with staged CR for multivessel disease at PPCI.MethodsThe Cardiovascular Magnetic Resonance (CMR) substudy of CvLPRIT was a multicentre, prospective, randomized, open label, blinded endpoint trial in PPCI patients with multivessel disease. These data refer to a post-hoc analysis in 93 patients randomized to the CR arm (63 immediate, 30 staged) who completed a pre-discharge CMR scan (median 2 and 4xa0days respectively) after PPCI. The decision to stage non-IRA revascularization was at the discretion of the treating interventional cardiologist.ResultsPatients treated with a staged approach had more visible thrombus (26/30 vs. 31/62, pu2009=u20090.001), higher SYNTAX score in the IRA (9.5, 8–16 vs. 8.0, 5.5–11, pu2009=u20090.04) and a greater incidence of no-reflow (23.3xa0% vs. 1.6xa0% pu2009<u20090.001) than those treated with immediate CR. After adjustment for confounders, staged patients had larger infarct size (19.7xa0% [11.7–37.6] vs. 11.6xa0% [6.8–18.2] of LV Mass, pu2009=u20090.012) and lower ejection fraction (42.2u2009±u200910xa0% vs. 47.4u2009±u20099xa0%, pu2009=u20090.019) compared with immediate CR.ConclusionsOf patients randomized to CR in the CMR substudy of CvLPRIT, those in whom the operator chose to stage revascularization had larger infarct size and lower ejection fraction, which persisted after adjusting for important covariates than those who underwent immediate CR. Prospective randomized trials are needed to assess whether immediate CR results in better clinical outcomes than staged CR.Trial registrationISRCTN70913605, Registered 24th February 2011.

How publication guidelines for clinical pharmacology trials may help to accelerate knowledge transfer

Reports and publications on late phase clinical trials and other medical research are nowadays highly regulated, in particular confirmatory trials aiming to demonstrate the efficacy and safety of health technologies. This does not only affect the actual submission of drug dossiers to health authorities to achieve marketing authorisation. It already starts with the registration of clinical trials in publicly available registers at the time when the study protocols have been finalised and extends to requirements and guidelines for publications in medical journals [1]. The key objective of these regulations is to achieve transparency how the research was actually planned, performed and analysed and which decisions had been made to accommodate unplanned situations. Thereby allowing the internal and external validity of the trial results to be judged, so that the interpretations and conclusions are comprehensible for readers. The targeted audience includes reviewers who are to decide whether an intended publication is fit to be presented to the wider scientific community. Thus, convincing the reader of the quality of one’s research means convincing the reviewer first. Accordingly, within the EQUATORnetwork (Enhancing the QUAlity and Transparency Of health Research), a large number of reporting recommendations have been developed. Starting with the CONSORT statement on confirmatory randomised parallel group clinical trials [2], there are now extensions for trials with particular designs (e.g. equivalence trials or N-of-1 trials), but also more general fields like systematic reviews (PRISMA) or diagnostic/prognostic studies. So it seems that most of the medical research has its own reporting guideline. Interestingly, these guidelines do not cover clinical pharmacology studies. There are some extensions that might appear to be closely related, such as the “reporting withinperson randomised trials,” or the “reporting randomised pilot and feasibility trials,” but a closer view clarifies that their overlap with clinical pharmacology is rather minor. For example, the “within-person trials” guideline does not cover conventional crossover trials (with sequential treatments), but trials in which two treatments are applied simultaneously to the same person (e.g. to both eyes, to teeth or to different places of the skin). The “pilot and feasibility trial” guideline focuses on the practical development of the trial design and its implementation for a confirmatory trial, rather than on the development of a pharmacological treatment in Phase I-IIa regarding pharmacokinetics, pharmacodynamics and proof of principle with “surrogates” like biomarkers. In a BJCP editorial about 2 years ago [3], it was asked whether clinical pharmacology would benefit from having such guidelines. On one hand, clinical pharmacology trials are very diverse, sometimes not randomised, with quite different objectives, designs, and analysis methods. On the other hand, the editors and reviewers of this journal and of other journals in this field will receive manuscripts of quite heterogeneous quality, and it sometimes takes a number of review cycles to expand a good research to a good publication. So it might be beneficial to have at least some general British Journal of Clinical Pharmacology Br J Clin Pharmacol (2018) 84 611–614 611

Statistical reporting of clinical pharmacology research

Research in clinical pharmacology covers a wide range of experiments, trials and investigations: clinical trials, systematic reviews and meta‐analyses of drug usage after market approval, the investigation of pharmacokinetic–pharmacodynamic relationships, the search for mechanisms of action or for potential signals for efficacy and safety using biomarkers. Often these investigations are exploratory in nature, which has implications for the way the data should be analysed and presented. Here we summarize some of the statistical issues that are of particular importance in clinical pharmacology research.

19 The randomised complete vs. lesion only primary PCI trial – cardiovascular MRI substudy (CVLPRIT-CMR)

Background Multivessel disease (MVD) occurs in ~40% of STEMI. Management is controversial. PRAMI and CVLPRIT showed improved clinical outcomes with complete versus infarct-related artery (IRA)-only revascularisation at primary percutaneous coronary intervention (PPCI). However, non-IRA PCI may cause additional infarcts. We aimed to determine whether in-hospital complete revascularisation was associated with increased myocardial injury versus an IRA-only strategy. Methods Multicentre, prospective, randomised, blinded endpoint trial. STEMI patients with MVD and <12 hr symptoms were randomised to IRA-only or complete in-hospital PCI. 1.5T CMR was performed acutely (median 3 days post-PPCI) and with adenosine stress at 9 months. The primary CMR endpoint was acute infarct size on late gadolinium imaging. Myocardial salvage index (MSI) was the proportion of non-infarcted area-at-risk. n = 100 per group gave 80% power to detect ±4% infarct size. The primary clinical outcome was 12 month combined MACE (death, repeat revascularisation, heart failure, MI). Validation studies optimised infarct, area-at-risk and strain quantification. Full-width half-maximum infarct quantification was more accurate, reproducible and correlated strongest with ejection fraction (LVEF) and infarct characteristics. Otsu’s Automated Thresholding most accurately and reproducibly assessed area-at-risk. Compared with tagging, Feature Tracking strain measurement was more robust, quicker, had better interobserver variability and correlated stronger with infarct, area-at-risk and MSI. Results (summarised in Table 1) 203 patients (98 complete revascularisation, 105 IRA-only) completed acute CMR. The groups were well matched. There was no difference in infarct size, MSI, LVEF, circumferential strain or ischaemic burden between groups. Complete revascularisation patients had increased non-IRA MI at acute CMR (Figure 1). 12 month MACE was reduced in complete revascularisation patients (8.2% vs. 17.1%, p = 0.055, hazard ratio 0.43). Conclusions Complete revascularisation in STEMI with MVD leads to a small increase in CMR-detected non-IRA MI, but total infarct size and 12 month MACE are not increased. This provides further reassurance that complete revascularisation can be considered at PPCI. Abstract 19 Table 1 Baseline, angiographic and CMR characteristics Variable IRA-only revascularisation (n = 105) Complete revascularisation (n = 98) p Baseline characteristics Age (y) 64.1 ± 10.8 63.1 ± 11.3 0.53 Male sex (n,%) 83/105 (79.0) 87/98 (88.8) 0.06 Anterior infarct (n,%) 37/105 (37.2) 35/98 (35.7) 0.94 Diabetes Mellitus (n,%) 13/105 (12.4) 15/98 (15.3) 0.55 Angiographic markers TIMI pre PCI grade 0–2 (n,%) 97/105 (92.4) 89/98 (90.8) 0.69 SYNTAX score (total) 18 (14–22) 17.3 (13–23.5) 0.81 Symptom-PCI time (TTR, min) 171 (127–268) 192 (131–302) 0.20 TIMI post PCI grade 3 (n,%) 100/105 (95.2) 89/98 (90.8) 0.21 Acute CMR Time to acute CMR (d) 2.8 (1.8–3.4) 3.0 (2.0–4.3) 0.13 LV ejection fraction (%) 45.1 ± 9.5 45.9 ± 9.9 0.60 Peak LV circumferential strain (Ecc,%) −18.1 ± 6.0 -18.6 ± 6.1 0.86 Total infarct size (% LV mass) 13.5 (6.2–21.9) 12.6 (7.2–22.6) 0.57 Patients with >1 infarct 11/105 (10.5) 22/98 (22.4) 0.02 Patients >1 acute infarct 5/105 (4.8) 17/98 (17.1) 0.004 Myocardial salvage index (%) 60.5 (40.6–81.9) 58.5 (32.8–74.9) 0.14 Follow-up CMR Time to follow-up CMR (CMR2, mth) 9.3 (8.9–9.9) 9.4 (9.0–10) 0.20 LV ejection fraction (%) 50.8 ± 8.7 49.7 ± 9.4 0.42 Peak LV circumferential strain (Ecc,%) −23.6 ± 6.3 −22.5 ± 6.3 0.28 Total infarct size (% LV mass) 7.6 (3.2–15.1) 7.3 (3.0–14.4) 0.41 Patients with >1 infarct (%) 9/80 (11.2) 20/84 (23.8) 0.035 Presence of ischaemia (n,%) in all pats 16/77 (20.8) 17/82 (20.7) 0.99 Global ischaemic burden (%) all pats 4.3 ± 11.3 3.4 ± 8.9 0.81 Abstract 19 Figure 1 Multiple infarcts on late gadolinium imaging in complete revascularisation patients The 2 images on left and 2 images on right are 2 different patients. A = main infarct-related artery territory infarct B = infarct in non-infarct related artery territory