James Howard

Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis.

Objective To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function. Design Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information. Data sources PubMed and Embase from inception to April 2013. Eligibility for selecting studies Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction. Results There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman’s r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of −0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%. Conclusions Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero.

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial

BACKGROUND Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. INTERPRETATION In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with focus on trial design: the CONVERGE report

Objective 30 mm Hg drops in office systolic blood pressure are reported in trials of renal denervation, but ambulatory reductions are much smaller. This disparity is assumed to have a physiological basis and also be present with antihypertensive drugs. Design We examine this office-ambulatory discrepancy through meta-analysis of drug and denervation trials, categorising by trial design. Patients (studies) 31 drug trials enrolling 4121 patients and 23 renal denervation trials enrolling 720 patients met the criteria. Results In drug trials without randomisation or blinding, pressure reductions are 5.6 mm Hg (95% CI 2.98 to 8.22 mm Hg) larger on office measurements than ambulatory blood pressure monitoring (p<0.0001). By contrast, with randomisation and blinding, office reductions are identical to ambulatory reductions (difference −0.88 mm Hg, 95% CI −3.18 to 1.43, p=0.45). For renal denervation, there are no randomised blinded trial results. In unblinded trials, office pressure drops were 27.6 mm Hg versus pretreatment, and 26.6 mm Hg versus unintervened controls. By contrast, ambulatory pressure drops averaged 15.7 mm Hg across all trials. Among those where the baseline ambulatory pressure was not the deciding factor for enrolment (avoiding regression to the mean), ambulatory drops averaged only 11.9 mm Hg. Conclusions Discrepancies in drug trials between office and ambulatory blood pressure reductions disappear once double-blinded placebo control is implemented. Renal denervation trials may also undergo similar evolution. We predict that as denervation trial designs gradually improve in bias-resistance, office and ambulatory pressure drops will converge. We predict that it is the office drops that will move to match the ambulatory drops, that is, not 30, but nearer 13.

2014 Global geographic analysis of mortality from ischaemic heart disease by country, age and income: Statistics from World Health Organisation and United Nations

Background Ischaemic heart disease (IHD) is the leading cause of death worldwide and its prevention is a public health priority. Method We analysed worldwide IHD mortality data from the World Health Organisation as of February 2014 by country, age and income. Age-standardised mortality rates by country were calculated. We constructed a cartogram which is an algorithmically transformed world map that conveys numbers of deaths in the form of spatial area. Results Of the countries that provided mortality data, Russia, the United States of America and Ukraine contributed the largest numbers of deaths. India and China were estimated to have even larger numbers of deaths. Death rates from IHD increase rapidly with age. Crude mortality rates appear to be stable whilst age-standardised mortality rates are falling. Over half of the worlds countries (113/216) have provided IHD mortality data for 2008 or later. Of these, 13 countries provided data in 2012. No countries have yet provided 2013 data. Of the 103 remaining countries, 24 provided data in 2007 or earlier, and 79 have never provided data in the ICD9 or ICD10 format. Conclusions In the countries for which there are good longitudinal data, predominantly European countries, recent years have shown a continuing decline in age-standardised IHD mortality. However, the progressive aging of populations has kept crude IHD mortality high. It is not known whether the pattern is consistent globally because many countries have not provided regular annual data including wealthy countries such as the United Arab Emirates and large countries such as India and China.

Removing the hype from hypertension

Symplicity HTN-3 illustrates the importance of randomisation and blinding for exciting new treatments

Implantable cardioverter defibrillators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials

Abstract Aims Primary prevention implantable cardioverter defibrillators (ICDs) are established therapy for reducing mortality in patients with left ventricular systolic dysfunction and ischaemic heart disease (IHD). However, their efficacy in patients without IHD has been controversial. We undertook a meta-analysis of the totality of the evidence. Methods and results We systematically identified all RCTs comparing ICD vs. no ICD in primary prevention. Eligible RCTs were those that recruited patients with left ventricular dysfunction, reported all-cause mortality, and presented their results stratified by the presence of IHD (or recruited only those with or without). Our primary endpoint was all-cause mortality. We identified 11 studies enrolling 8567 participants with left ventricular dysfunction, including 3128 patients without IHD and 5439 patients with IHD. In patients without IHD, ICD therapy reduced mortality by 24% (HR 0.76, 95% CI 0.64 to 0.90, P = 0.001). In patients with IHD, ICD implantation (at a dedicated procedure), also reduced mortality by 24% (HR 0.76, 95% CI 0.60 to 0.96, P = 0.02). Conclusions Until now, it has never been explicitly stated that the patients without IHD in COMPANION showed significant survival benefit from adding ICD therapy (to a background of CRT). Even before DANISH, meta-analysis of patients without ischaemic heart disease already showed reduced mortality. DANISH is consistent with these data. With a significant 24% mortality reduction in both aetiologies, it may no longer be necessary to distinguish between them when deciding on primary prevention ICD implantation.

Quantifying the 3 Biases That Lead to Unintentional Overestimation of the Blood Pressure–Lowering Effect of Renal Denervation

Background—Studies of renal denervation report disparate results. Meta-analysis by trial design may allow quantitative estimation of sources and magnitude of biases in denervation studies. Methods and Results—One hundred forty nonrandomized, 6 randomized open-label, and 2 randomized blinded studies were analyzed for 2 outcomes: (1) blood pressure changes for nonrandomized, open-label randomized, and blinded studies; and (2) quantification of 3 biases potentially contributing to apparent antihypertensive effects: (a) regression to the mean, (b) asymmetrical data handling, and (c) true blood pressure drops caused by something other than the tested therapy (confounding). Nonrandomized studies and open-label randomized trials reported large reductions in office blood pressure of 23.6 mm Hg (95% confidence interval [CI], 22.0 to 25.3) and 29.1 mm Hg (95% CI, 25.2 to 33.1 mm Hg), respectively. They reported smaller reductions in ambulatory blood pressures (11.2 mm Hg; 95% CI, 10.0 to 12.4). The blinded trials found no significant reduction in blood pressure (2.9 mm Hg; 95% CI, −0.4 to 6.3). Analyses of these data indicate the magnitude of the 3 potential sources of bias to be regression to the mean, −1.01 mm Hg (95% CI, 4.24 to −6.27); asymmetrical data handling, −10.8 mm Hg (95% CI, −8.77 to −12.87); and confounding, −8.3 mm Hg (95% CI, −4.73 to −11.83). Conclusions—Increasingly bias-resistant trial designs report effect sizes of decreasing magnitude. This disparity may be caused by asymmetrical data handling and confounding (eg, increased drug adherence). If these differences are caused by trial design and not by some other differences in patients or procedures, which happen to match the trial design, then randomization alone is not enough: blinding is also needed. This has broad implications across trials of medications and devices.

Patent foramen ovale closure vs. medical therapy for cryptogenic stroke: a meta-analysis of randomized controlled trials

Abstract Aims The efficacy of patent foramen ovale (PFO) closure for cryptogenic stroke has been controversial. We undertook a meta-analysis of randomized controlled trials (RCTs) comparing device closure with medical therapy to prevent recurrent stroke for patients with PFO. Methods and results We systematically identified all RCTs comparing device closure to medical therapy for cryptogenic stroke in patients with PFO. The primary efficacy endpoint was recurrent stroke, analysed on an intention-to-treat basis. The primary safety endpoint was new onset atrial fibrillation (AF). Five studies (3440 patients) were included. In all, 1829 patients were randomized to device closure and 1611 to medical therapy. Across all patients, PFO closure was superior to medical therapy for prevention of stroke [hazard ratio (HR) 0.32, 95% confidence interval (95% CI) 0.13–0.82; P = 0.018, I2 = 73.4%]. The risk of AF was significantly increased with device closure [risk ratio (RR) 4.68, 95% CI 2.19–10.00, P<0.001, heterogeneity I2 = 27.5%)]. In patients with large shunts, PFO closure was associated with a significant reduction in stroke (HR 0.33, 95% CI 0.16–0.72; P = 0.005), whilst there was no significant reduction in stroke in patients with a small shunt (HR 0.90, 95% CI 0.50–1.60; P = 0.712). There was no effect from the presence or absence of an atrial septal aneurysm on outcomes (P = 0.994). Conclusion In selected patients with cryptogenic stroke, PFO closure is superior to medical therapy for the prevention of further stroke: this is particularly true for patients with moderate-to-large shunts. Guidelines should be updated to reflect this.

Hierarchical Statistical Techniques are Necessary to Draw Reliable Conclusions from Analysis of Isolated Cardiomyocyte Studies.

Abstract Aims It is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests). Methods and results Ca2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF. Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF. Conclusion Ca2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for reliable conclusions. We present cost-free simple tools for performing these analyses.

Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Single-Vessel Coronary Artery Disease: Physiology-Stratified Analysis of ORBITA

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], –4.0 to 45.5; P=0.100) with no interaction of FFR (Pinteraction=0.318) or iFR (Pinteraction=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR (Pinteraction<0.00001) and decreasing iFR (Pinteraction<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96–2.80; P=0.072) with no detectable evidence of interaction with FFR (Pinteraction=0.849) or iFR (Pinteraction=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P=0.006) but neither FFR (Pinteraction=0.693) nor iFR (Pinteraction=0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.