Cardiovascular Intervention Trials Research Articles

Ascertainment and Statistical Issues for Randomized Trials of Cardiovascular Interventions for Cognitive Impairment and Dementia.

There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up.

P2Y12 inhibitors in neuroendovascular surgery: An opportunity for precision medicine.

Dual antiplatelet therapy (DAPT), primarily the combination of aspirin with a P2Y12 inhibitor, in patients undergoing intravascular stent or flow diverter placement remains the primary strategy to reduce device-related thromboembolic complications. However, selection, timing, and dosing of DAPT is critical and can be challenging given the existing significant inter- and intraindividual response variations to P2Y12 inhibitors. Assessment of indexed, peer-reviewed literature from 2000 to 2020 in interventional cardiology and neuroendovascular therapeutics with critical, peer-reviewed appraisal and extraction of evidence and strategies to utilize DAPT in cardio- and neurovascular patients with endoluminal devices. Both geno- and phenotyping for DAPT are rapidly and conveniently available as point-of-care testing at a favorable cost-benefit ratio. Furthermore, systematic inclusion of a quantifying clinical risk score combined with an operator-linked, technical risk assessment for potential adverse events allows a more precise and individualized approach to new P2Y12 inhibitor therapy. The latest evidence, primarily obtained from cardiovascular intervention trials, supports that combining patient pharmacogenetics with drug response monitoring, as part of an individually tailored, precision medicine approach, is both predictive and cost-effective in achieving and maintaining individual target platelet inhibition levels. Indirect evidence supports that this gain in optimizing drug responses translates to reducing main adverse events and overall treatment costs in patients undergoing DAPT after intracranial stent or flow diverting treatment.

Reporting of sex-specific outcomes in trials of interventions for cardiovascular disease: Has there been progress?

In the past decade, the leading international cardiology societies have released statements that emphasize the importance of sex-specific reporting of the findings of clinical trials in cardiovascular research. To find out whether this has led to improvement, we compared sex-specific reporting of efficacy and safety outcomes for trials of cardiovascular drug interventions presented at the major clinical trials sessions of the European Society of Cardiology (ESC), American Heart Association (AHA) and the American College of Cardiology (ACC) before and after publication of these statements. We found that sex-specific efficacy and safety outcomes of the most influential cardiovascular intervention trials are still not systematically presented.

The Cost of Innovation and Evidence in Cardiac Surgery.

This review summarizes a systematic analysis of 216 randomized trials of cardiovascular interventions performed during 2008-2019, according to the source of trial funding. The systematic analysis showed that on average the results of each trial would change significance if only 5 patients experienced different outcomes. Industry-sponsored trials were more likely to use composite endpoints, noninferiority designs, and twice as likely as nonindustry trials to report results favoring the device arm. Over 80% of industry trials used reporting strategies or "spin" suggesting the device arm was advantageous versus fewer than half of non-industry trials. The review discusses the implications of these findings.

Assessement of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes

Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority. To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit. This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018. Incident vascular events and diabetes and statin therapy. Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial. Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging. The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies. isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630.

Molecular Actions of PPARα in Lipid Metabolism and Inflammation.

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.

Representation of Patients With Kidney Disease in Trials of Cardiovascular Interventions: An Updated Systematic Review.

Representation of Patients With Kidney Disease in Trials of Cardiovascular Interventions: An Updated Systematic Review.

Publication of Trials Funded by the National Heart, Lung, and Blood Institute

BackgroundRapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized.MethodsWe analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal.ResultsAs of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan–Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P=0.004) and higher costs of conducting the trial, up to a threshold of approximately $5 million (P<0.001). The 37 trials that focused on clinical events and cost at least $5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative.ConclusionsResults of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.)

Short Communication: Dating Components of Human Atherosclerotic Plaques

Atherosclerotic plaques that give rise to acute clinical symptoms are typically characterized by degradation of the connective tissue and plaque rupture. Experimental studies have shown that mechanisms to repair vulnerable lesions exist, but the rate of remodeling of human plaque tissue has not been studied. In the present study, we determined the biological age of different components of advanced human atherosclerotic plaques by analyzing tissue levels of (14)C released into the atmosphere during the nuclear weapons tests in the late 1950s and early 1960s. Atherosclerotic plaques were obtained from 10 patients (age 46 to 80 years) undergoing carotid surgery. Different regions of the plaques were dissected and analyzed for (14)C content using accelerator mass spectrometry. At the time of surgery, the mean biological age of the cap region was 6.4+/-3.2 years, which was significantly lower than that of the shoulder region (12.9+/-3.0 years, P<0.01), the interface toward the media (12.4+/-3.3 years, P<0.01), and the core (9.8+/-4.5 years, P<0.05). Analysis of proliferative activity and rate of apoptosis showed no signs of increased cellular turnover in the cap, suggesting that the lower (14)C content reflected a more recent time of formation. These results show that the turnover time of human plaque tissue is very long and may explain why regression of atherosclerotic plaque size rarely is observed in cardiovascular intervention trials.

Recent Clinical Trials of Pharmacologic Cardiovascular Interventions in Patients with Chronic Kidney Disease

End stage kidney disease (ESKD) is associated with a 10- to 20-fold increased risk of cardiovascular mortality compared with age- and sex-matched controls without CKD. In spite of this marked increase in risk, the vast majority of cardiovascular intervention clinical trials to date have specifically excluded subjects with CKD. The aim of this paper is to critically review the recently published clinical trial evidence that cardiac outcomes in CKD patients are modified by cardiovascular risk factor interventions, including erythropoiesis stimulating agent therapy (US Normal Hematocrit, CHOIR and CREATE trials), statins (PPP, 4D and ALERT), fibrates (VA-HIT), folic acid (ASFAST, US folic acid trial, HOST), anti-oxidative stress therapy (SPACE, HOPE and ATIC), N-acetylcysteine, sevelamer (D-COR), cinacalcet (Cunningham meta-analysis), carvedilol, angiotensin converting enzyme inhibitor (FOSIDIAL), telmisartan, aspirin (HOT study re-analysis) and multidisciplinary multiple cardiovascular risk factor intervention clinics (LANDMARK). Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of CKD or because the pathogenesis of cardiovascular disease in CKD patients is different to that in the general population. Further large, well-conducted, multi-centre randomised controlled trials in this area are urgently required.

Poststroke Care

See related article, pages 1899–1904. “Thinking is easy, acting is difficult, and to put one’s thoughts into action is the most difficult thing in the world”. — —Goethe (1749–1832) Major advances in acute stroke management have been seen over the past decade, including the use of thrombolysis, antithrombotic therapy, and organized in-hospital stroke care. However, relatively few studies have evaluated the effectiveness of these interventions in routine clinical practice, or have assessed issues related to delivery of services, access to care, and long-term care after discharge from stroke. In this issue of Stroke , Bravata et al1 contribute to our understanding of outcomes after stroke by analyzing readmissions and deaths in the first 5 years after a hospitalization for stroke. The target population included stroke survivors aged over 65 years who were Medicare beneficiaries and who were discharged from Connecticut acute care hospitals in 1995. This population was followed from discharge in 1995 through 2000 using Medicare claims and Social Security Administration mortality data. Among 2603 patients discharged alive, 40% were readmitted at least once within the first year of discharge, 53% had died or been readmitted within 1 year and only 15% survived admission-free for 5 years. Leading causes for readmission included pneumonia (8.2% to 9.0%), stroke (3.9% to 6.1%) and acute myocardial infarction (4.2% to 6.0%). There was no apparent association between length of hospital stay and readmission rate (unreported data kindly provided by the authors, 2007), and no information was available on potential patient and system factors associated with higher hospital readmission rates. Lower readmission rates of 25% to 27% within 1 year have been previously reported.2,3 These studies found that the average number of days of rehospitalization was 23.2 Stroke was the single most frequent reason for readmission followed by cardiac disease, …

Modification of cardiovascular risk in hemodialysis patients: An evidence‐based review

Cardiovascular disease accounts for 40% to 50% of deaths in dialysis populations. Overall, the risk of cardiac mortality is 10-fold to 20-fold greater in dialysis patients than in age and sex-matched controls without chronic kidney disease. The aim of this paper is to review critically the evidence that cardiac outcomes in dialysis patients are modified by cardiovascular risk factor interventions. There is limited, but as yet inconclusive controlled trial evidence that cardiovascular outcomes in dialysis populations may be improved by antioxidants (vitamin E or acetylcysteine), ensuring that hemoglobin levels do not exceed 120 g/L (especially in the setting of known cardiovascular disease), prescribing carvedilol in the setting of dilated cardiomyopathy, and by using cinacalcet in uncontrolled secondary hyperparathyroidism. Similarly, there are a number of negative controlled trials, which have demonstrated that statins, high-dose folic acid, angiotensin-converting enzyme inhibitors, multiple risk factor intervention via multidisciplinary clinics, and high-dose or high-flux dialysis are ineffective in preventing cardiovascular disease. Although none of these studies could be considered conclusive, the negative trials to date should raise significant concerns about the heavy reliance of current clinical practice guidelines on extrapolation of findings from cardiovascular intervention trials in the general population. It may be that cardiovascular disease in dialysis populations is less amenable to intervention, either because of the advanced stage of chronic kidney disease or because the pathogenesis of cardiovascular disease in dialysis patients is different from that in the general population. Large, well-conducted, multicenter randomized-controlled trials in this area are urgently required.

Diabetes and cardiovascular intervention trials in Australia (DACIT)

Diabetes and cardiovascular intervention trials in Australia (DACIT)

West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials

We assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of coronary heart disease (CHD) by lipid lowering with the benefits of blood pressure reduction in the primary prevention of stroke. We did a subgroup analysis of placebo-treated men in the WOSCOPS population by age, vascular disease at trial entry, and other established risk factors. We also compared WOSCOPS findings with those of the Scandinavian Simvastatin Survival Study (4S) and the Medical Research Council (MRC) trial of treatment for mild to moderate hypertension in middle-aged men. The WOSCOPS population comprised 6595 men aged 45-64 years with no history of myocardial infarction (MI) and plasma total cholesterol concentrations of 6.5-8.0 mmol/L at initial screening. Participants were randomly allocated pravastatin (40 mg daily) or placebo, and followed up for an average of 4.9 years. Coronary event rates at 5 years in the WOSCOPS placebo group were higher than 10% (the recommended treatment threshold) in men with pre-existing vascular disease and in those 55 years or older without symptoms or signs of CHD but with at least one other risk factor. Event rates were low in men with hypercholesterolaemia but no other risk factor: 3.5% (95% CI 1.3-5.7) for men aged 45-54 years and 5.3% (2.7-8.0) for men aged 55-64 years. Three times more men had to be treated for 5 years to prevent one endpoint in WOSCOPS than in 4S. By contrast, two to four times fewer men with hyperlipidaemia were treated to save one coronary event in WOSCOPS than hypertensives to save one stroke in the MRC trial. These differences persisted after adjustment for the low-risk status of many of the patients with hypertension who took part in the MRC trial. There were a substantial number of men whose risk of a coronary event was more than 10% at 5 years in the WOSCOPS cohort. The absolute benefit of pravastatin treatment of hyperlipidaemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged men.

Meaningful Interpretation of Risk Reduction from Clinical Drug Trials

To illustrate the concepts of relative and absolute risk reduction, and by example, present and discuss the results of prevention trials that have evaluated the impact of drug therapy on cardiovascular disease. Additional approaches to evaluating the results of prevention trials are also presented. Data were gathered from eight frequently quoted major cardiovascular intervention trials. Reference to large reductions in relative risk in review papers, newspapers, and at professional meetings can lead to false expectations among clinicians and patients regarding the potential impact of the treatment in individual patients. When making decisions about preventive drug therapy, clinicians are encouraged to examine measures other than relative risk reduction and to include the patient in the decision process. Educators should emphasize these other measures of outcome and not rely solely on relative risk reduction in discussing particular areas of therapeutics.