Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials.MethodsWe conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Results57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3–5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06–1.73; p = 0.01).ConclusionThis meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.     

Effect of Antioxidant Vitamin Supplementation on Cardiovascular Outcomes: A Meta-Analysis of Randomized Controlled Trials

Background

Antioxidant vitamin (vitamin E, beta-carotene, and vitamin C) are widely used for preventing major cardiovascular outcomes. However, the effect of antioxidant vitamin on cardiovascular events remains unclear.

Methodology and Principal Findings

We searched PubMed, EmBase, the Cochrane Central Register of Controlled Trials, and the proceedings of major conferences for relevant literature. Eligible studies were randomized controlled trials that reported on the effects of antioxidant vitamin on cardiovascular outcomes as compared to placebo. Outcomes analyzed were major cardiovascular events, myocardial infarction, stroke, cardiac death, total death, and any possible adverse events. We used the I² statistic to measure heterogeneity between trials and calculated risk estimates for cardiovascular outcomes with random-effect meta-analysis. Independent extraction was performed by two reviewers and consensus was reached. Of 293 identified studies, we included 15 trials reporting data on 188209 participants. These studies reported 12749 major cardiovascular events, 6699 myocardial infarction, 3749 strokes, 14122 total death, and 5980 cardiac deaths. Overall, antioxidant vitamin supplementation as compared to placebo had no effect on major cardiovascular events (RR, 1.00; 95%CI, 0.96–1.03), myocardial infarction (RR, 0.98; 95%CI, 0.92–1.04), stroke (RR, 0.99; 95%CI, 0.93–1.05), total death (RR, 1.03; 95%CI, 0.98–1.07), cardiac death (RR, 1.02; 95%CI, 0.97–1.07), revascularization (RR, 1.00; 95%CI, 0.95–1.05), total CHD (RR, 0.96; 95%CI, 0.87–1.05), angina (RR, 0.98; 95%CI, 0.90–1.07), and congestive heart failure (RR, 1.07; 95%CI, 0.96 to 1.19).

Conclusion/Significance

Antioxidant vitamin supplementation has no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, total death, and cardiac death.     

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

Background aimsEvidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs.MethodsA systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19.ResultsEight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42–0.94, P = 0.02, I² = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB.ConclusionsMSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.     

Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management

ObjectiveImmune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)—rare but lethal endocrine immune-related adverse events—in patients who underwent ICI therapy.MethodsWe searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs.ResultsWe identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs.ConclusionGiven the morbidity and mortality associated with acute adrenal crisis, physicians—especially endocrinologists and oncologists—should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.     

Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies

ObjectiveTo compare risks of cardiovascular outcomes between patients with type 2 diabetes and patients with established coronary heart disease.DesignCross sectional study and cohort study using routinely collected datasets.SettingTayside, Scotland (population 400 000) during 1988-95.SubjectsIn the cross sectional study, among patients aged 45-64, 1155 with type 2 diabetes were compared with 1347 who had had a myocardial infarction in the preceding 8 years. In the cohort study 3477 patients of all ages with newly diagnosed type 2 diabetes were compared with 7414 patients who had just had a myocardial infarction.ResultsIn the cross sectional study the adjusted risk ratio for death from all causes was 2.27 (95% confidence interval 1.82 to 2.83) for patients who had had myocardial infarction compared with those with diabetes, and the risk ratio for hospital admission for myocardial infarction was 1.33 (1.14 to 1.55). In the cohort study, patients who had just had a myocardial infarction had a higher risk of death from all causes (adjusted risk ratio 1.35 (1.25 to 1.44)), cardiovascular death (2.93 (2.54 to 3.41)), and hospital admission for myocardial infarction (3.10 (2.57 to 3.73)).ConclusionsPatients with type 2 diabetes were at lower risk of cardiovascular outcomes than patients with established coronary heart disease.

What is already known on this topic

A recent influential study suggested that patients with type 2 diabetes without established cardiovascular disease have as high a risk of cardiovascular events and death as non-diabetic patients who have had a myocardial infarctionSome clinicians therefore advocate aggressive treatment of cardiovascular risk factors in the presence of diabetes

What this study adds

Patients with type 2 diabetes are at lower risk of death from all causes or cardiovascular causes and of hospital admission for myocardial infarction than patients with established coronary heart disease     

Characteristics of patients with lung cancer in clinical practice and their potential eligibility for clinical trials evaluating tyrosine kinase inhibitors or immune checkpoint inhibitors

IntroductionIn- and exclusion criteria of randomized clinical trials (RCTs) aim to include a homogeneous study-population. This study compared characteristics of lung cancer patients from phase III RCTs evaluating tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) with characteristics of lung cancer patients in a real world setting in the United Kingdom.MethodsA retrospective study was conducted using the Clinical Practice Research Datalink GOLD. Patients (N = 9239) with a first ever lung cancer registration between 2014 and 2018 were identified. Eligibility for inclusion was assessed for twelve RCTs (evaluating TKIs or ICIs). Reasons for potential exclusion and the number of unmet criteria were assessed for each RCT independently. OS was assessed using Kaplan-Meier and Cox proportional hazards analyses.ResultsThe proportion of potentially eligible patients was 74.3% and 51.9% for TKI and ICI RCTs, respectively. History of another malignancy, renal insufficiency or concomitant drug-use were main reasons for exclusion. OS was considerably longer for potentially eligible patients. Hazards ratios varied from 1.17 (95% confidence interval, 1.11–1.24) to 1.35 (1.20–1.42) across the RCTs.ConclusionThis study showed that a considerable proportion of lung cancer patients in a real-world setting would have been ineligible for participation in phase III RCTs and that potentially ineligible patients experienced a shorter OS.     

A systematic review and meta-analysis of immune checkpoint therapy in relapsed or refractory non-Hodgkin lymphoma; a friend or foe?

Over the last decades, a revolution has occurred in oncology with the development of immune checkpoint inhibitors (ICIs). Following tremendous successes in solid tumors, interest has risen to explore these inhibitors in hematologic malignancies; while Hodgkin's lymphoma (HL) has shown overwhelming achievements, available data on different types of non-Hodgkin's lymphoma (NHL) vary considerably. To the best of our knowledge, no meta-analysis has assessed the efficacy and safety of ICI therapy in relapsed or refractory NHL patients. Meta-analysis of the included studies (n = 29) indicated PD-1 may probably be the more attractive ICI target rather than PD-L1 and CTLA-4 in NHL patients. Also, there is a plausible correlation between NHL subtypes and response to ICI therapy. While MF, ENKTL, RT, and PMBCL showed promising responses to ICI monotherapy, neither FL nor DLBCL had satisfactory responses; further necessitating novel strategies such as the application of ICIs in combination with other treatment strategies. Notably, among different combinations, BTK inhibitors showed an obvious improvement as compared to ICI monotherapy in both FL and DLBCL, however, the best results were obtained when ICI was combined with anti-CD20 monoclonal antibodies. Finally, while most NHL patients who received ICI treatment have experienced mild AEs, larger trials with long-term follow-up are required to confirm the safety, as well as the efficacy, of ICI therapy in NHL patients.     

Oral contraceptives and myocardial infarction: results of the MICA case-control study

ObjectivesTo determine the association between myocardial infarction and use of different types of oral contraception in young women.DesignCommunity based case-control study. Data from interviews and general practice records.SettingEngland, Scotland, and Wales.ParticipantsCases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice.ResultsThe adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2.52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day.ConclusionsThere was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

Key message

• There is no evidence of a difference between second and third generation oral contraceptives on risk of myocardial infarction
• There is no significantly increased risk of myocardial infarction in users of oral contraceptives
• Of women aged under 45 years who suffered a myocardial infarction, 87% were not taking any oral contraceptive
• Of women who suffered myocardial infarction, 88% had one or more known cardiovascular risk factors
• Young women who wish to preserve cardiovascular health should be advised to stop smoking, above all else

     

Association between Number of Teeth and Chronic Systemic Diseases: A Cohort Study Followed for 13 Years

BackgroundThere is growing evidence of an association between oral health, specifically dental status, and chronic systemic diseases. However, varying measures of dental status across different populations and low study sample has made comparison of studies and conclusion of findings unclear. Our aim is to examine whether the number of teeth as a measure of dental status is associated with incident chronic diseases in a cohort setting.MethodsWe conducted a cohort study among 24,313 middle-aged Germans followed up for 13 years. Data on number of teeth as a measure of dental status were obtained through self-reports. Outcomes were clinically–verified incident non–fatal myocardial infarction, stroke, type 2 diabetes mellitus, and cancer. Hazard ratio (HR) and 95% confidence intervals (CI) were obtained from Cox regression models.ResultsIncreasing number of teeth is inversely related to risk of myocardial infarction (HR: 0.97; 95% CI: 0.96, 0.99). The full multivariate model of teeth groups showed a strong linear trend for myocardial infarction, a less strong trend for stroke, and no relation with type 2 diabetes mellitus and cancer in a competing risk model. Participants with 18–23 teeth and those without teeth were at 76% (95%CI: 1.04, 3) and 2.93 times (95%CI: 1.61, 5.18) higher risk of myocardial infarction compared to those with nearly all teeth (28–32 teeth).ConclusionsNumber of teeth is specifically associated with myocardial infarction and not with other chronic disease indicating that dental status further strengthens the link between oral health and cardiovascular diseases.     

Evaluation of Zhilong Huoxue Tongyu capsule in the treatment of acute cerebral infarction: A systematic review and meta-analysis of randomized controlled trials

BackgroundZhilong Huoxue Tongyu capsule (ZL) is a Chinese patent medicine and used for the treatment of acute cerebral infarction (ACI) and its clinical application has gradually been widely recognized in China. However, the effects of ZL for patients with ACI have never been systematically evaluated.PurposeA systematic review and meta-analysis was performed to evaluate the efficacy of ZL in ACI.Study designA systematic review and meta-analysis of randomized clinical trials (RCTs).Materials and methodsA systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The comprehensive literature search was accomplished in 6 electronic databases to find relevant randomized controlled trials from their inception until October 31, 2020. The Cochrane Handbook for Systematic Reviews of Interventions was used for methodological quality and independent evaluation. Review Manager 5.3 was used to analyze all the data obtained. The Clinical Effective Rate (CER) was the primary outcome, and the National Institutes of Health Stroke Score (NIHSS), Barthel Index (BI), and Modified Rankin Scale (MRS) were the secondary outcomes.ResultsSeven clinical studies recruiting 571 eligible patients were included in this meta-analysis. The results of meta-analysis suggested that compared with conventional treatment alone, ZL combined with conventional treatment significantly improved CER (RR = 1.20, 95% CI: 1.12-1.29, p < 0.00001), decrease National Institutes of Health Stroke Scale Score (NIHSS) (MD = -2.60, 95% CI: -3.41–1.79, p < 0.00001), Barthel Index (BI) (MD = -9.75, 95% CI: 7.15-12.36, p < 0.00001) and Modified Rankin Scale (MRS) (MD = -0.57, 95% CI: -0.84–0.30, p < 0.00001). There were no reported adverse events in the studies. Most results were robust and the quality of evidence was from moderate to low.ConclusionZL combined with conventional treatment can improve the short-term outcomes of ACI patients, indicating ZL is a promising treatment choice for ACI and may be used as adjunctive treatment to the conventional treatment of ACI. However, due to the limitations of included clinical trials, high-quality clinical trials with longer follow-ups are still needed to further assess the effectiveness and safety of ZL for ACI patients.     

Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta-analysis

Background

Folic acid is widely used to lower homocysteine concentrations and prevent adverse cardiovascular outcomes. However, the effect of folic acid on cardiovascular events is not clear at the present time. We carried out a comprehensive systematic review and meta-analysis to assess the effects of folic acid supplementation on cardiovascular outcomes.

Methodology and Principal Findings

We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings for relevant literature. We included randomized placebo-controlled trials that reported on the effects of folic acid on cardiovascular events compared to placebo. Of 1594 identified studies, we included 16 trials reporting data on 44841 patients. These studies reported 8238 major cardiovascular events, 2001 strokes, 2917 myocardial infarctions, and 6314 deaths. Folic acid supplementation as compared to placebo had no effect on major cardiovascular events (RR, 0.98; 95% CI, 0.93–1.04), stroke (RR, 0.89; 95% CI,0.78–1.01), myocardial infarction (RR, 1.00; 95% CI, 0.93–1.07), or deaths from any cause (RR, 1.00;95% CI, 0.96–1.05). Moreover, folic acid as compared to placebo also had no effect on the following secondary outcomes: risk of revascularization (RR, 1.05; 95%CI, 0.95–1.16), acute coronary syndrome (RR, 1.06; 95%CI, 0.97–1.15), cancer (RR, 1.08; 95%CI, 0.98–1.21), vascular death (RR, 0.94; 95%CI,0.88–1.02), or non-vascular death (RR, 1.06; 95%CI, 0.97–1.15).

Conclusion/Significance

Folic acid supplementation does not effect on the incidence of major cardiovascular events, stroke, myocardial infarction or all cause mortality.     

Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies

Background

Ischemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients.

Objective

To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation.

Methods and results

Using systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2–3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively.

Conclusions

Translation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence.     

Risk of developing hypothyroidism with the use of tyrosine kinase inhibitors and immune checkpoint inhibitors

BackgroundThe survival rate of patients with cancer has been increasing because of the sustained anticancer effect of new drugs, such as immune checkpoints inhibitors (ICI). Unlike the existing cytotoxic chemotherapies, immunotherapy causes immune system disturbance, such as hypothyroidism. Comparative studies on hypothyroidism following administration of ICI alone and in combination with other drugs are scarce. Therefore, we investigated the incidence of hypothyroidism after ICI in patients with cancer using a national population-based database.MethodsUsing the claims data from the Health Insurance Review and Assessment service in Korea, we retrospectively investigated patients with cancer who received chemotherapy between January 1, 2014 and February 28, 2021.ResultsOf all patients with cancer (n = 665,445) who received all kinds of chemotherapy, those who have received ICI accounted for 1.91 %. Compare with cytotoxic chemotherapy and angiogenesis inhibitors (AIs), ICI was associated with earlier (236.1 ± 248.4 vs. 811.1 ± 661.7, P < 0.01) and more frequent (7.7 % vs. 4.4 %, P < 0.01) occurrence of hypothyroidism, as well as an increased risk of developing hypothyroidism (odds ratio [OR] 1.69, 95 % confidence interval [CI] 1.58–1.80). However, the incidence of grade 2 or higher hypothyroidism was similar in both groups of patients who received ICI (3.3 %) and AI (3.1 %). The incidence of hypothyroidism was 4.4 times higher in patients who received both AI and ICI than in those who were treated with ICI alone (OR 4.41, 95 % CI 3.40–5.71).ConclusionsThis study showed a synergistic effect in patients who received multiple administrations of a drug that might be associated with thyroid dysfunction. Therefore, special attention should be paid to the treatment-related side effects when using drugs, such as AIs, concomitant with ICI treatment.     

Reporting on quality of life in randomised controlled trials: bibliographic study

ObjectivesTo examine the frequency and quality of reporting on quality of life in randomised controlled trials.DesignSearch of the Cochrane Controlled Trials Register 1980 to 1997 to identify trials from all disciplines, from oncology, and from cardiovascular medicine that reported on quality of life. Assessment of abstracts from articles published from 1993 to 1996. Assessment of a sample of full reports with a standardised instrument.ResultsDuring 1980-97 reporting on quality of life increased from 0.63% to 4.2% for trials from all disciplines, from 1.5% to 8.2% for cancer trials, and from 0.34% to 3.6% for cardiovascular trials. Of 364 abstracts, 65% reported on drug interventions. Of a sample of 67 full reports, authors of 48 (72%) used 62 established quality of life instruments. In 15 reports (22%) authors developed their own measures, and in 2 (3%) methods were unclear. Response rates were given in 38 (57%), and complete reporting on all items and scales occurred in 31 (46%).ConclusionsLess than 5% of all randomised controlled trials reported on quality of life, and this proportion was below 10% even for cancer trials. A plethora of instruments was used in different studies, and the reporting of methods and results was often inadequate. Standards for the measurement and reporting of quality of life in clinical trials research need to be developed.

Key messages

• We examined the reporting on quality of life in randomised controlled trials listed in the Cochrane Controlled Trials Register
• Although reporting on quality of life increased over time, fewer than 5% of trials overall and fewer than 10% of cancer trials included quality of life in 1997
• Among 67 articles selected at random for detailed examination, a wide range of established and self developed measures of quality of life were used
• Only about half of trials gave response rates, and less than half reported on all items and scales used
• Standards for assessing and reporting quality of life in clinical research trials need to be developed

     

Changes in the survival of adult patients with metastasized melanoma with the approval of immune checkpoint inhibitors: A retrospective study from the United States database

BackgroundImmune-checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic melanoma. Ipilimumab and Ipilimumab-Nivolumab combination therapies were approved by the United States Food and Drug Administration in 2011 and 2015, respectively. We aimed to evaluate potential changes in the survival of patients with metastatic melanoma following the approval of these agents.MethodsWe extracted data from the Surveillance, Epidemiology, and End Results (SEER) database (Nov 2021 submission). All patients aged 20 and above who were diagnosed with ‘distant’ melanoma (per ‘combined summary stage’) from 2007 through 2018 were included in the study. This time period was further sub-categorized into 2007–2010 (pre-ICI era), 2011–2014 (single-agent ICI era), and 2015–2018 (combination ICI era) based on the approval timeline of ICI.ResultsThe median overall survival (OS) was 8, 10, and 14 months in the pre-ICI, single-agent ICI, and combination ICI eras respectively (log-rank test, χ² = 189.03, p < 0.001). On Cox-proportional hazard analysis, patients diagnosed in the single-agent and combination ICI eras had a significantly lower risk of dying [HR 0.82 (95% CI 0.78–0.87) and 0.67 (0.64–0.71), respectively] compared to patients diagnosed in the pre-ICI era. Patients who were of the male gender, aged ≥ 65 years, and those receiving chemotherapy and/or radiotherapy were at a significantly higher risk of dying. Married individuals had a significantly lower risk of dying compared to patients who were divorced, separated, or widowed at the time of diagnosis. There was no significant difference in survival demonstrated among non-Hispanic blacks versus non-Hispanic whites.ConclusionSurvival of patients with metastatic melanoma has improved in the era of immune checkpoint inhibitors. It implies that the survival of patients reported in trials can be correlated at a population level as well. Future analysis from the SEER database is needed when new data becomes available to see if there is a further increase in OS.     

Sudden death and its predictors in myocardial infarction survivors in an Indian population

ObjectiveThis study was conducted to assess the incidence of sudden cardiac death (SCD) in post myocardial infarction patients and to determine the predictive value of various risk markers in identifying cardiac mortality and SCD.MethodsLeft ventricular function, arrhythmias on Holter and microvolt T wave alternans (MTWA) were assessed in patients with prior myocardial infarction and ejection fraction ≤ 40%. The primary outcome was a composite of cardiac death and resuscitated cardiac arrest during follow up. Secondary outcomes included total mortality and SCD.ResultsFifty-eight patients were included in the study. Eight patients (15.5%) died during a mean follow-up of 22.3 ± 6.6 months. Seven of them (12.1%) had SCD. Among the various risk markers studied, left ventricular ejection fraction (LVEF) ≤ 30% (Hazard ratio 5.6, 95% CI 1.39 to 23) and non-sustained ventricular tachycardia (NSVT) in holter (5.7, 95% CI 1.14 to 29) were significantly associated with the primary outcome in multivariate analysis. Other measures, including QRS width, heart rate variability, heart rate turbulence and MTWA showed no association.ConclusionsAmong patients with prior myocardial infarction and reduced left ventricular function, the rate of cardiac death was substantial, with most of these being sudden cardiac death. Both LVEF ≤30% and NSVT were associated with cardiac death whereas only LVEF predicted SCD. Other parameters did not appear useful for prediction of events in these patients. These findings have implications for decision making for the use of implantable cardioverter defibrillators for primary prevention in these patients.     

Reporting of Positive Results in Randomized Controlled Trials of Mindfulness-Based Mental Health Interventions

BackgroundA large proportion of mindfulness-based therapy trials report statistically significant results, even in the context of very low statistical power. The objective of the present study was to characterize the reporting of “positive” results in randomized controlled trials of mindfulness-based therapy. We also assessed mindfulness-based therapy trial registrations for indications of possible reporting bias and reviewed recent systematic reviews and meta-analyses to determine whether reporting biases were identified.MethodsCINAHL, Cochrane CENTRAL, EMBASE, ISI, MEDLINE, PsycInfo, and SCOPUS databases were searched for randomized controlled trials of mindfulness-based therapy. The number of positive trials was described and compared to the number that might be expected if mindfulness-based therapy were similarly effective compared to individual therapy for depression. Trial registries were searched for mindfulness-based therapy registrations. CINAHL, Cochrane CENTRAL, EMBASE, ISI, MEDLINE, PsycInfo, and SCOPUS were also searched for mindfulness-based therapy systematic reviews and meta-analyses.Results108 (87%) of 124 published trials reported ≥1 positive outcome in the abstract, and 109 (88%) concluded that mindfulness-based therapy was effective, 1.6 times greater than the expected number of positive trials based on effect size d = 0.55 (expected number positive trials = 65.7). Of 21 trial registrations, 13 (62%) remained unpublished 30 months post-trial completion. No trial registrations adequately specified a single primary outcome measure with time of assessment. None of 36 systematic reviews and meta-analyses concluded that effect estimates were overestimated due to reporting biases.ConclusionsThe proportion of mindfulness-based therapy trials with statistically significant results may overstate what would occur in practice.     

Impact of Multiple Cardiovascular Risk Factors on Carotid Intima-Media Thickness and Elasticity

Background

Carotid intima-media thickness (IMT) and elasticity have been shown to be independent predictors of cardiovascular disease (CVD). Cardiovascular risk factors (CVRFs) includes hypertension, dyslipidemia, diabetes, overweight and smoking. The objective was to investigate whether the clustering of three or more components of CVRFs has a greater impact on carotid IMT and elasticity than individual components of CVRFs.

Methods

One hundred and seventy-three participants without clinical CVD were classified as the multiple CVRFs patients with three or more CVRFs (n  = 55) and control group with two or less CVRFs (n  = 118). Carotid IMT and elastic modulus were measured by B-mode ultrasound and vessel texture matching method (VTMM), respectively.

Results

The multiple CVRFs conferred a disproportionate increase in carotid IMT (43%, p<0.0001) and elastic modulus (60%, p<0.0001), compared with control group. Multiple regression models, which included age, gender, as well as each individual component of CVRFs as continuous variables, showed that multiple CVRFs was an independent determinant of both IMT (p  = 0.042) and elasticity (p  = 0.008). In the analysis of variance adjusted with age, subjects with single, double, and multiple CVRFs, increased by 8.1%, 42.2%, and 66% for IMT, 54.6%, 94.3%, and 125.2% for elastic modulus, respectively, compared to subjects without CVRFs.

Conclusions

The clustering of multiple CVRFs has a greater impact on carotid IMT and elasticity than individual components of CVRFs. This suggests that the components of CVRFs interact to synergistically impact carotid IMT and elasticity.     

Mesenchymal stem/stromal cell–based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19

BackgroundMesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy.Methods and FindingsAll English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I² = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, –0.69; 95% CI, –1.15 to –0.22; P = .004; I² = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality.ConclusionUse of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.     

Effect of genetic variants of chemokine receptors on the development of myocardial infarction in Turkish population

Inflammation is a crucial component of coronary atherosclerosis and myocardial infarction (MI). Chemokine receptors are important modulators of inflammation. Polymorphisms in genes coding for chemokine receptors, CCR2 and CCR5, have been studied as genetic markers of coronary artery disease. In the present study, we investigated whether genetic variants of CCR2-V64I and CCR5-delta32 chemokine receptors have any effect on the development of myocardial infarction. A total of 146 MI patients and 202 control subjects were genotyped for CCR2 and CCR5. CCR2-V64I genotypes were not significantly different between patients with MI and controls (P > 0.05). CCR5-delta32 genotype distribution in cases was significantly different from that of controls (P = 0.042). The CCR5-delta32 wt/deletion genotype frequencies for controls and cases were 0.10 and 0.19, respectively and individuals with CCR5-delta32 wt/deletion genotype had a 2.13-fold increased risk of myocardial infarction (P = 0.0013). Individuals carrying the CCR5-delta32 heterozygote or homozygous variant genotype (deletion/deletion + wt/deletion) had a 1.96-fold increased risk of myocardial infarction compared with the wild-type genotype (wt/wt) (p: 0.016). In conclusion, our data have suggested that genetic variant of CCR5 might be associated with the development of MI. Further larger sample size studies are required to confirm our findings.