Christopher P Cannon’s research while affiliated with Brigham and Women's Hospital and other places

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Publications (317)


20 Years of Critical Pathways
  • Article

November 2022

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7 Reads

Critical Pathways in Cardiology A Journal of Evidence-Based Medicine

Christopher P Cannon

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Liuba Fusco

Low Levels of Low-Density Lipoprotein Cholesterol, Intracerebral Hemorrhage, and Other Safety Issues: Is There Still a Matter of Debate?
  • Article
  • Full-text available

May 2022

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153 Reads

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8 Citations

European Heart Journal Open

Although some observational studies suggest a potential association of low levels of low-density lipoprotein cholesterol (LDL-C) with intracerebral hemorrhage (ICH), these analyzes have issues of confounding where other factors (e.g., older age, frailty) that likely explain the findings, and the number of events was very low. More recent results from randomized clinical trials have not found an increased risk in ICH, most notably trials using PCSK9 inhibitors that achieve very low levels of LDL-C, but also in the long-term follow-up of the IMPROVE-IT trial. Also, other statin-associated safety issues, including new onset diabetes (NOD) and the cancer risk should not be the reason of statin discontinuation, especially for the former the benefits highly outweigh the risk (even 5x), and for the latter there is no confirmed link suggesting any increased risk, in opposite, data exist suggesting benefits of statin therapy in cancer prevention. Furthermore, use of intensive lipid lowering strategies with statins, and non-statin drugs lead to decrease of ischemic major adverse cardiac events (MACE), without safety concern, in a large population of atherosclerotic cardiovascular disease (ASCVD) patients. These data should promote the concept “the earlier, the lower, the longer, the better” for the lipid management of ASCVD patients. While few uncertainties remain in several populations that have been underrepresented in clinical trials (African American and Asian patients, low weight individuals), the most recent data with intensive LDL-C lowering with PCSK9 inhibitors are reassuring that the benefit outweighs any possible risk.

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Canagliflozin and Atrial Fibrillation in Type 2 Diabetes Mellitus: A secondary analysis from the CANVAS Program and CREDENCE trials and meta‐analysis

May 2022

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74 Reads

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17 Citations

Diabetes Obesity and Metabolism

Chao Li

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Carinna Hockham

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[...]

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Clare Arnott

Aims: The effect of sodium-glucose co-transporter 2 inhibitors on atrial fibrillation/flutter (AF/AFL) is unclear. We assessed the effects of canagliflozin on the incidence of AF/AFL and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and methods: Participants with T2D and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL related complications (ischemic stroke/transient ischemic attack/hospitalisation for heart failure). Major adverse cardiovascular events (MACE), and a renal-specific outcome by baseline AF/AFL status were analysed using Cox regression models. Results: Overall 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (HR 0.82; 95% CI, 0.67, 1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78; 95% CI, 0.62, 0.99). Canagliflozin was also associated with a reduction in AF/AFL related complications (HR 0.74; 95% CI, 0.65, 0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all Pinteraction >0.14). Meta-analysis of five SGLT2 inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81; 95% CI 0.72, 0.92). Conclusions: Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta-analysis suggests SGLT2 inhibition reduces AF/AFL incidence. This article is protected by copyright. All rights reserved.


Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis

November 2021

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113 Reads

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69 Citations

JACC CardioOncology

Cardiovascular disease and cancer are the 2 leading causes of death worldwide. Emerging evidence suggests common mechanisms between cancer and cardiovascular disease, including atrial fibrillation and atherosclerosis. With advances in cancer therapies, screening, and diagnostics, cancer-specific survival and outcomes have improved. This increase in survival has led to the coincidence of cardiovascular disease, including atrial fibrillation and atherosclerosis, as patients with cancer live longer. Additionally, cancer and cardiovascular disease share several risk factors and underlying pathophysiologic mechanisms, including inflammation, cancer-related factors including treatment effects, and alterations in platelet function. Patients with cancer are at increased risk for bleeding and thrombosis compared with the general population. Although optimal antithrombotic therapy, including agent choice and duration, has been extensively studied in the general population, this area remains understudied in patients with cancer despite their altered thrombotic and bleeding risk. Future investigation, including incorporation of cancer-specific characteristics to traditional thrombotic and bleeding risk scores, clinical trials in the cancer population, and the development of novel antithrombotic and anti-inflammatory strategies on the basis of shared pathophysiologic mechanisms, is warranted to improve outcomes in this patient population.


Effects of canagliflozin on cardiovascular and renal outcomes in participants in the CANVAS Program, stratified by baseline use of any diuretic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with the use of Cox regression models, with stratification according to trial and history of cardiovascular disease for all canagliflozin groups combined versus placebo. CV, cardiovascular; HF, heart failure; MACE, major adverse cardiovascular event, including death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; MI, myocardial infarction. *40% reduction in estimated glomerular filtration rate, end‐stage kidney disease, or death from renal causes.
Effects of canagliflozin on major adverse cardiac events in participants in the CANVAS Program, stratified by baseline use of diuretic classes*. *In CANVAS Program, any diuretics were categorized as loop or non‐loop diuretics. In CANVAS trial, non‐loop diuretics were further categorized with specific drug classes. **Includes thiazide, thiazide‐like, or other diuretics.
Effect of canagliflozin* on (A) systolic blood pressure; (B) pulse; (C) body weight; (D) haemoglobin A1c; (E) urinary albumin‐to‐creatinine ratio; (F) serum uric acid; and (G) haematocrit in participants in the CANVAS Program, stratified by baseline use of any diuretic. *Calculated as mean change from baseline across the entire follow‐up period. The average change in these continuous outcomes from baseline by canagliflozin treatment and the difference in treatment effect between those on and not on diuretics at baseline were analysed using mixed‐effect models for repeated measures including all data up to Week 312 and covariates for study, visit, treatment, baseline measures, treatment‐by‐visit, and baseline‐by‐visit interactions.
Adverse events in the CANVAS Program participants stratified by baseline use of any diuretic. CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CI, confidence interval. *The annualized event rates are reported with data from CANVAS alone through 7 January 2014, because after this time, only serious adverse events or adverse events leading to discontinuation were collected. In CANVAS‐R, only serious adverse events or adverse events leading to discontinuation were collected. Owing to the differences between the two trials in methods of collection of the data, an integrated analysis of these adverse events is not possible. §Data collected in CANVAS and CANVAS‐R.
Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program

February 2021

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88 Reads

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17 Citations

Aims: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes. Methods and results: The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, Pheterogeneity = 0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity > 0.07). Conclusions: Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.


Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial

December 2020

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49 Reads

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44 Citations

American Heart Journal

We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P<0.001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >0.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.


Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes

September 2020

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150 Reads

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1,246 Citations

The New-England Medical Review and Journal

Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).


Design of the Mass General Brigham Lp(a) Registry. CPT, current procedural terminology; ICD, International Classification of Diseases; Lp(a), lipoprotein(a)
Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: Design and rationale of the Mass General Brigham Lp(a) Registry

September 2020

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143 Reads

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10 Citations

Lipoprotein(a) [Lp(a)] is independently associated with atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Elevated Lp(a) affects approximately one in five individuals and meaningfully contributes to the residual cardiovascular risk in individuals with otherwise well-controlled risk factors. With targeted therapies in the therapeutic pipeline, there is a need to further characterize the clinical phenotypes and outcomes of individuals with elevated levels of this unique biomarker. The Mass General Brigham Lp(a) Registry will be built from the longitudinal electronic health record of two large academic medical centers in Boston, Massachusetts, to develop a detailed cohort of patients who have had their Lp(a) measured. In combination with structured data sources, clinical documentation will be analyzed using natural language processing techniques to accurately characterize baseline characteristics. Important outcome measures including all-cause mortality, cardiovascular mortality, and cardiovascular events will be available for analysis. Approximately 30 000 patients who have had their Lp(a) tested within the Mass General Brigham system from January 2000 to July 2019 will be included in the registry. This large Lp(a) cohort will provide meaningful observational data regarding the differential risk associated with Lp(a) values and cardiovascular disease. With a new frontier of targeted Lp(a) therapies on the horizon, the Mass General Brigham Lp(a) Registry will help provide a deeper understanding of Lp(a)'s role in long term cardiovascular outcomes.


Safety and efficacy of drug eluting stents vs bare metal stents in patients with atrial fibrillation: A systematic review and meta-analysis

July 2020

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144 Reads

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5 Citations

Thrombosis Research

Objective A systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients. Methods We systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy. Results Ten studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89–1.28, p = 0.47; I² = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81–1.13, p = 0.60; I² = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61–1.01, p = 0.06; I² = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08–2.03, p = 0.01; I² = 12%). For both types of stents, MACE risk was similar between TAT and DAT. Conclusions In patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT.


The effect of canagliflozin on amputation risk in the CANVAS program and the CREDENCE trial

May 2020

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167 Reads

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40 Citations

Diabetes Obesity and Metabolism

Aims: The SGLT2 inhibitor canagliflozin was associated with increased amputation risk in the CANVAS Program but not in CREDENCE. We explored possible explanations for these differences in amputation risk. Methods: We performed a pooled analysis of patient-level data from the CANVAS Program and CREDENCE trial. Patient characteristics associated with amputation risk were assessed in univariable and multivariable regression models and compared between studies. Effects of canagliflozin on amputation risk were determined from Cox proportional hazards models and compared between studies, subgroups, and for a range of amputation outcomes. Effects over time were explored by cumulative event curves. Results: In the CANVAS Program (n=10,142; median follow-up 2·4y) and CREDENCE trial (n=4401; median follow-up 2·5y), 2·3% and 5·3% of participants, respectively, reported baseline amputation history. Key differences at baseline were the proportions with nephropathy (CREDENCE higher, 100% vs 17·5%) and cardiovascular disease (CANVAS Program higher, 66% vs 50%). There were 133 amputations in CREDENCE (3·0% annual event rate) and 187 amputations in CANVAS (1·8% annual event rate), with prior amputation being the strongest predictor of future amputation in both groups. Effects of canagliflozin on amputation risk were significantly different between trials (pheterogeneity 0·02, I2 =82%), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols instituted during CREDENCE ameliorated amputation risk. Conclusions: We identified no explanation for the difference in amputation risk between CREDENCE and the CANVAS Program. In the context of null effects of SGLT2 inhibition on amputation in CREDENCE and all other large trials, there is a possibility that the finding in CANVAS was the result of chance. This article is protected by copyright. All rights reserved.


Citations (90)


... A meta-analysis comprising 23 prospective studies also reported consistent findings [12]. However, some randomized controlled trials on statin therapy have failed to identify such a relationship [20]. A 2015 meta-analysis of 26 randomized trials demonstrated that patients in the statin therapy group who experienced significant reductions in LDL cholesterol levels (approximately 0.5 mmol/L for more intensive versus less intensive therapy) did not exhibit a significant increase in hemorrhagic stroke during follow-up (RR 1.12, 95% CI 0.93-1.35; ...

Reference:

Association between the low-density lipoprotein to high-density lipoprotein ratio and prognosis in critically ill intracerebral hemorrhage patients: a retrospective cohort study from the MIMIC-IV database
Low Levels of Low-Density Lipoprotein Cholesterol, Intracerebral Hemorrhage, and Other Safety Issues: Is There Still a Matter of Debate?

European Heart Journal Open

... This finding was supported by a meta-analysis of 16 randomized controlled trials in T2D patients that various SGLT2i treatment reduced the occurrence of AF/ AFL and all-cause mortality compared to placebo [34]. A secondary analysis from the CANVAS program and CREDENCE trial demonstrated that canagliflozin could reduce the incidence of AF/AFL in participants with no AF/AFL history and alleviated AF/AFL-related complications [35]. Another meta-analysis of 22 RCTs in T2D or HF patients showed that SGLT2i treatment had less AF/AFL, arrhythmia and intracardiac thrombosis. ...

Canagliflozin and Atrial Fibrillation in Type 2 Diabetes Mellitus: A secondary analysis from the CANVAS Program and CREDENCE trials and meta‐analysis

Diabetes Obesity and Metabolism

... Malignancy exerts detrimental effects on the cardiovascular system. Chronic inflammation, a hallmark of cancer, can induce and exacerbate atherosclerosis, leading to an increased risk of cardiovascular diseases [10,11]. Additionally, cancer-associated factors can promote endothelial damage, impair vascular function, and disturb the delicate balance of thrombotic and fibrinolytic processes, further contributing to cardiovascular complications [12,13]. ...

Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis

JACC CardioOncology

... m 2 ). For nine studies the main kidney outcomes were unavailable in different eGFR subgroups, and thus we use a re-analysis of eGFR data to derive kidney outcomes [22][23][24][25][26][27][28][29][30][31]. ...

Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program

... Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are the latest addition to the treatment of HF and the only drug category that has shown benefits in the whole spectrum of HF, regardless of the LVEF [3]. Several studies have been conducted regarding the SGLT2i [4][5][6][7][8][9][10]. These trials have shown beneficial results in patients with HF, with or without diabetes, who already receive the optimal treatment for HF. ...

Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial
  • Citing Article
  • December 2020

American Heart Journal

... In the subgroup analysis of patients with T2DM, this study included data from seven RCTs [28][29][30][31]34,36,37]. ...

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes
  • Citing Article
  • September 2020

The New-England Medical Review and Journal

... In turn, one of the largest registries dedicated to Lp(a) is the Mass General Brigham Lp(a) Registry, which collects data from approximately 30,000 patients in whom Lp(a) concentration was determined as part of routine clinical care. Unfortunately, this registry is limited by the fact that it is retrospec-tive and includes data from the period from January 2000 to January 2019 only [30]. Hopefully a similar registry including even more patients will soon be established as a national project of the Polish Lipid Association (PoLA). ...

Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: Design and rationale of the Mass General Brigham Lp(a) Registry

... However, in current clinical treatments, physicians rarely consider using metal stents to assist with AVF maturation, mostly because, after the three months of fistula maturation, the stent remains inside the body for a long time, leading to the risk of vascular occlusions or serious complications. Biodegradable stents offer the advantage of being metabolized by the human body over time, reducing the risk of complications associated with long-term stent presence and the need for a second surgery [10][11][12][13][14][15][16][17][18]. Biodegradable metal stents are primarily composed of magnesium (Mg), iron (Fe), zinc (Zn), and their alloys [19][20][21][22]. ...

Safety and efficacy of drug eluting stents vs bare metal stents in patients with atrial fibrillation: A systematic review and meta-analysis
  • Citing Article
  • July 2020

Thrombosis Research

... Overall, such a thorough clinical evaluation is essential to detect masked PAD in patients with T2DM [26]. Arnott et al. [34] Post-hoc analysis of 3 doubleblind, randomized trials, involving 10,142 patients with T2DM in CANVAS and 4401 patients with T2DM in CREDENCE, to determine if there was an explanation as to why the effects of canagliflozin on amputation risk vary between CANVAS and CREDENCE Median follow-up was 2.4 years in CANVAS and 2.5 years in CREDENCE There were 133 amputations in CREDENCE and 187 amputations in CANVAS, with prior amputation as strongest predictor of future amputations Effect of canagliflozin on amputation risk was significantly different between CANVAS and CREDENCE (p heterogeneity of 0.02), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols in CREDENCE ameliorated amputation risk ...

The effect of canagliflozin on amputation risk in the CANVAS program and the CREDENCE trial
  • Citing Article
  • May 2020

Diabetes Obesity and Metabolism

... Just three years ago it was recommended to cover 50-60% of daily energy requirement with carbohydrates while now it is recommended that carbohydrates should comprise 45-50% of the daily energy requirement. The recommended lower amount of carbohydrates and choosing products with low GI values obviously lowers the glycaemic load of a diet (Adamska and Górska, 2008;Vaduganathan et al., 2020). ...

Contemporary Trends in Prescription of Dipeptidyl Peptidase-4 Inhibitors in the Context of US Food and Drug Administration Warnings of Heart Failure Risk
  • Citing Article
  • March 2020

The American Journal of Cardiology