Research Spotlight

Baylor Health Sciences Library brings to you each month the latest published research from the Baylor Scott & White community. Each newly published article features the researcher, the abstract, and link to the full text. For information on including your own research, please contact John Fullinwider, john.fullinwider@baylorhealth.edu. 214-828-8989.


Posted January 15th 2017

Randomised trials in left main disease: a NOBLE effort.

Michael J. Mack M.D.

Michael J. Mack, M.D.

Mack, M. and D. R. Holmes (2016). “Randomised trials in left main disease: a NOBLE effort.” Lancet 388(10061): 2715-2716.

Full text of this article.

The NOBLE trial enrolled 1201 patients in 36 centres, randomly assigned to either PCI primarily with the Biolimus–eluting stent (Biomatrix Flex) or CABG. The primary endpoint was major adverse cardiac and cerebrovascular events including all-cause mortality, myocardial infarction, stroke, and repeat revascularisation at a median follow-up of 3 years. The trial was designed as a non-inferiority trial with a relatively wide confidence interval of 1·35. The primary endpoint occurred in 29% of patients in the PCI group and 19% of patients in the CABG group (HR 1·48 [95% CI 1·11–1·96]), exceeding the limit for non-inferiority and was in fact statistically significant for superiority of CABG over PCI (p=0·0079). Outcomes were similar in both intention-to-treat and per-protocol analyses. Regarding the individual components of the composite primary endpoint, 5 year Kaplan Meier estimates of all-cause mortality and stroke were the same but there were significantly fewer clinically apparent myocardial infarctions and fewer repeat revascularisation procedures with CABG. The conclusion of the trial is that CABG might be superior to PCI for treatment of left main stem coronary artery disease. There are a few specific findings of this trial that are noteworthy and somewhat surprising but there are also some concerns. The first is that the benefit of CABG was noted in all ranges of the SYNTAX score, which is contrary to the SYNTAX trial in which patients with less complex disease did as well with PCI as with CABG. This finding might partly be explained by the fact that 81% of the patients in NOBLE had bifurcation left main disease, which is more difficult to treat than ostial or trunk left main disease and might be associated with a worse outcome with PCI. The second finding is that there was a trend toward a higher incidence of stroke at 5 years with PCI, which is the opposite to what has been noted in most previous comparative trials. This result is perplexing in that with PCI at 30 days, there were no strokes. The stroke rate only gradually increased over time with PCI to an estimated 4·9% at 5 years. The reasons for the late stroke rate in PCI might be due to chance in the absence of any reasons for this late event. The third point is that the trial primary endpoint was changed from the original design. This trial was event driven, in which a specific number of events was needed; this requirement was based on events in the SYNTAX trial. When that number could not be reached in 5 years of follow-up, the primary endpoint was assessed at a median of 3 years. Might that have affected the results? Fourth, procedural purists on both sides will argue that optimal procedures were not done, with only 75% of the patients with PCI undergoing intravascular ultrasound assessment, only 93% of patients with CABG receiving a left internal mammary artery graft, and 86% of patients receiving at least one saphenous vein graft. However, we suspect that this is probably representative of real world practice. (Excerpt from text of this commentary, p. 2715-2716.)


Posted January 15th 2017

Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. and J. J. McMurray (2016). “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.” Lancet: 2016 Dec [Epub ahead of print].

Full text of this article.

The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.


Posted January 15th 2017

Oxidative stress reflected by increased F2-isoprostanes is associated with increasing urinary 11-dehydro thromboxane B2 levels in patients with coronary artery disease.

Peter McCullough M.D.

Peter McCullough, M.D.

McCullough, P. A., A. Vasudevan, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and T. Bottiglieri (2016). “Oxidative stress reflected by increased F2-isoprostanes is associated with increasing urinary 11-dehydro thromboxane B2 levels in patients with coronary artery disease.” Thromb Res 148: 85-88.

Full text of this article.

Our study demonstrated that: 1) CAD patients with higher levels of 8-isoPGF2α had higher levels of 11dhTxB2, which could be related to poor inhibition of COX-1 pathway in spite of adequate ASA treatment, 2) 8-isoPGF2α is an independent determinant of 11dhTxB2 and 3) 8-isoPGF2α levels were significantly higher in females and patients with diabetes and COPD. Patients with diabetes and central obesity have been observed to have an incomplete ASA response manifested as incomplete inhibition of thromboxane production, in a pro-inflammatory background with enhanced oxidative stress. Oxidative stress enhances the production of platelet isoprostanes and is believed to mitigate the aspirin mediated TxA2 inhibition among diabetic patients on low-dose aspirin [9]. Among F2-isoprostanes metabolites, 8-isoPGF2α is a marker of in vivo oxidative stress, which has been shown to stimulate the activation of platelets by direct binding to the thromboxane platelet receptor. Elevated 8-isoPGF2α levels in our ASA-treated CAD patients indicate the presence of an active oxidative stress environment that is not affected by ASA treatment. Because ASA inhibits over 95% of platelet COX-1 activity in practically all subjects, the residual platelet activation in poor ASA responders can be explained by alternative sources of TxA2 produced by non-platelet inflammatory COX-2 pathways. Our findings are congruent with the notion that oxidative stress mechanisms play an important role in platelet activation in addition to their role on the initiation, progression, and consequences of atherogenesis. Excessive production of ROS may damage lipoproteins creating an inflammatory and atherogenic background and also enhance the arachidonic acid production of F2-isoprostanes that are capable of activating platelets and making them resistant to the therapeutic effect of ASA. These observations support the concept that oxidative stress maintains platelet hyperactivity linking proatherogenic mechanisms to platelet dysfunction in patients with stable CAD. Considering that thromboxanes are not the only factor contributing to platelet activation and atherothrombosis, it is not surprising that a single anti-platelet agent such as ASA does not prevent all adverse events. Cyclo-oxygenase-1 derived TxA2 activates the same and nearby platelets in an autocrine signaling fashion. Due to the very short half-life of TxA2 (20–30 s) and low concentrations (1–60 pg/mL), a constant production of TxA2 is necessary to maintain a homeostatic (physiologic) control of platelet activity. However, the half-life of 8-isoPGF2α is much longer (10 min), with concentrations that are thirty-fold higher. If 8-isoPGF2α can bind and stimulate thromboxane platelet receptors with similar affinity, its longer half-life and concentration makes it a relevant agonist for platelet activation in patients with an underlying oxidative process. Because ASA blocks most of COX-1 activity reducing the production of TxA2, it is possible that the thromboxane platelet receptor can still be activated by TxA2 produced via the 8-isoPGF2α pathway. In this situation, blocking 8-isoPGF2α TPR stimulation could be a potential therapeutic target instead of increasing the dose of ASA. Sex related differences in platelet function and ASA pharmacokinetics exist with female gender associated with elevated 11dhTxB2. We found that females had significantly higher 8-isoPGF2α levels, suggesting an enhanced oxidative stress and lesser attenuation of TxA2. Elevated 11dhTxB2 was found to increase the risk of adverse events in patients with stable CAD and myocardial infarction. (Excerpt from text, p. 86-87.)


Posted January 15th 2017

Incidence, Characteristics, Predictors, and Outcomes of Repeat Revascularization After Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting: The SYNTAX Trial at 5 Years.

Michael J. Mack M.D.

Michael J. Mack M.D.

Parasca, C. A., S. J. Head, M. Milojevic, M. J. Mack, P. W. Serruys, M. C. Morice, F. W. Mohr, T. E. Feldman, A. Colombo, K. D. Dawkins, D. R. Holmes, Jr. and P. A. Kappetein (2016). “Incidence, characteristics, predictors, and outcomes of repeat revascularization after percutaneous coronary intervention and coronary artery bypass grafting: The syntax trial at 5 years.” JACC Cardiovasc Interv 9(24): 2493-2507.

Full text of this article.

OBJECTIVES: The study sought to determine the incidence, predictors, characteristics, and outcomes of repeat revascularization during 5-year follow-up of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) trial. BACKGROUND: Limited in-depth long-term data on repeat revascularization are available from randomized trials comparing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). METHODS: Incidence and timing of repeat revascularization and its relation to the long-term composite safety endpoint of death, stroke, and myocardial infarction were analyzed in the SYNTAX trial (n = 1,800) using Kaplan-Meier analysis. RESULTS: At 5 years, repeat revascularization occurred more often after initial PCI than after initial CABG (25.9% vs. 13.7%, respectively; p < 0.001), and more often consisted of multiple repeat revascularizations (9.0% vs. 2.8%, respectively; p = 0.022). Significantly more repeat PCI procedures were performed on de novo lesions in patients after initial PCI than initial CABG (33.3% vs. 13.4%, respectively; p < 0.001). At 5-year follow-up, patients who underwent repeat revascularization versus patients not undergoing repeat revascularization had significantly higher rates of the composite safety endpoint of death, stroke, and myocardial infarction after initial PCI (33.8% vs. 16.6%, respectively; p < 0.001), and a trend was found after initial CABG (22.4% vs. 15.8%, respectively; p = 0.07). After multivariate adjustment, repeat revascularization was an independent predictor of the composite safety endpoint after both initial PCI (hazard ratio [HR]: 2.2; 95% confidence interval [CI]: 1.6 to 3.0; p < 0.001) and initial CABG (HR: 1.8; 95% CI: 1.2 to 2.9; p = 0.011). CONCLUSIONS: Repeat revascularization rates are significantly higher after initial PCI than after initial CABG for complex coronary disease. Repeat revascularization is an independent predictor of death, stroke, and myocardial infarction for myocardial revascularization.


Posted January 15th 2017

Efficacy of Secukinumab on Moderate-to-severe Plaque Psoriasis Affecting Different Body Regions: a Pooled Analysis of Four Phase 3 Studies.

Alan M. Menter M.D.

Alan M. Menter, M.D.

Menter, A., J. C. Cather, M. Jarratt, X. Meng, A. Guana and J. Nyirady (2016). “Efficacy of Secukinumab on Moderate-to-severe Plaque Psoriasis Affecting Different Body Regions: a Pooled Analysis of Four Phase 3 Studies.” Dermatol Ther (Heidelb) 6(4): 639-647.

Full text of this article.

INTRODUCTION: The impact of psoriasis varies with the body region affected. In addition, patients have different perceptions of disease improvement and treatment satisfaction based on the location of skin clearance with treatment. The monoclonal antibody secukinumab selectively targets interleukin-17A-a central cytokine of psoriasis-and provides rapid and sustained clearance for moderate-to-severe psoriasis affecting all body regions. The objective of this study was to evaluate the efficacy of secukinumab on moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs. METHODS: Data were pooled from four phase 3 studies. To be included in the analysis for each body region, patients were required to have a Psoriasis Area and Severity Index (PASI) score >/=12 for that body region and psoriasis covering >/=10% of the surface area of that region. Secukinumab was administered at Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48. RESULTS: Across the trunk, upper limbs, and lower limbs, initial PASI subscore responses were sustained to Week 52. At Week 52, trunk (T) PASI 90/100 responses were achieved by 78.4%/71.1% of patients receiving secukinumab 300 mg, respectively, and by 66.3%/56.9% of patients receiving secukinumab 150 mg, respectively. At Week 52, upper limb (UL) PASI 90/100 responses were achieved by 67.3%/59.1% of patients receiving secukinumab 300 mg, respectively, and by 50.3%/43.3% of patients receiving secukinumab 150 mg, respectively. At Week 52, lower limb (LL) PASI 90/100 responses were achieved by 63.9%/55.3% of patients receiving secukinumab 300 mg, respectively, and by 45.1%/36.4% of patients receiving secukinumab 150 mg, respectively. A 50% reduction in mean PASI subscore occurred after 2.8, 2.9, and 3.4 weeks with secukinumab 300 mg on the trunk, upper limbs, and lower limbs, respectively. CONCLUSION: Secukinumab provided robust and sustained efficacy for moderate-to-severe psoriasis affecting the trunk, upper limbs, and lower limbs.