Sanjay Kaul

Standardized Bleeding Definitions for Cardiovascular Clinical Trials A Consensus Report From the Bleeding Academic Research Consortium

Advances in antithrombotic therapy, along with an early invasive strategy, have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes (ACS; unstable angina, non–ST-segment–elevation myocardial infarction [MI], and ST-segment–elevation MI).1,–,4 However, the combination of multiple pharmacotherapies, including aspirin, platelet P2Y12 inhibitors, heparin plus glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitors, and the increasing use of invasive procedures, has also been associated with an increased risk of bleeding. Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes, including MI, stroke, stent thrombosis, and death, in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting.11,12 Thus, balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients. Prior randomized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS, bleeding events have been systematically identified as a crucial end point for the assessment of the safety of drugs during the course of randomized clinical trials, and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events (eg, cardiac death, MI, stent thrombosis), for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use. Lack of standardization makes it difficult to optimally organize key clinical trial processes such as adjudication, and even more difficult to interpret relative …

ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents

ACCF TASK FORCE MEMBERS Robert A. Harrington, MD, FACC, Chair; Eric R. Bates, MD, FACC; Charles R. Bridges, MD, MPH, FACC; Mark J. Eisenberg, MD, MPH, FACC; Victor A. Ferrari, MD, FACC; Mark A. Hlatky, MD, FACC; Sanjay Kaul, MBBS, FACC; Jonathan R. Lindner, MD, FACC‡; David J. Moliterno, MD, FACC; Debabrata Mukherjee, MD, FACC; Richard S. Schofield, MD, FACC‡; Robert S. Rosenson, MD, FACC; James H. Stein, MD, FACC; Howard H. Weitz, MD, FACC; Deborah J. Wesley, RN, BSN

2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement.

Robert A. Harrington, MD, FACC, Chair Deepak L. Bhatt, MD, MPH, FACC, Vice Chair Victor A. Ferrari, MD, FACC John D. Fisher, MD, FACC Mario J. Garcia, MD, FACC Timothy J. Gardner, MD, FACC Federico Gentile, MD, FACC Michael F. Gilson, MD, FACC Adrian F. Hernandez, MD, FACC Alice K. Jacobs

Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease

The pharmaceutical preparation sildenafil citrate (Viagra) is being widely prescribed as a treatment for male erectile dysfunction, a common problem that in the United States affects between 10 and 30 million men. The introduction of sildenafil has been a valuable contribution to the treatment of erectile dysfunction, which is a relatively common occurrence in patients with cardiovascular disease. This article is written to appropriately caution and not to unduly alarm physicians in their use of sildenafil in patients with heart disease. Reported cardiovascular side effects in the normal healthy population are typically minor and associated with vasodilatation (ie, headache, flushing, and small decreases in systolic and diastolic blood pressures). However, although their incidence is small, serious cardiovascular events, including significant hypotension, can occur in certain populations at risk. Most at risk are individuals who are concurrently taking organic nitrates. Organic nitrate preparations are commonly prescribed to manage the symptoms of angina pectoris. The coadministration of nitrates and Viagra significantly increases the risk of potentially life-threatening hypotension. Therefore, Viagra should not be prescribed to patients receiving any form of nitrate therapy. Although definitive evidence is currently lacking, it is possible that a precipitous reduction in blood pressure with nitrate use may occur over the initial 24 hours after a dose of Viagra. Thus, for patients who experience an acute cardiac ischemic event and who have taken Viagra within the past 24 hours, administration of nitrates should be avoided. In the event that nitrates are given, especially within this critical time interval, it is essential to have the capability to support the patient with fluid resuscitation and α-adrenergic agonists if needed. In patients with recurring angina after Viagra use, other nonnitrate antianginal agents, such as β-blockers, should be considered. Other patients in whom the use of Viagra is potentially hazardous include those …

American College of Cardiology/Society for Cardiac Angiography and Interventions Clinical Expert Consensus Document on Cardiac Catheterization Laboratory Standards: A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents

This document has been developed as a Clinical Expert Consensus Document (CECD), combining the resources of the American College of Cardiology (ACC) and the Society for Cardiac Angiography and Interventions (SCA&I). It is intended to provide a perspective on the current state of cardiac

Membrane Type 1 Matrix Metalloproteinase Expression in Human Atherosclerotic Plaques Evidence for Activation by Proinflammatory Mediators

BACKGROUND Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where in their active form, they may contribute to vascular remodeling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro-MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and that its expression is regulated by proinflammatory molecules. METHODS AND RESULTS MT1-MMP expression was examined in normal and atherosclerotic human arteries by immunocytochemistry with specific antibodies. MT1-MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in response to proinflammatory molecules (interleukin [IL]-1alpha, tumor necrosis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipitation for protein, and gelatin zymography for catalytic activity. Medial SMCs of normal vessel wall expressed MT1-MMP. In atherosclerotic arteries, MT1-MMP expression was noted within the complex atheroma colocalizing with SMCs and macrophages (Mphi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-dependent manner within 4 to 8 hours of exposure to IL-1alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expression by human monocyte-derived Mphi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha. CONCLUSIONS This study demonstrates that MT1-MMP, an activator of pro-MMP-2, is expressed by SMCs and Mphi in human atherosclerotic plaques. Furthermore, proinflammatory molecules upregulate MT1-MMP expression in vascular SMCs and Mphi. Thus, activation of SMCs and Mphi by proinflammatory molecules may influence extracellular matrix remodeling in atherosclerosis by regulating MT1-MMP expression.

Oxidized Low-Density Lipoprotein Regulates Matrix Metalloproteinase-9 and Its Tissue Inhibitor in Human Monocyte-Derived Macrophages

BACKGROUND Macrophages in human atherosclerotic plaques produce a family of matrix metalloproteinases (MMPs), which may influence vascular remodeling and plaque disruption. Because oxidized LDL (ox-LDL) is implicated in many proatherogenic events, we hypothesized that ox-LDL would regulate expression of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in monocyte-derived macrophages. MWRHOSA AND RESULTS: Mononuclear cells were isolated from normal human subjects with Ficoll-Paque density gradient centrifugation, and adherent cells were allowed to differentiate into macrophages during 7 days of culture in plastic dishes. On day 7, by use of serum-free medium, the macrophages were incubated with various concentrations of native LDL (n-LDL) and copper-oxidized LDL. Exposure to ox-LDL (10 to 50 microg/mL) increased MMP-9 mRNA expression as analyzed by Northern blot, protein expression as measured by ELISA and Western blot, and gelatinolytic activity as determined by zymography. The increase in MMP-9 expression was associated with increased nuclear binding of transcription factor NF-kappaB and AP-1 complex on electromobility shift assay. In contrast, ox-LDL (10 to 50 microg/mL) decreased TIMP-1 expression. Ox-LDL-induced increase in MMP-9 expression was abrogated by HDL (100 microg/mL). n-LDL had no significant effect on MMP-9 or TIMP-1 expression. CONCLUSIONS These data demonstrate that unlike n-LDL, ox-LDL upregulates MMP-9 expression while reducing TIMP-1 expression in monocyte-derived macrophages. Furthermore, HDL abrogates ox-LDL-induced MMP-9 expression. Thus, ox-LDL may contribute to macrophage-mediated matrix breakdown in the atherosclerotic plaques, thereby predisposing them to plaque disruption and/or vascular remodeling.

ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

This document has been developed as an Expert Consensus Document (ECD) by the American College of Cardiology Foundation (ACCF), American Association for Clinical Chemistry (AACC), American College of Chest Physicians (ACCP), American College of Emergency Physicians (ACEP), American College of

Effects of Recombinant Apolipoprotein A-IMilano on Aortic Atherosclerosis in Apolipoprotein E–Deficient Mice

BACKGROUND We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I(Milano)/phospholipid complex (A-I[Milano]/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I(Milano)/PC would inhibit aortic atherosclerosis in apo E-deficient mice. METHODS AND RESULTS Thirty-five apo E-deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I(Milano)/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11 +/- 1% versus 17 +/- 5% of the aortic surface, P=.002), and lipid content increased by 45% (22 +/- 8% versus 32 +/- 6% of plaque area, P=.02) without a significant change in macrophage content (10.8 +/- 2% versus 13.2 +/- 6%). Compared with 20-week-old untreated control mice, PC only-treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11 +/- 1% versus 15 +/- 4%, P=.01) and an increase in lipid content (22 +/- 8% versus 47 +/- 3%, P<.0001) without a change in macrophage content (10.8 +/- 2% versus 11 +/- 2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I(Milano)/PC-treated mice demonstrated no increase in aortic atherosclerosis (11 +/- 1% versus 10 +/- 4%, P=NS), a 40% reduction in lipid content (22 +/- 8% versus 13 +/- 8%, P=.01), and a 46% reduction in macrophage content (10.8 +/- 2% versus 5.8 +/- 2.9%; P=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I(Milano)/PC or PC only. In vitro, apo A-I(Milano)/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I(Miano) had no effect. CONCLUSIONS Recombinant A-I(Milano)/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E-deficient mice despite severe hypercholesterolemia. Thus, A-I(Milano)/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.

Trial and error. How to avoid commonly encountered limitations of published clinical trials.

The randomized controlled clinical trial is the gold standard scientific method for the evaluation of diagnostic and treatment interventions. Such trials are cited frequently as the authoritative foundation for evidence-based management policies. Nevertheless, they have a number of limitations that challenge the interpretation of the results. The strength of evidence is often judged by conventional tests that rely heavily on statistical significance. Less attention has been paid to the clinical significance or the practical importance of the treatment effects. One should be cautious that extremely large studies might be more likely to find a formally statistically significant difference for a trivial effect that is not really meaningfully different from the null. Trials often employ composite end points that, although they enable assessment of nonfatal events and improve trial efficiency and statistical precision, entail a number of shortcomings that can potentially undermine the scientific validity of the conclusions drawn from these trials. Finally, clinical trials often employ extensive subgroup analysis. However, lack of attention to proper methods can lead to chance findings that might misinform research and result in suboptimal practice. Accordingly, this review highlights these limitations using numerous examples of published clinical trials and describes ways to overcome these limitations, thereby improving the interpretability of research findings.