David Kong - Academia.edu (original) (raw)
Papers by David Kong
Purpose: Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening d... more Purpose: Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. Methods: Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. Results: MBL gene expression was not detected in unchallenged HCECs. Exposure of HCECs to P. aeruginosa resulted in rapid induction of the transcriptional expression of MBL, IL-6, and IL-8. In addition, expression of several complement proteins of the classical and lectin pathways, but not the alternative pathway, were upregulated after 5 h of challenge, including MBL-associated serine protease 1. However, MBL protein secretion was not detectable 18 h after challenge with P. aeruginosa. Conclusions: MK due to P. aeruginosa triggers activation of MBL and the lectin pathway of complement. However, the physiologic relevance of this finding is unclear, as corresponding MBL oligomer production was not observed.
International journal of antimicrobial agents, 2014
This study aimed to investigate the probability of target attainment (PTA) of various anidulafung... more This study aimed to investigate the probability of target attainment (PTA) of various anidulafungin dosing regimens against Candida spp. in patients with acute leukaemia. A Monte Carlo simulation was performed using a previously published population pharmacokinetic model. The following dosing scenarios were evaluated: 200 mg loading dose (LD) on Day 1 then 100 mg daily (manufacturer's recommended dosing regimen); 200 mg LD on Day 1 then 100 mg every 48 h (q48 h); and 200 mg q48 h, 200 mg every 72 h (q72 h) and 300 mg q72 h. For each dosing regimen, free drug concentrations were calculated to evaluate the effect of 99% protein binding. The PTA at various pharmacodynamic (PD) targets was determined as the percentage of subjects who achieved a free drug area under the plasma concentration-time curve over the minimum inhibitory concentration ratio (ƒAUC/MIC) or a free drug maximum plasma concentration over the minimum inhibitory concentration ratio (ƒC(max)/MIC) above the PD targets...
The Medical journal of Australia, Jan 2, 2015
To explore organisational workflow and workplace culture influencing antibiotic prescribing behav... more To explore organisational workflow and workplace culture influencing antibiotic prescribing behaviour from the perspective of key health care providers working in residential aged care facilities (RACFs). Qualitative approach using semistructured interviews, focus groups and onsite observation between 8 January 2013 and 2 July 2013. Nursing staff, general practitioners and pharmacists servicing residents at 12 high-level care RACFs in Victoria were recruited. Emergent themes on antibiotic prescribing practices in RACFs. Sixty-one participants (40 nurses, 15 GPs and six pharmacists) participated. Factors influencing antibiotic prescribing practice have been divided into workflow-related and culture-related factors. Five major themes emerged among workflow-related factors: logistical challenges with provision of medical care, pharmacy support, nurse-driven infection management, institutional policies and guidelines, and external expertise and diagnostic facilities. Lack of onsite medical and pharmacy staff led to nursing staff adopting significant roles in infection management. However, numerous barriers hindered optimal antibiotic prescribing, especially inexperienced staff, lack of training of nurses in antibiotic use and lack of institutional infection management guidelines. With regard to culture-related factors, pressure from family to prescribe and institutional use of advance care directives were identified as important influences on antibiotic prescribing practices. Workflow- and culture-related barriers to optimal antibiotic prescribing were identified. This study has provided important insights to guide antimicrobial stewardship interventions in the RACF setting, particularly highlighting the role of nurses.
Journal of the American College of Cardiology, 2004
We conducted a systematic overview (meta-analysis) of randomized trials of balloon angioplasty ve... more We conducted a systematic overview (meta-analysis) of randomized trials of balloon angioplasty versus coronary atherectomy, laser angioplasty, or cutting balloon atherotomy to evaluate the effects of plaque modification during percutaneous coronary intervention. BACKGROUND Several mechanical approaches have been developed that ablate or section atheromatous plaque during percutaneous coronary interventions to optimize acute results, minimize intimal injury, and reduce complications and restenosis.
Journal of the American College of Cardiology, 2010
Current cardiology reports, 2008
Stents that elute antiproliferative drugs prevent restenosis after percutaneous coronary artery r... more Stents that elute antiproliferative drugs prevent restenosis after percutaneous coronary artery revascularization, reducing the need for repeat procedures. Randomized trials in low-risk patients supported initial regulatory approval for drug-eluting stents (DES). In 2006, meta-analyses of long-term outcomes from these trials associated DES use with adverse events, believed to be attributable to late stent thrombosis, occurring more than 9 months after the initial procedure. This article appraises these late adverse effects and illustrates the power and shortcomings of large national registries, focused, well-conducted clinical trials, and meta-analyses of clinical trial data. This timely, robust evidence base reflects an alignment of academic, industry, and public health priorities.
Expert Opinion on Pharmacotherapy, 2005
Percutaneous coronary intervention is an increasingly common treatment for many people with coron... more Percutaneous coronary intervention is an increasingly common treatment for many people with coronary disease. Randomised trials using antiproliferative, drug-eluting stents (DES) have shown important reductions in the need for repeat procedures after initial percutaneous coronary intervention. These trials indicate that the growing use of DES has the potential to create major clinical benefits for patients; however, in actual practice, the associated costs may cause financial crises for hospital systems. This paper reviews previously published DES economic decision models from both societal and hospital perspectives. From a social perspective, additional spending for new technologies may be acceptable if these technologies convincingly improve the lives of patients. The models reviewed suggest that DES incurs large costs to both society and hospitals, and currently offers uncertain clinical benefits. More research is recommended to identify high-risk patients who stand to gain significant health benefits from this therapy.
American Journal of Cardiovascular Drugs
Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed dose... more Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed doses defined for other pharmacological effects of the drug (such as analgesic effects). Antioxidant and anti-inflammatory mechanisms with different dose-response relationships may contribute to the clinical effect of aspirin in cardiovascular disease. The optimal aspirin dose remains uncertain. Although the difference between 325 mg/day and 81 mg/day of aspirin sounds trivial, finding an optimal aspirin dose has enormous potential to reduce ischemic events. Large aspirin doses have not been associated with proportionally greater benefit. For patients with ischemic heart disease, overall consensus defines a range between 75 and 160 mg/day for the secondary prevention of myocardial infarction, stroke, and vascular death. Any benefit of aspirin must be measured against its adverse effects, principally gastrointestinal hemorrhage. The potential for adverse bleeding events may be lower with a 81...
American Heart Journal, 1998
Implantation Trial (MADIT)I was a randomized clinical trial comparing patients receiving prophyla... more Implantation Trial (MADIT)I was a randomized clinical trial comparing patients receiving prophylactic therapy for coronary disease with asymptomatic, nonsustalned ventricular tachycardia (3 to 30 beats) and an implanted defibrillator with conventional medical therapy in patients with previous myocardial infarction and left ventricular dysfunction. In this study, the pattern and predictors of shock delivery in the implantable defibrillator arm of the trial were examined. Ninety patients with inducible but not suppressible ventricular tachycardia at electrophysiologic testing, mean age 62 _+ 9, mean left ventricular ejection fraction of 27% -+ 7%, who received an implantable defibrillator were followed-up for up to 5 years. Patients who received shocks (group 1, n = 44) were compared with those who did not receive shocks (group 2) regarding their demographic, clinical, arrhythmia, and electrophysiologic characteristics.The mean ejection fraction of patients receiving shocks was slightly lower (26% + 7%) than those who did not (28% + 6%, p = 0.09).At baseline, group 1 had a higher incidence of more than one myocardial infarction than did group 2 (49% vs 24%,p = 0.013) and a trend toward more diabetes.There was no other clinical difference between groups and no significant difference in the use of drug therapy, coronary artery bypass grafting, or percutaneous transltuninal coronary angioplasty. Both groups had simi-Interpretation: In MADIT patients who received implantable defibrillators, history of recurrent myocardial infarction, diabetes mellitus, and longer ventricular tachycardia episodes were associated with an increased incidence of shock delivery.
Circulation
Prior studies of coronary pattern and outcome after arterial switch operation (ASO) for transposi... more Prior studies of coronary pattern and outcome after arterial switch operation (ASO) for transposition of the great arteries (TGA) have been hindered by limited statistical power. This meta-analysis assesses the effect of coronary anatomy on post-ASO mortality, both overall and adjusted for time. A literature search revealed 9 independent series that reported post-ASO mortality by coronary pattern in a total of 1942 patients. Odds ratios comparing all-cause mortality in patients with usual versus variant coronary patterns were calculated and combined by use of an empirical Bayesian model. Single coronary patterns, both of which loop around the great vessels, were associated with significant mortality (OR 2.9, 95% CI 1.3 to 6.8), whereas looping patterns that arose from 2 separate ostia were not (OR 1.2, 95% CI 0.8 to 1.9). This latter group includes patients with the most common variant, circumflex from right coronary artery. Patients with an intramural coronary artery had the greate...
American Heart Journal, 1998
American Heart Journal, Volume 135, Issue 1, Pages 157-180, January 1998, Authors:John H. Alexand... more American Heart Journal, Volume 135, Issue 1, Pages 157-180, January 1998, Authors:John H. Alexander, MD; Karen Alexander, MD; David F. Kong, MD; Chen Y. Tung, MD; David Whellan, MD.
Molecular vision, 2014
Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. P... more Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. MBL gene expression was not de...
American Heart Journal, 2004
glycoprotein IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary in... more glycoprotein IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary intervention (PCI). Only one study, 1 however, has formally evaluated adjunctive glycoprotein IIb/IIIa inhibition in the setting of coronary stent implantation, even though stents are now used in more than 80% of all percutaneous interventions. Moreover, in the clinical trials performed to date, eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has appeared to be less potent than the monoclonal antibody abciximab. It has since been recognized that an approximately 4 times higher dose of eptifibatide than that used in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial would be required to achieve maximal platelet inhibition in coronary interventions.The ESPRIT trial was designed to test the safety and efficacy of an adjunctive, highdose, double-bolus regimen of eptifibatide in coronary stenting. Patients with known coronary artery disease who were scheduled to undergo elective PCI with stent implantation in a native coronary artery and who, in the opinion of the treating physician, would not routinely be treated with a IIb/IIIa inhibitor, were eligible for inclusion. Patients with a myocardial infarction (MI) within 24 hours before randomization were excluded from the trial. Patients were randomly assigned to receive either placebo or eptifibatide started immediately before PCI. Eptifibatide was given as two 180-µg/kg boluses 10 minutes apart and as a continuous infusion of 2.0 µg/kg per minute (or 1.0 µg/kg per minute in patients with serum creatinine >2.0 mg/dL) started at the same time as the first bolus and continued for 18 to 24 hours.All patients received concomitant aspirin.A weight-adjusted heparin regimen was recommended (initial bolus of 60 U/kg, not to exceed 6000 U) with a target activated clotting time between 200 and 300 seconds.Treatment with ticlopidine or clopidogrel was strongly encouraged on the day of the procedure but not before then; the use of a loading dose was also encouraged.
Cardiology Clinics, 1999
Worldwide, UA represents a significant allocation of resources. UA represents a syndrome where no... more Worldwide, UA represents a significant allocation of resources. UA represents a syndrome where not only do many therapies exist, but considerable clinical trial evidence has accumulated. Universal application of effective practice patterns is warranted if we are to successfully reduce the burden of UA. Economic analyses cannot resolve many of the underlying societal issues that affect decision making. Often, the acceptability of an economic burden is dependent on the willingness of both individuals and society to pay. In an interesting study, Chestnut et al evaluated the willingness of 50 patients to pay for avoiding a worsening of their angina symptoms. On average, the patients were willing to pay between 210and210 and 210and499 to avoid four to eight additional angina episodes each month. The "rule of rescue" suggests that society is often willing to pay large sums of money to save those in extreme need, such as the 55-year-old man rushed to the emergency department clutching his chest. Only recently has attention been paid to how much this disease entity costs us. Whereas the 1980s and 1990s saw a focus on costs, the next century will increasingly focus on value--obtaining the best health outcome for the dollars spent. Debate has shifted, at least in part, from purely financial costs to medical effectiveness and outcomes management. Continuing assessments of value of interventions and application of evidence based-management strategies permit rational selection of therapy and allow us best to bear the burden of UA.
Hospital Practice, 2000
Acute coronary syndromes is a new term that encompasses the many permutations of acute ischemic h... more Acute coronary syndromes is a new term that encompasses the many permutations of acute ischemic heart disease. Management guidelines can help steer clinicians through diagnosis and facilitate rational selection of therapy from the myriad of available treatments.
Background: Recent pharmacokinetic/pharmacodynamic (PK/PD) evaluations find that higher oseltamiv... more Background: Recent pharmacokinetic/pharmacodynamic (PK/PD) evaluations find that higher oseltamivir exposures may reduce duration of viral shedding and symptoms. However, the impact of such findings on pandemic planning decisions and use of stockpiles has not been described. This study explored the economic impact of oseltamivir dose optimization in supporting pandemic influenza planning decisions in the US. Methods: We simulated the infected population across a 1 year seasonal influenza outbreak using a health economic model linked to a PK/PD-epidemiology model (SEIR). Different scenarios were considered to evaluate the cost-effectiveness of high dose (150mg BID) vs standard dose (75mg BID) oseltamivir, low and high virulence, varying transmissibility (low and high attack rates (37% and 67.5% respectively)) and drug uptake (25%, 50%, and 80%). The analysis was conducted from a societal perspective, incorporating both direct and indirect costs. Disease epidemiology and costs were US...
Background: Whilst the potential for pharmacokinetic/pharmacodynamic (PK/PD) optimisation of anti... more Background: Whilst the potential for pharmacokinetic/pharmacodynamic (PK/PD) optimisation of anti-influenza therapy to improve individual patient outcomes has been published, the indirect benefits of reducing disease transmission has not been described. We explored the latter using a novel approach to link oseltamivir (OS) PK/PD to epidemiological models of influenza (flu) transmission. With this linked PK/PD-Epi model, we examined the impact of high and low doses of OS on flu attack rates (AR) under different levels of infectiousness and percentages of patients receiving OS. Methods: OS active metabolite (OC) AUC distributions were simulated for 75 and 150mg po BID via a published population PK model. In the model, flu viral shedding duration (Tshed) is impacted by OC exposure according to published PK/PD breakpoints. The effect of treatment with OS on Tshed was linked to an SEIR (Susceptible, Exposed, Infected, Recovered) compartmental model incorporating OS treatment. Using Monte...
JACC. Cardiovascular interventions, 2014
This study sought to determine the effect of radial access on outcomes in women undergoing percut... more This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significa...
The Medical Journal of Australia, 2014
Journal of the American Heart Association, 2013
Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology d... more Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology development. Our goal was to describe the cardiovascular clinical research portfolio from ClinicalTrials.gov. We identified 40 970 clinical research studies registered between 2007 and 2010 in which patients received diagnostic, therapeutic, or other interventions per protocol. By annotating 18 491 descriptors from the National Library of Medicine's Medical Subject Heading thesaurus and 1220 free-text terms to select those relevant to cardiovascular disease, we identified studies that related to the diagnosis, treatment, or prevention of diseases of the heart and peripheral arteries in adults (n = 2325 [66%] included from review of 3503 potential studies). The study intervention involved a drug in 44.6%, a device or procedure in 39.3%, behavioral intervention in 8.1%, and biological or genetic interventions in 3.0% of the trials. More than half of the trials were postmarket approval (...
Purpose: Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening d... more Purpose: Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. Methods: Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. Results: MBL gene expression was not detected in unchallenged HCECs. Exposure of HCECs to P. aeruginosa resulted in rapid induction of the transcriptional expression of MBL, IL-6, and IL-8. In addition, expression of several complement proteins of the classical and lectin pathways, but not the alternative pathway, were upregulated after 5 h of challenge, including MBL-associated serine protease 1. However, MBL protein secretion was not detectable 18 h after challenge with P. aeruginosa. Conclusions: MK due to P. aeruginosa triggers activation of MBL and the lectin pathway of complement. However, the physiologic relevance of this finding is unclear, as corresponding MBL oligomer production was not observed.
International journal of antimicrobial agents, 2014
This study aimed to investigate the probability of target attainment (PTA) of various anidulafung... more This study aimed to investigate the probability of target attainment (PTA) of various anidulafungin dosing regimens against Candida spp. in patients with acute leukaemia. A Monte Carlo simulation was performed using a previously published population pharmacokinetic model. The following dosing scenarios were evaluated: 200 mg loading dose (LD) on Day 1 then 100 mg daily (manufacturer's recommended dosing regimen); 200 mg LD on Day 1 then 100 mg every 48 h (q48 h); and 200 mg q48 h, 200 mg every 72 h (q72 h) and 300 mg q72 h. For each dosing regimen, free drug concentrations were calculated to evaluate the effect of 99% protein binding. The PTA at various pharmacodynamic (PD) targets was determined as the percentage of subjects who achieved a free drug area under the plasma concentration-time curve over the minimum inhibitory concentration ratio (ƒAUC/MIC) or a free drug maximum plasma concentration over the minimum inhibitory concentration ratio (ƒC(max)/MIC) above the PD targets...
The Medical journal of Australia, Jan 2, 2015
To explore organisational workflow and workplace culture influencing antibiotic prescribing behav... more To explore organisational workflow and workplace culture influencing antibiotic prescribing behaviour from the perspective of key health care providers working in residential aged care facilities (RACFs). Qualitative approach using semistructured interviews, focus groups and onsite observation between 8 January 2013 and 2 July 2013. Nursing staff, general practitioners and pharmacists servicing residents at 12 high-level care RACFs in Victoria were recruited. Emergent themes on antibiotic prescribing practices in RACFs. Sixty-one participants (40 nurses, 15 GPs and six pharmacists) participated. Factors influencing antibiotic prescribing practice have been divided into workflow-related and culture-related factors. Five major themes emerged among workflow-related factors: logistical challenges with provision of medical care, pharmacy support, nurse-driven infection management, institutional policies and guidelines, and external expertise and diagnostic facilities. Lack of onsite medical and pharmacy staff led to nursing staff adopting significant roles in infection management. However, numerous barriers hindered optimal antibiotic prescribing, especially inexperienced staff, lack of training of nurses in antibiotic use and lack of institutional infection management guidelines. With regard to culture-related factors, pressure from family to prescribe and institutional use of advance care directives were identified as important influences on antibiotic prescribing practices. Workflow- and culture-related barriers to optimal antibiotic prescribing were identified. This study has provided important insights to guide antimicrobial stewardship interventions in the RACF setting, particularly highlighting the role of nurses.
Journal of the American College of Cardiology, 2004
We conducted a systematic overview (meta-analysis) of randomized trials of balloon angioplasty ve... more We conducted a systematic overview (meta-analysis) of randomized trials of balloon angioplasty versus coronary atherectomy, laser angioplasty, or cutting balloon atherotomy to evaluate the effects of plaque modification during percutaneous coronary intervention. BACKGROUND Several mechanical approaches have been developed that ablate or section atheromatous plaque during percutaneous coronary interventions to optimize acute results, minimize intimal injury, and reduce complications and restenosis.
Journal of the American College of Cardiology, 2010
Current cardiology reports, 2008
Stents that elute antiproliferative drugs prevent restenosis after percutaneous coronary artery r... more Stents that elute antiproliferative drugs prevent restenosis after percutaneous coronary artery revascularization, reducing the need for repeat procedures. Randomized trials in low-risk patients supported initial regulatory approval for drug-eluting stents (DES). In 2006, meta-analyses of long-term outcomes from these trials associated DES use with adverse events, believed to be attributable to late stent thrombosis, occurring more than 9 months after the initial procedure. This article appraises these late adverse effects and illustrates the power and shortcomings of large national registries, focused, well-conducted clinical trials, and meta-analyses of clinical trial data. This timely, robust evidence base reflects an alignment of academic, industry, and public health priorities.
Expert Opinion on Pharmacotherapy, 2005
Percutaneous coronary intervention is an increasingly common treatment for many people with coron... more Percutaneous coronary intervention is an increasingly common treatment for many people with coronary disease. Randomised trials using antiproliferative, drug-eluting stents (DES) have shown important reductions in the need for repeat procedures after initial percutaneous coronary intervention. These trials indicate that the growing use of DES has the potential to create major clinical benefits for patients; however, in actual practice, the associated costs may cause financial crises for hospital systems. This paper reviews previously published DES economic decision models from both societal and hospital perspectives. From a social perspective, additional spending for new technologies may be acceptable if these technologies convincingly improve the lives of patients. The models reviewed suggest that DES incurs large costs to both society and hospitals, and currently offers uncertain clinical benefits. More research is recommended to identify high-risk patients who stand to gain significant health benefits from this therapy.
American Journal of Cardiovascular Drugs
Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed dose... more Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed doses defined for other pharmacological effects of the drug (such as analgesic effects). Antioxidant and anti-inflammatory mechanisms with different dose-response relationships may contribute to the clinical effect of aspirin in cardiovascular disease. The optimal aspirin dose remains uncertain. Although the difference between 325 mg/day and 81 mg/day of aspirin sounds trivial, finding an optimal aspirin dose has enormous potential to reduce ischemic events. Large aspirin doses have not been associated with proportionally greater benefit. For patients with ischemic heart disease, overall consensus defines a range between 75 and 160 mg/day for the secondary prevention of myocardial infarction, stroke, and vascular death. Any benefit of aspirin must be measured against its adverse effects, principally gastrointestinal hemorrhage. The potential for adverse bleeding events may be lower with a 81...
American Heart Journal, 1998
Implantation Trial (MADIT)I was a randomized clinical trial comparing patients receiving prophyla... more Implantation Trial (MADIT)I was a randomized clinical trial comparing patients receiving prophylactic therapy for coronary disease with asymptomatic, nonsustalned ventricular tachycardia (3 to 30 beats) and an implanted defibrillator with conventional medical therapy in patients with previous myocardial infarction and left ventricular dysfunction. In this study, the pattern and predictors of shock delivery in the implantable defibrillator arm of the trial were examined. Ninety patients with inducible but not suppressible ventricular tachycardia at electrophysiologic testing, mean age 62 _+ 9, mean left ventricular ejection fraction of 27% -+ 7%, who received an implantable defibrillator were followed-up for up to 5 years. Patients who received shocks (group 1, n = 44) were compared with those who did not receive shocks (group 2) regarding their demographic, clinical, arrhythmia, and electrophysiologic characteristics.The mean ejection fraction of patients receiving shocks was slightly lower (26% + 7%) than those who did not (28% + 6%, p = 0.09).At baseline, group 1 had a higher incidence of more than one myocardial infarction than did group 2 (49% vs 24%,p = 0.013) and a trend toward more diabetes.There was no other clinical difference between groups and no significant difference in the use of drug therapy, coronary artery bypass grafting, or percutaneous transltuninal coronary angioplasty. Both groups had simi-Interpretation: In MADIT patients who received implantable defibrillators, history of recurrent myocardial infarction, diabetes mellitus, and longer ventricular tachycardia episodes were associated with an increased incidence of shock delivery.
Circulation
Prior studies of coronary pattern and outcome after arterial switch operation (ASO) for transposi... more Prior studies of coronary pattern and outcome after arterial switch operation (ASO) for transposition of the great arteries (TGA) have been hindered by limited statistical power. This meta-analysis assesses the effect of coronary anatomy on post-ASO mortality, both overall and adjusted for time. A literature search revealed 9 independent series that reported post-ASO mortality by coronary pattern in a total of 1942 patients. Odds ratios comparing all-cause mortality in patients with usual versus variant coronary patterns were calculated and combined by use of an empirical Bayesian model. Single coronary patterns, both of which loop around the great vessels, were associated with significant mortality (OR 2.9, 95% CI 1.3 to 6.8), whereas looping patterns that arose from 2 separate ostia were not (OR 1.2, 95% CI 0.8 to 1.9). This latter group includes patients with the most common variant, circumflex from right coronary artery. Patients with an intramural coronary artery had the greate...
American Heart Journal, 1998
American Heart Journal, Volume 135, Issue 1, Pages 157-180, January 1998, Authors:John H. Alexand... more American Heart Journal, Volume 135, Issue 1, Pages 157-180, January 1998, Authors:John H. Alexander, MD; Karen Alexander, MD; David F. Kong, MD; Chen Y. Tung, MD; David Whellan, MD.
Molecular vision, 2014
Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. P... more Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. MBL gene expression was not de...
American Heart Journal, 2004
glycoprotein IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary in... more glycoprotein IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary intervention (PCI). Only one study, 1 however, has formally evaluated adjunctive glycoprotein IIb/IIIa inhibition in the setting of coronary stent implantation, even though stents are now used in more than 80% of all percutaneous interventions. Moreover, in the clinical trials performed to date, eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has appeared to be less potent than the monoclonal antibody abciximab. It has since been recognized that an approximately 4 times higher dose of eptifibatide than that used in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial would be required to achieve maximal platelet inhibition in coronary interventions.The ESPRIT trial was designed to test the safety and efficacy of an adjunctive, highdose, double-bolus regimen of eptifibatide in coronary stenting. Patients with known coronary artery disease who were scheduled to undergo elective PCI with stent implantation in a native coronary artery and who, in the opinion of the treating physician, would not routinely be treated with a IIb/IIIa inhibitor, were eligible for inclusion. Patients with a myocardial infarction (MI) within 24 hours before randomization were excluded from the trial. Patients were randomly assigned to receive either placebo or eptifibatide started immediately before PCI. Eptifibatide was given as two 180-µg/kg boluses 10 minutes apart and as a continuous infusion of 2.0 µg/kg per minute (or 1.0 µg/kg per minute in patients with serum creatinine >2.0 mg/dL) started at the same time as the first bolus and continued for 18 to 24 hours.All patients received concomitant aspirin.A weight-adjusted heparin regimen was recommended (initial bolus of 60 U/kg, not to exceed 6000 U) with a target activated clotting time between 200 and 300 seconds.Treatment with ticlopidine or clopidogrel was strongly encouraged on the day of the procedure but not before then; the use of a loading dose was also encouraged.
Cardiology Clinics, 1999
Worldwide, UA represents a significant allocation of resources. UA represents a syndrome where no... more Worldwide, UA represents a significant allocation of resources. UA represents a syndrome where not only do many therapies exist, but considerable clinical trial evidence has accumulated. Universal application of effective practice patterns is warranted if we are to successfully reduce the burden of UA. Economic analyses cannot resolve many of the underlying societal issues that affect decision making. Often, the acceptability of an economic burden is dependent on the willingness of both individuals and society to pay. In an interesting study, Chestnut et al evaluated the willingness of 50 patients to pay for avoiding a worsening of their angina symptoms. On average, the patients were willing to pay between 210and210 and 210and499 to avoid four to eight additional angina episodes each month. The "rule of rescue" suggests that society is often willing to pay large sums of money to save those in extreme need, such as the 55-year-old man rushed to the emergency department clutching his chest. Only recently has attention been paid to how much this disease entity costs us. Whereas the 1980s and 1990s saw a focus on costs, the next century will increasingly focus on value--obtaining the best health outcome for the dollars spent. Debate has shifted, at least in part, from purely financial costs to medical effectiveness and outcomes management. Continuing assessments of value of interventions and application of evidence based-management strategies permit rational selection of therapy and allow us best to bear the burden of UA.
Hospital Practice, 2000
Acute coronary syndromes is a new term that encompasses the many permutations of acute ischemic h... more Acute coronary syndromes is a new term that encompasses the many permutations of acute ischemic heart disease. Management guidelines can help steer clinicians through diagnosis and facilitate rational selection of therapy from the myriad of available treatments.
Background: Recent pharmacokinetic/pharmacodynamic (PK/PD) evaluations find that higher oseltamiv... more Background: Recent pharmacokinetic/pharmacodynamic (PK/PD) evaluations find that higher oseltamivir exposures may reduce duration of viral shedding and symptoms. However, the impact of such findings on pandemic planning decisions and use of stockpiles has not been described. This study explored the economic impact of oseltamivir dose optimization in supporting pandemic influenza planning decisions in the US. Methods: We simulated the infected population across a 1 year seasonal influenza outbreak using a health economic model linked to a PK/PD-epidemiology model (SEIR). Different scenarios were considered to evaluate the cost-effectiveness of high dose (150mg BID) vs standard dose (75mg BID) oseltamivir, low and high virulence, varying transmissibility (low and high attack rates (37% and 67.5% respectively)) and drug uptake (25%, 50%, and 80%). The analysis was conducted from a societal perspective, incorporating both direct and indirect costs. Disease epidemiology and costs were US...
Background: Whilst the potential for pharmacokinetic/pharmacodynamic (PK/PD) optimisation of anti... more Background: Whilst the potential for pharmacokinetic/pharmacodynamic (PK/PD) optimisation of anti-influenza therapy to improve individual patient outcomes has been published, the indirect benefits of reducing disease transmission has not been described. We explored the latter using a novel approach to link oseltamivir (OS) PK/PD to epidemiological models of influenza (flu) transmission. With this linked PK/PD-Epi model, we examined the impact of high and low doses of OS on flu attack rates (AR) under different levels of infectiousness and percentages of patients receiving OS. Methods: OS active metabolite (OC) AUC distributions were simulated for 75 and 150mg po BID via a published population PK model. In the model, flu viral shedding duration (Tshed) is impacted by OC exposure according to published PK/PD breakpoints. The effect of treatment with OS on Tshed was linked to an SEIR (Susceptible, Exposed, Infected, Recovered) compartmental model incorporating OS treatment. Using Monte...
JACC. Cardiovascular interventions, 2014
This study sought to determine the effect of radial access on outcomes in women undergoing percut... more This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significa...
The Medical Journal of Australia, 2014
Journal of the American Heart Association, 2013
Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology d... more Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology development. Our goal was to describe the cardiovascular clinical research portfolio from ClinicalTrials.gov. We identified 40 970 clinical research studies registered between 2007 and 2010 in which patients received diagnostic, therapeutic, or other interventions per protocol. By annotating 18 491 descriptors from the National Library of Medicine's Medical Subject Heading thesaurus and 1220 free-text terms to select those relevant to cardiovascular disease, we identified studies that related to the diagnosis, treatment, or prevention of diseases of the heart and peripheral arteries in adults (n = 2325 [66%] included from review of 3503 potential studies). The study intervention involved a drug in 44.6%, a device or procedure in 39.3%, behavioral intervention in 8.1%, and biological or genetic interventions in 3.0% of the trials. More than half of the trials were postmarket approval (...