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1.  Validity of International Classification of Disease Codes to Identify Ischemic Stroke and Intracranial Hemorrhage among Individuals with Associated Diagnosis of Atrial Fibrillation 
Due to its association with death and disability, stroke is a focus of outcomes in atrial fibrillation (AF) research. International Classification of Disease 9th (ICD-9) edition codes are commonly used to identify stroke in research, particularly in large administrative data. We sought to assess the validity of ICD-9 codes in stroke case ascertainment and for AF across three institutions.
Methods and Results
Participating centers included Boston Medical Center (safety net hospital), Geisinger Health System (rural Pennsylvania), and the University of Alabama (academic center in the southeastern “stroke belt”). ICD-9 codes for ischemic stroke (433-434, 436) and intracranial hemorrhage (ICH) (430-432) identified 1,812 stroke cases with an associated code for atrial fibrillation (427.31) from 2006-2010. Cases were vetted through chart review with final adjudication by a stroke neurologist.
Review deemed 94.2% of ICD-9 identified stroke cases valid with decreased accuracy for concurrent AF diagnosis (82.28%) and stroke attributable to AF (72.8%). Among events with “without infarction” modifiers, 7.2% were valid strokes. ICD-9 stroke code accuracy did not differ by stroke type or site. Stroke code 434 displayed higher accuracy than 433 (94.4% vs. 85.2%; p<0.01) and primary stroke codes were more accurate than non-primary codes (97.2% vs. 83.7%; p<0.0001).
Using ICD-9 stroke and AF codes to identify patients with stroke plus AF resulted in inaccuracies. Given the expanded financial and policy implications of patient-oriented research, conclusions derived solely from administrative data without validation of outcome events should be interpreted with caution.
PMCID: PMC4654947  PMID: 25587093
ischemic stroke; intracranial hemorrhage; hemorrhagic stroke; atrial fibrillation; International Classification of Disease 9th Edition Codes
2.  Would Tirofiban Have Been Shown Non-Inferior to Abciximab Had the TENACITY Trial Not Been Terminated for Financial Reasons? 
To investigate whether tirofiban would have been non-inferior to abciximab had the trial completed enrollment, and we place the termination of this trial in a broader research ethics context.
TENACITY was terminated by the sponsor for financial reasons. At the time, event rates for the 2 treatment arms were unknown.
TENACITY was designed to compare tirofiban with abciximab in approximately 8000 patients; however, enrollment was terminated after 383 (4.8%) patients. The primary endpoint was a composite of 30-day death, myocardial infarction, and urgent target vessel revascularization. Non-inferiority was defined as the likelihood that tirofiban would preserve at least 50% of the ability of abciximab to reduce the primary endpoint at 30 days, based on abciximab’s demonstrated ability to reduce such events by 43% (relative risk, 0.573; 95% confidence interval [CI], 0.507–0.648; P<0.001). To determine the probability of non-inferiority given the patients already enrolled, a Bayesian approach was used.
The primary composite endpoint occurred in 8.8% of patients randomized to abciximab vs. 6.9% receiving high-bolus-dose tirofiban (odds ratio, 0.77; 95% CI, 0.37–1.64). The estimated conditional power for the test that tirofiban would be non-inferior to abciximab if all patients been enrolled is 93.7%. Using the estimated predictive power method, the likelihood was 84.8%.
TENACITY was well-powered to identify non-inferiority with tirofiban vs. abciximab, and the patients enrolled strengthened the probability that this would have been the outcome had the trial been completed. When a clinical trial is terminated solely for financial reasons, it is incumbent upon the sponsor to provide proper patient follow-up and publication of the findings.
PMCID: PMC4156852  PMID: 23379785
glycoprotein IIb/IIIa inhibitors; clinical trial; tirofiban; abciximab
3.  Pro-Inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated by Oxidized Phospholipids and Lipoprotein (a) 
To assess the influence of pro-inflammatory IL-1 genotype status on the risk of CAD, defined as >50% diameter stenosis, and cardiovascular events mediated by OxPL and Lp(a).
Oxidized phospholipids (OxPL) are pro-inflammatory, circulate on lipoprotein (a) [Lp(a)] and mediate coronary artery disease (CAD). Genetic variations in the interleukin-1 (IL-1) region are associated with increased inflammatory mediators.
IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB) and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by three single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(−).
Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk of CAD compared to the lowest quartile (OR 2.84, P=0.001). This effect was accentuated in patients ≤60 years old (OR 7.03, P<0.001). In IL-1(−) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR 1.99, P=0.004) and Lp(a) (OR 1.96, P<0.001) in IL-1(+) versus IL-1(−) groups for patients ≤60 years old but not for patients >60 years old. In IL-1(+) patients ≤60 years old, after adjusting for established risk factors, high sensitivity C-reactive protein and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (P=0.002) and had worse 4-year event-free survival (death, MI, stroke, and revascularization) compared to other groups (P=0.006).
Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically-relevant biological link between pro-inflammatory IL-1 genotypes, oxidation of phospholipids, Lp(a) and genetic predisposition to CAD and cardiovascular events.
PMCID: PMC4008715  PMID: 24530664
lipoproteins; oxidation; atherosclerosis; lipoprotein (a); oxidized phospholipids; IL-1; polymorphism; haplotype; inflammation; genetic risk stratification
4.  Risk Stratification for Long-Term Mortality Following Percutaneous Coronary Intervention 
A simple risk score to predict long-term mortality after percutaneous coronary intervention (PCI) using pre-procedural risk factors is currently not available. In this study, we created one by simplifying the results of a Cox proportional hazards model.
Methods and Results
A total of 11,897 patients who underwent PCI from October through December 2003 in New York State were randomly divided into derivation and validation samples. Patients’ vital statuses were tracked using the National Death Index through the end of 2008. A Cox proportional hazards model was fit to predict death after PCI using the derivation sample, and a simplified risk score was created. The Cox model identified 12 separate risk factors for mortality including older age, extreme body mass indexes, multivessel disease, a lower ejection fraction, unstable hemodynamic state or shock, a number of comorbidities (cerebrovascular disease, peripheral vascular disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, and renal failure), and a history of coronary artery bypass graft surgery. The C statistics of this model when applied to the validation sample were 0.787, 0.785, and 0.773 for risks of death within 1, 3, and 5 years after PCI, respectively. In addition, the point-based risk score demonstrated good agreement between patients’ observed and predicted risks of death.
A simple risk score created from a more complicated Cox proportional hazards model can be used to accurately predict a patient's risk of long-term mortality after PCI.
PMCID: PMC4121885  PMID: 24425588
PCI; follow-up study; mortality; risk score
5.  Impact of Proton Pump Inhibitor Therapy on the Efficacy of Clopidogrel in the CAPRIE and CREDO Trials 
Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.
Methods and Results
The impact of PPI use on the 1‐year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death, MI, or urgent target vessel revascularization) and 1‐year (all‐cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non‐PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non‐PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).
In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non‐PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
PMCID: PMC3603228  PMID: 23525436
CAPRIE; clopidogrel; CREDO; drug–drug interaction; proton pump inhibitors
6.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
7.  Distal protection devices during percutaneous coronary and carotid interventions 
Distal embolization of particulate matter complicates percutaneous coronary and peripheral interventions more often than had been recognized until recently. A number of distal protection devices are under development. The PercuSurge GuardWire™ is a balloon occlusion thrombectomy device approved by the United States Food and Drug Administration for saphenous vein graft intervention. A number of filter devices utilize an expandable filter mounted on the angioplasty guidewire to facilitate entrapment of particles and safe removal. The Parodi Anti-Emboli System™ is an example of a catheter occlusion device that establishes protection by reversing blood flow in the target vessel.
PMCID: PMC64830  PMID: 11806815
angioplasty; distal protection device; procedural myocardial infarction
8.  Results of the Ticlid or Plavix Post-Stents (TOPPS) trial: do they justify the switch from ticlopidine to clopidogrel after coronary stent placement? 
In the Ticlid or Plavix Post-Stents (TOPPS) trial, 1016 patients undergoing successful coronary stent placement were randomized to receive aspirin and either ticlopidine or clopidogrel. In this trial, the dosages and regimens of ticlopidine and clopidogrel resembled more closely those used in most catheterization laboratories than did the two previous randomized trials comparing ticlopidine and clopidogrel. The results of the TOPPS trial support the current practice of substituting ticlopidine for clopidogrel in stent patients.
PMCID: PMC59605  PMID: 11714416
angioplasty; antiplatelet drugs; clopidogrel; stents; thienopyridine; ticlopidine

Results 1-8 (8)