Prediction of infarct coronary artery recanalization after intravenous thrombolytic therapy

Clinical assessment of patients with evolving acute myocardial infarction may suggest recanalization of the infarct coronary artery if chest pain, electrocardiographic ST-segment elevation and reperfusion arrhythmia are diminished. These 3 criteria, however, have not been correlated with immediate coronary angiography. Determination of which patients will achieve myocardial reperfusion after intravenous fibrinolytic therapy would allow for appropriate triage; those in whom it falls may be considered for mechanical or surgical recanalization. Fifty-six patients were studied: 28 received intravenous streptokinase and 28 intravenous recombinant tissue-type plasminogen activator. None of these clinical criteria, considered separately, was predictive of infarct artery recanalization status. Using the presence or absence of all 3 criteria, the specificity and predictive value increased to 100%. However, only 9% of patients in the series had all 3 criteria present (all had a patent infarct artery) and 34% had no criteria present (all had an occluded vessel). Noninvasive clinical markers are simple and practical, but only concordance of all 3 major criteria, when present, accurately predicts results of thrombolytic therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26794/1/0000350.pd

Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention

AbstractObjectives. We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide.Background. Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain.Methods. Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n = 3,535) and CK-MB (n = 2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site’s upper normal limit).Results. Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure.Conclusions. Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI

Systematic adjudication of myocardial infarction end-points in an international clinical trial

BACKGROUND: Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected end-point (post-enrolment) myocardial infarction (MI) in the large Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial. METHODS: The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. A central adjudication process was established prospectively to identify all suspected MIs and adjudicate events based on protocol definitions of MI. Suspected MIs were identified by systematic review of data collection forms, cardiac enzyme results, and electrocardiograms. Two physicians independently reviewed all suspected events. If they disagreed whether a MI had occurred, a committee of cardiologists adjudicated the case. RESULTS: The CEC identified 5005 patients with suspected infarction (46%), of which 1415 (28%) were adjudicated as end-point infarctions. As expected, the process identified more end-point events than did the site investigators. Absolute and relative treatment effects of eptifibatide were smaller when using CEC-determined MI rates rather than site investigator-determined rates. The site-investigator reporting of MI and the CEC assessment of MI disagreed in 20% of the cases reviewed by the CEC. CONCLUSIONS: End-point adjudication by a CEC is important, to provide standardised, systematic, independent, and unbiased assessment of end-points, particularly in trials that span geographic regions and clinical practice settings. Understanding the CEC process used is important in the interpretation of trial results and event rates

Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study

BACKGROUND: Limited information has been published regarding how specific processes for event adjudication can affect event rates in trials. We reviewed nonfatal myocardial infarctions (MIs) reported by site investigators in the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and those adjudicated by a central clinical events committee (CEC) to determine the reasons for differences in event rates. METHODS: The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. The primary end-point was death or post-enrolment MI at 30 days as assessed by the CEC; this end-point was also constructed using site-reported events. The CEC identified suspected MIs by systematic review of clinical, cardiac enzyme, and electrocardiographic data. RESULTS: The CEC identified 5005 (46%) suspected events, of which 1415 (28%) were adjudicated as MI. The site investigator and CEC assessments of whether a MI had occurred disagreed in 983 (20%) of the 5005 patients with suspected MI, mostly reflecting site misclassification of post-enrolment MIs (as enrolment MIs) or underreported periprocedural MIs. Patients for whom the CEC and site investigator agreed that no end-point MI had occurred had the lowest mortality at 30 days and between 30 days and 6 months, and those with agreement that a MI had occurred had the highest mortality. CONCLUSION: CEC adjudication provides a standard, systematic, independent, and unbiased assessment of end-points, particularly for trials that span geographic regions and clinical practice settings. Understanding the review process and reasons for disagreement between CEC and site investigator assessments of MI is important to design future trials and interpret event rates between trials

Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes.

AIM: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronar

Twelve Years' Experience with Direct-to-Consumer Advertising of Prescription Drugs in Canada: A Cautionary Tale

Direct-to-consumer advertising (DTCA) of prescription drugs is illegal in Canada as a health protection measure, but is permitted in the United States. However, in 2000, Canadian policy was changed to allow 'reminder' advertising of prescription drugs. This is a form of advertising that states the brand name without health claims. 'Reminder' advertising is prohibited in the US for drugs that have 'black box' warnings of serious risks. This study examines spending on DTCA in Canada from 1995 to 2006, 12 years spanning this policy shift. We ask how annual per capita spending compares to that in the US, and whether drugs with Canadian or US regulatory safety warnings are advertised to the Canadian public in reminder advertising.Prescription drug advertising spending data were extracted from a data set on health sector spending in Canada obtained from a market research company, TNS Media Inc. Spending was adjusted for inflation and compared with US spending. Inflation-adjusted spending on branded DTCA in Canada grew from under CAD$2 million per year before 1999 to over$22 million in 2006. The major growth was in broadcast advertising, accounting for 83% of spending in 2006. US annual per capita spending was on average 24 times Canadian levels. Celebrex (celecoxib), which has a US black box and was subject to three safety advisories in Canada, was the most heavily advertised drug on Canadian television in 2005 and 2006. Of 8 brands with >$500,000 spending, which together accounted for 59% of branded DTCA in all media, 6 were subject to Canadian safety advisories, and 4 had US black box warnings.Branded 'reminder' advertising has grown rapidly in Canada since 2000, mainly due to a growth in television advertising. Although DTCA spending per capita is much lower in Canada than in the US, there is no evidence of safer content or product choice; many heavily-advertised drugs in Canada have been subject to safety advisories. For governments searching for compromise solutions to industry pressure for expanded advertising, Canada's experience stands as a stark warning

No evidence for cardiac dysfunction in Kif6 mutant mice.

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function

The Intensive Diet and Exercise for Arthritis (IDEA) trial: design and rationale

Background: Obesity is the most modifiable risk factor, and dietary induced weight loss potentially the best nonpharmacologic intervention to prevent or to slow osteoarthritis (OA) disease progression. We are currently conducting a study to test the hypothesis that intensive weight loss will reduce inflammation and joint loads sufficiently to alter disease progression, either with or without exercise. This article describes the intervention, the empirical evidence to support it, and test-retest reliability data. Methods/Design: This is a prospective, single-blind, randomized controlled trial. The study population consists of 450 overweight and obese (BMI = 27-40.5 kg/m2) older (age greater than or equal to 55 yrs) adults with tibiofemoral osteoarthritis. Participants are randomized to one of three 18-month interventions: intensive dietary restriction-plus-exercise; exercise-only; or intensive dietary restriction-only. The primary aims are to compare the effects of these interventions on inflammatory biomarkers and knee joint loads. Secondary aims will examine the effects of these interventions on function, pain, and mobility; the dose response to weight loss on disease progression; if inflammatory biomarkers and knee joint loads are mediators of the interventions; and the association between quadriceps strength and disease progression. Results: Test-retest reliability results indicated that the ICCs for knee joint load variables were excellent, ranging from 0.86 - 0.98. Knee flexion/extension moments were most affected by BMI, with lower reliability with the highest tertile of BMI. The reliability of the semi-quantitative scoring of the knee joint using MRI exceeded previously reported results, ranging from a low of 0.66 for synovitis to a high of 0.99 for bone marrow lesion size. Discussion: The IDEA trial has the potential to enhance our understanding of the OA disease process, refine weight loss and exercise recommendations in this prevalent disease, and reduce the burden of disability. Originally published BMC Musculoskeletal Disorders, Vol. 10, No. 93, July 200

A High-Density Genome-Wide Association Screen of Sporadic ALS in US Veterans

Following reports of an increased incidence of amyotrophic lateral sclerosis (ALS) in U.S. veterans, we have conducted a high-density genome-wide association study (GWAS) of ALS outcome and survival time in a sample of U.S. veterans. We tested ∼1.3 million single nucleotide polymorphisms (SNPs) for association with ALS outcome in 442 incident Caucasian veteran cases diagnosed with definite or probable ALS and 348 Caucasian veteran controls. To increase power, we also included genotypes from 5909 publicly-available non-veteran controls in the analysis. In the survival analysis, we tested for association between SNPs and post-diagnosis survival time in 639 Caucasian veteran cases with definite or probable ALS. After this discovery phase, we performed follow-up genotyping of 299 SNPs in an independent replication sample of Caucasian veterans and non-veterans (ALS outcome: 183 cases and 961 controls; survival: 118 cases). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p = 4.4×10−4) and rs6985069 near ELP3 (p = 4.8×10−4). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder