International Study Of Infarct Survival Research Articles

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Randomized Trials Fit for the 21st Century: A Joint Opinion From the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation.

Stopping β-Blockers After Myocardial Infarction

See Article by Neumann et al For more than 3 decades, β-blockers have been the mainstay of medical treatment for patients with myocardial infarction (MI). By the mid-1980s, landmark studies by the Norwegian study group, the North American BHAT (Beta-Blocker Heart Attack Trial), and the ISIS-I (First International Study of Infarct Survival) had firmly established the ability of β-blockers to reduce mortality in MI.1 A meta-analysis by Freemantle et al1 of 82 randomized trials encompassing 54 234 MI patients found that β-blockers reduced the odds of death by 23% when used for longer than 6 months. Despite the overwhelming clinical importance in support of the use of β-blockers in reducing mortality, substantial underutilization persisted through the 1990s, such that only 1 in 2 ideal patients >65 years were prescribed therapy after hospitalization for an MI.2 These observations stimulated research to evaluate barriers of treatment, dispel misconceptions of β-blockers, and optimize treatment implementation. It also created a culture of ongoing quality improvement such that by the 2000s, the use of β-blockers after MI became so consistent that ongoing tracking as a quality indicator was no longer needed. Since the widespread adoption of β-blockers, there have been many advances in the treatment of MI such as dual antiplatelet therapy, statins, angiotensin-converting enzyme inhibitors, fibrinolytic therapy, and percutaneous coronary interventions. There have also been advances in the diagnostic ability of MI with the introduction of normal and high-sensitivity troponin assays that allow for identification of smaller infarctions. These factors have resulted in a substantial and progressive reduction in the risk of dying after an MI over the past several decades. This led investigators to question whether β-blockers, one of the earliest post-MI therapies, were still beneficial in this setting. Using data from the REACH registry (Reduction of Atherothrombosis for Continued Health), …

Aspirin in heart failure: don't throw the baby (aspirin) out with the bathwater.

Aspirin in heart failure: don't throw the baby (aspirin) out with the bathwater.

Does aspirin detract from the benefits of mineralocorticoid receptor antagonists in patients with heart failure and a reduced left ventricular ejection fraction? Probably!

Does aspirin detract from the benefits of mineralocorticoid receptor antagonists in patients with heart failure and a reduced left ventricular ejection fraction? Probably!

Aspirin for Heart Failure

There is fading evidence that chronic aspirin therapy reduces cardiovascular morbidity or mortality.1,2 One large trial (The Second International Study of Infarct Survival:ISIS-2) performed 30 years ago showed that aspirin, at a dose of 162.5 mg/d given for just 28 days, reduced mortality compared with placebo after an acute myocardial infarction.3 This success has never been repeated. Although aspirin must have been discontinued at the end of the double-blind period of ISIS-2, the effect of this short course of aspirin persisted for 10 years.4 Thus, there is good evidence, in the era before statin therapy or primary angioplasty, that aspirin, given at this dose for this duration, is effective. There is no robust evidence that any other antiplatelet regimen, in terms of dose, agent, or duration, is superior; most subsequent studies having permitted the inclusion of patients receiving lower, nonevidence-based doses of aspirin.5–7 No substantial trial of long-term aspirin therapy for the primary or secondary prevention of cardiac events has ever confirmed this reduction in mortality. No long-term trial after myocardial infarction has ever even studied doses <300 mg/d.2 The results of meta-analyses have been driven by the ludicrously positive results of some small trials and the absence of small negative trials.1,8 This most likely reflects reporting and publication bias, which renders meta-analysis an intrinsically unreliable form of evidence that should be relegated to a method of confirming the results of an adequately powered, definitive trial or for generating hypotheses.9 Journal editors, unaware of their biases and the damage they might do, are only too willing to publish small implausibly positive results but reluctant …

From Concept to Reality

> Perseverance is not a long race: it is many short races one after another. > > —Walter Elliott, 19th Century spiritual writer The treatment and outcome of patients with ST-segment elevation myocardial infarction (STEMI) has improved dramatically over the 30 years since I graduated from medical school. In 1982, bed rest, treatment of complications such as ventricular arrhythmias or mural thrombus and prayer (for those so inclined) were the standard of care. In the first decade, pharmacological therapy was developed, and the open artery hypothesis was confirmed. The Second International Study of Infarct Survival (ISIS-2) trial demonstrated the benefit of not only aspirin, but also the combination of aspirin and streptokinase1 leading to a series of randomized clinical trials to determine the preferred fibrinolytic and adjunctive medications. The second decade was filled with trials that compared fibrinolytic therapy with primary percutaneous coronary intervention (PCI), which ultimately confirmed primary PCI as the preferred method of reperfusion if performed in a timely manner in high-volume centers.2 European trials extended the benefits of PCI to STEMI patients who presented to non-PCI centers requiring transfer for primary PCI.3,4 In particular, the Danish Multicenter Randomized Study on Thrombolytic Therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI-2), a well-designed, multicenter, randomized trial including 24 referral hospitals and 5 PCI centers in Denmark, was stopped early when it demonstrated a significant reduction in the primary end point of death, reinfarction, and stroke at 30 days (8% for primary PCI versus 13.7% for fibrinolysis, P <0.001).4 Article see p 189 These randomized clinical trials stimulated interest in regional STEMI systems in the United States, but many believed it would be challenging to replicate the results seen in a small European country with short-duration transfers (mean, 34 miles) and an organized national emergency medical system (EMS).5 In 2002, …

Clinical Trial Subgroups

Heart disease is the leading cause of death in women in the United States.1 To combat this phenomenon, professional guidelines for primary and secondary prevention as well as sex-specific guidelines for women have been developed and promulgated.2–4 Despite these efforts, there remains some controversy surrounding the benefits of statin therapy in women,5 although a 2004 meta-analysis clearly demonstrated benefits for secondary prevention on nonmortal cardiovascular events.6 In light of these data, current secondary prevention guidelines endorse statin therapy as a class IA recommendation for all patients recovering from an acute coronary syndrome, not just men.7 Article see p 328 Despite these recommendations for the use of statin therapy as an effective means for secondary prevention, it remains unclear whether the intensity of lipid-lowering therapy is important. In fact, the entire concept of treating patients to target lipid values, rather than treating on the basis of risk, has been questioned.8 In light of this concern, the current study by Truong et al,9 in this issue of Circulation: Cardiovascular Quality and Outcomes , examines the sex-specific benefits of more-intensive statin therapy after acute coronary syndromes in women. Using data from the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial,10 the authors conducted a thorough analysis of outcomes stratified by sex and extended the existing literature by exploring treatment effects among women according to …

Poor outcome after recurrent acute myocardial infarction: A plea for optimal secondary prevention

The prognosis after ST-elevation myocardial infarction (STEMI) has improved dramatically over the last 2 decades, mainly due to early and sustained reperfusion and the increased use of concomitant medication [ 1 Zijlstra F. de Boer M.J. Hoorntje J.C.A. et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med. 1993; 328: 680-684 Crossref PubMed Scopus (1181) Google Scholar , 2 Grines C.L. Browne K.F. Marco J. et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The primary angioplasty in Myocardial Infarction Study Group. N Engl J Med. 1993; 328: 673-679 Crossref PubMed Scopus (1885) Google Scholar , 3 Keeley E.C. Boura J.A. Grines C.L. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003; 361: 13-20 Abstract Full Text Full Text PDF PubMed Scopus (3560) Google Scholar , 4 Collins R. Peto R. Baigent C. Sleight P. Aspirin, heparin, and fibrinolytic therapy in suspected acute myocardial infarction. N Engl J Med. 1997; 336: 847-860 Crossref PubMed Scopus (273) Google Scholar , 5 ISIS-1 (First International Study of Infarct Survival) Collaborative Study GroupRandomized trial of intravenous atenolol among (16,027) cases of suspected acute myocardial infarction. Lancet. 1986; 2: 57-65 PubMed Google Scholar , 6 Pfeffer M.A. Braunwald E. Moyé L.A. et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992; 327: 669-677 Crossref PubMed Scopus (5450) Google Scholar , 7 Hennekens C. Albert C. Godfried S.L. et al. Adjunctive drug therapy of acute myocardial infarction evidence from clinical trials. N Engl J Med. 1996; 335: 1660-1667 Crossref PubMed Scopus (221) Google Scholar ]. However, the outcome of STEMI after previous myocardial infarction (MI) is less clear. We assessed implications of previous MI in patients with STEMI who were all treated by primary Percutaneous Coronary Intervention (PCI).

Stroke Genome-Wide Association Studies

See related article, pages 825–832. With a swiftly moving, highly technical field, it helps to have a reliable guide. In this issue of Stroke, Lanktree et al1 provide a timely overview of genomic analysis applied to stroke.1 Readers find a clear and concise synopsis of single-nucleotide polymorphisms, copy number variations, listings of the strengths and limitations of genome-wide association studies (GWAS), and a distillation of the findings from GWAS performed in 6 cohorts (5 of which were ischemic stroke cohorts). The review also covers a topic not usually found in clinical reviews, namely techniques to visually display quantitative information. Excellence in statistical graphics should, among other things, avoid distorting what the data have to say, present many numbers in a small space, and make large data sets coherent.2 The Manhattan and quantile–quantile plots are excellent examples of statistical graphics that have become invaluable for interpreting GWAS results. Along with visualization comes interpretation of data in the context of GWAS. Clinical investigators are well aware of the problem of multiple testing from such settings as interim and subgroup analyses in clinical trials, which can lead to wildly spurious conclusions, such as concluding that aspirin only helped individuals of certain astrological signs in the second International Study of Infarct Survival.3 GWAS simply escalates the problem of multiple testing by orders of magnitude. Because single-nucleotide polymorphism-based GWAS test hundreds of thousands …

Magnesium and cardiovascular system.

Hypomagnesemia is common in hospitalized patients, especially in the elderly with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. The data regarding its use in patients with acute myocardial infarction (AMI) is conflicting. Although some previous, relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any advantage of intravenous magnesium over placebo. Nevertheless, there are theoretical potential benefits of magnesium supplementation as a cardioprotective agent in CAD patients, as well as promising results from previous work in animal and humans. These studies are cost effective, easy to handle and are relatively free of adverse effects, which gives magnesium a role in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as Torsades de Pointes and intractable ventricular tachycardia.

Aspirin as Preventive Therapy in Patients With Asymptomatic Vascular Disease

cause of death in the western world and a leading cause of death worldwide. Assessing patients’ cardiovascular risk may be used to target preventive treatments to asymptomatic individuals at high risk for future CVD events. For these high-risk individuals, strategies including medication, diet, and comprehensive lifestyle approaches have been shown to improve cardiovascular morbidity and mortality. 1 Antiplatelet therapy has long been a cornerstone in the prevention and treatment of CVD. In a systematic overview and meta-analysis, the Antiplatelet Trialists’ Collaboration demonstrated that antiplatelet therapy was associated with reduced rates of myocardial infarction (MI), stroke, and death. 2 The strong data that support aspirin as a therapeutic intervention are in the setting of acute MI or stroke. In the Second International Study of Infarct Survival (ISIS-2), which included patients with suspected MI, aspirin reduced the rate of early vascular mortality by 23% vs placebo (P.001). 3 Similarly, a combined analysis of 2 large stroke trials (International Stroke Trial and Chinese Acute Stroke Trial) found that low-dose aspirin was associated with a significant reduction in recurrent ischemic stroke and mortality. 4 A meta-analysis of 6 trials involving patients with symptomatic stable CVD demonstrated a consistent association between aspirin therapy and reduction of cardiovascular morbidity and mortality. 5 These benefits of aspirin in patients with established CVD, along with the low cost of aspirin therapy, have been extrapolated to high-risk patients without established CVD in an effort to reduce the risk of cardiovascular events. However, preventive therapy presupposes a threat that can be averted at an acceptable risk. In the case of aspirin, the major risk is bleeding. In this issue of JAMA, Fowkes and colleagues 6 report the results of the Aspirin for Asymptomatic Atherosclerosis trial. In this double-blind randomized trial, 3350 patients aged 50 to 75 years without clinically evident CVD but with a screening-detected ankle brachial index (ABI) of 0.95 or less were randomly assigned to receive aspirin (enteric coated 100 mg/d) or placebo. After a mean (SD) follow-up of 8.2 (1.6) years, aspirin was no more effective than placebo at reducing the primary end point of a fatal or nonfatal coronary event, stroke, or revascularization and had no significant effect on any of the secondary end points. Aspirin therapy was, however, associated with a statistically nonsignificant increased risk of major hemorrhage (2.0% vs 1.2%, hazard ratio [HR], 1.71, 95% confidence interval, 0.99-2.97). Intracranial hemorrhage occurred in 11 participants (including 3 fatal subarachnoid/subdural hemorrhages) in the aspirin group and 7 in the placebo group. The results of the trial raise an important question about preventing cardiovascular events—should aspirin be used inprimaryprevention?Althoughthepopulationstudiedhad subclinical atherosclerosis as determined by the ABI, participants had no previous history of CVD events. Thus the goal remains the same—prevention of a first cardiovascular event. The findings of the trial are consistent with those of previous primary prevention trials. The lower boundary of the 95% confidence interval cannot rule out a 16% benefit or exclude a 27% increase in harm. Meta-analyses on theefficacyofaspirininprimarypreventionshowedamodest 12% benefit. 7,8

The Need for Large-Scale Randomized Evidence Without Undue Emphasis on Small Trials, Meta-analyses, or Subgroup Analyses

RANDOMIZED TRIALS OF ADEQUATE SIZE AND DURATION designed to test a priori hypotheses represent the most reliable design strategy to detect the most realistically small to moderate therapeutic effects of drugs. Such trials should achieve high adherence to an adequate dose of the drug and a sufficient number of clinical end points to distinguish reliably between the null hypothesis and the most plausible alternative hypothesis of small to moderate benefit or harm. With regard to the development of drugs to treat diabetes mellitus, the US Food and Drug Administration (FDA) has developed guidance for industry that somewhat overemphasizes results from meta-analyses of phase 2 trials that were not large enough to test realistic hypotheses about clinical cardiovascular (CV)events. Even inaggregate, suchresults should be considered more as hypothesis formulating than as hypothesis testing. The main need now is for trials that are large enough to have adequate statistical power. The quality and usefulness of any meta-analysis are dependent on the quality and comparability of data from the component trials. In particular, the trials combined should have high adherence and follow-up rates and should have reasonably comparable drugs, doses, and outcomes. The characteristics of the participants and the magnitude of effect from each trial must be sufficiently similar so that their combination will not produce a distorted estimate. Thus, metaanalyses can reduce the role of chance in the interpretation but may introduce bias and confounding. For example, a meta-analysis of rosiglitazone involved 42 randomized trials with a total of 26 011 patients who experienced 158 myocardial infarctions (MIs) and 61 deaths due to CV causes (CV death). The investigators concluded that rosiglitazone was associated with a significant increase in risk of MI (relative risk [RR],1.43; 95% confidence interval [CI], 1.03-1.98) as well as a nonsignificant increase in CV death (RR,1.64; 95% CI, 0.98-2.74). The chief value of this report should have been to formulate a hypothesis about one possible hazard of rosiglitazone that may offset any potential benefits. Furthermore, the widths of the CIs suggest that this meta-analysis was unable to distinguish reliably whether rosiglitazone conferred no hazard or a substantial hazard of CV events. Hypothesis formulation should lead to adequate hypothesis testing in another randomized trial of adequate size and duration designed a priori to address the question. The Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial was designed a priori to assess the noninferiority of rosiglitazone added to metformin or sulfonylurea compared with dual therapy metformin and sulfonylurea on reducing CV events among 4447 patients with type 2 diabetes. The primary prespecified outcome was time to first CV hospitalization or CV death with a hazard ratio (HR) noninferiority margin of 1.20, which is the upper bound of the 95% CI as recommended by the FDA. During a mean 5.5-year follow up, there were 321 incident primary clinical events in the rosiglitazone group and 323 in the active comparator group (HR, 0.99; 95% CI, 0.85-1.16), meeting the criterion for noninferiority. Thus, the results of the large-scale trial did not support the hypothesis formulated from the meta-analysis of smaller trials. Likewise, in a meta-analysis of 7 small trials evaluating use of intravenous magnesium during suspected acute MI, there were 25 deaths among 657 patients in the magnesium group vs 53 deaths among 644 patients in the placebo group (HR, 0.45; 95% CI, 0.15-0.74). Although the existing totality of evidence was compatible with the possibility that intravenous magnesium was an effective, safe, and inexpensive intervention, a prudent approach was to await the results of the large fourth International Study of Infarct Survival (ISIS-4) trial before routinely using this therapy. In ISIS-4, 58 050 patients with suspected MI were randomized to receive either intravenous magnesium or usual care. Patients treated with magnesium had a nonsignificant 6% increase in mortality, as well as significant increases in heart failure, death attributable to cardiogenic shock, and bradycardia. In subgroup analyses (which are useful to formulate but not test hypotheses) no significant differences were found among patients treated less than 6 hours after the onset of symptoms, those who received intravenous magnesium within 2 hours after thrombolytic therapy, and those who received neither thrombolytic therapy

On Looking at Subgroups

More than 20 years ago in this journal, Furberg and Byington1 showed how dicing a population from a randomized trial could unearth apparent subgroup findings. They used the Beta-Blocker in Heart Attack Trial, a double-blind randomized trial that showed conclusive evidence of benefit of β-blockers on mortality in patients who had experienced a myocardial infarction. In spite of this overall benefit, the authors showed that some subgroups exhibited no effect and some subgroups exhibited harm; they argued cogently that these “findings” were likely spurious. A few years later came the well-known example of spurious interaction from the International Study of Infarct Survival 2 (ISIS-2),2 a trial that showed a medically important and statistically significant benefit of aspirin in preventing fatal heart attacks. To demonstrate the pitfalls of subgroup analysis, the ISIS investigators classified all study participants by their astrological signs; subgroup analysis showed that whereas aspirin significantly benefited the population at large, it appeared actually to harm people born under Gemini or Libra. Most nonastrologers would believe the findings due to chance. Article p 922 Most randomized clinical trials aim to show an effect of an experimental treatment in a given study population. Because most illnesses are variable, it seems quite natural to look to clinical trials for information about specific subgroups of patients in the hope that subgroup-specific estimates of treatment effects, rather than the overall effect, will predict more accurately the effect on specific patients. Unfortunately, few trials have sufficient statistical power to measure reliably the effect of a treatment within subgroups. Trials are even less likely to provide reliable information on interactions, that is, whether the effect of a treatment differs among subgroups. The persistence of subgroup analyses, in spite of nearly all statisticians’ and many clinicians’ oft-stated warnings about their unreliability, must be due …

The Transforming Growth Factor-β/Smad3 Pathway

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …

LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway

The discovery of NO as the endothelium-derived relaxing factor unleashed new horizons. NO is a ubiquitous radical exerting both hemodynamic and tissue growth–modifying effects. The vasodilative and antiproliferative properties of NO produced by endothelial NO synthase are considered to act beneficially within the cardiovascular system. However, under certain circumstances, the inducible NO synthase produces large quantities of NO that may be harmful.1 Most NO effects can be attributed to the activation of soluble guanylate cyclase and the subsequent cascade of events including enhanced cGMP concentration, activation of cGMP-dependent kinase-1, and reduced intracellular calcium levels in target cells. NO acts as a principal regulator of vascular function. Venodilatation and arterial relaxation result in a decrease of left ventricular pressure and chamber size, leading to attenuation of oxygen consumption. NO dilates epicardial coronary arteries, enhances collateral flow, and inhibits platelet aggregation. Moreover, NO was shown to inhibit collagen synthesis and to reduce cardiomyocyte growth. NO, thus, represents an opposing force to vasoconstrictors and growth-promoting substances, such as angiotensin II and endothelin. The depression of NO signaling, including downregulated expression and attenuated enzymatic activity of NO synthase and scavenging of NO by oxygen-derived free radicals, seems to be a principal disorder in endothelial dysfunction. NO deficiency is, therefore, related to many cardiovascular pathologies, such as coronary atherosclerosis with myocardial ischemia, arterial hypertension with left ventricular hypertrophy, or heart failure. It is obvious that NO plays an important role in the circulatory physiology. Nevertheless, the impact of therapeutically increased NO bioactivity on cardiovascular morbidity and mortality is unclear. In the Gruppo Italiano per lo Studio della Streptochinasi nell’Inffarto Miocardico 3 and International Study of Infarct Survival 4 trials, nitrates failed to reduce mortality when given after myocardial infarction.2 Although the effect of the combination of isosorbide dinitrate and hydralazine in the Vasodilator-Heart …

Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.

Is aspirin effective in diabetic patients? No

Is aspirin effective in diabetic patients? No

Clinical Trials in Cardiovascular Medicine in an Era of Marginal Benefit, Bias, and Hyperbole

Clinical trials in the modern medical era began in the mid-20th century with the first randomized, double-blind assessment of an antibiotic, streptomycin, for the treatment of pulmonary tuberculosis.1 Over the course of the next 50 years, the randomized, controlled trial became the “gold standard” for testing the efficacy of new therapies and is generally required for their approval by regulatory agencies worldwide. To be sure, many effective cardiovascular therapies have been identified and approved for use following this generally accepted approach. In this editorial, I will review the many factors that can and do adversely affect the performance and interpretation of contemporary clinical trials in cardiovascular medicine, hoping to shed light on what I view as a series of growing and only partly remediable challenges to effective clinical investigation. Clinical trials in cardiovascular medicine set the standard for randomized, controlled trial design owing to the population prevalence of the major cardiovascular diseases, the event rates in these patient populations, and the practicably achievable sample sizes sufficient to minimize type II errors. In the early studies of fibrinolytic therapy for myocardial infarction (ISIS [International Study of Infarct Survival] and TIMI [Thrombolysis In Myocardial Infarction]), for example, the expected 5-week mortality rate for conventionally treated patients was 12% to 13% at the time2,3 in Europe and the United States. Thus, with several thousand patients in each treatment arm, one could expect to detect confidently true reductions in absolute mortality of 3% to 4%, as was the case in these landmark trials. Over the past three decades, mortality rates for highly prevalent cardiovascular diseases, including acute coronary syndromes, heart failure, and sudden death, have continuously improved owing to the clear benefits of therapies proved to be efficacious in double-blind, randomized, controlled trials. With these mounting, cumulative successes, however, the marginal benefit …

Magnesium and myocardial infarction.

The data on magnesium supplementation in patients with acute myocardial infarction (AMI) is conflicting. Although a number of relatively small randomized clinical trials have demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any superiority of intravenous magnesium over placebo. Nevertheless, the theoretical potential benefits of magnesium supplementation as a cardioprotective agent in coronary artery disease (CAD) patients, in conjunction with previous promising results from work in animal and humans, its relatively low cost, easy administration, with no need for special expertise, and relatively free of adverse effects, gives magnesium a place in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia.

Structure and distribution of the phosphoprotein phosphatase genes, prpA and prpB, among Shigella subgroups

Phosphoprotein phosphatases encoded by the prpA and prpB genes function in signal transduction pathways for degradation of misfolded proteins in the extracytoplasmic compartments of Escherichia coli. In order to trace the evolution of prp genes and assess their roles in other enteric pathogens, the structure and distribution of these genes among closely related Shigella subgroups were studied. PCR amplification, probe hybridization studies and DNA sequencing were used to determine the prp genotypes of 58 strains from the four Shigella subgroups, Dysenteriae, Boydii, Sonnei and Flexneri. It was found that the prp alleles among Shigella subgroups were extremely susceptible to gene inactivation and that the mutations involved in prp allele inactivation were varied. They included IS insertions, gene replacement by an IS element, a small deletion within the gene or large deletion engulfing the entire gene region, and base substitutions that generated premature termination codons. As a result, of 58 strains studied, only eight (14 %) possessed intact prpA and prpB genes. Of the Shigella strains examined, 76 % (44/58) showed at least one of the prp alleles inactivated by one or more IS elements, including IS1, IS4, IS600 and IS629. Phylogenetic analysis revealed that IS elements have been independently acquired in multiple lineages of Shigella, suggesting that loss of functional alleles has been advantageous during Shigella strain evolution.