Control of health care-associated infections (HAI): winning both the battles and the war.

At present, the United States (US) experiences its greatest life expectancy due mainly to improvements in mortality from cardiovascular diseases, which include coronary heart disease and stroke. These, in turn, are due largely to decreases in cigarette smoking as well as earlier and more aggressive diagnoses and treatments. These advances in health care delivery are, not surprisingly, accompanied by increasing numbers of complicating health care-associated infections (HAI). HAIs are a major and increasing cause of morbidity and mortality in the US as well as around the world. To win both the battles and the war against HAI requires a multidisciplinary approach to the vigorous implementation and maintenance of proper infection control procedures. This should include continuous surveillance and reinforcement of guidelines to enhance evidence-based practices to prevent and control HAI. It will also be necessary to implement a new paradigm of early and formal education of future health care providers into the biology of infection as well as the principles of infection control in the classroom and subsequently, with translation into their clinical training. Finally, there must also be the incorporation and expansion of continuing medical education for established health care providers about prevention and control of HAI.

Hypothesis formulation from subgroup analyses: nonadherence or nonsteroidal anti-inflammatory drug use explains the lack of clinical benefit of aspirin on first myocardial infarction attributed to "aspirin resistance".

BACKGROUND: "Aspirin resistance" has been defined as the occurrence of cardiovascular events despite regular intake of aspirin. One major analytic study suggesting that "aspirin resistance" is a clinical reality was unable to control for confounding by nonadherence or nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We formulated a hypothesis from subgroup analyses in the Physicians' Health Study, a randomized double-blind placebo-controlled trial testing 325 mg of aspirin every other day among 22,071 apparently healthy US male physicians. We classified participants by nonadherence or NSAIDs and used time-varying Cox proportional hazard models to adjust for confounding. RESULTS: After 5 years, the blinded aspirin component was terminated early based on the unanimous recommendation of the Data and Safety Monitoring Board. Of 378 confirmed first myocardial infarctions (139 aspirin and 239 placebo), the relative risk (RR) was 0.56 (95% CI 0.45-0.70, P < .00001). There was no statistically significant reduction among aspirin <150/180 pills/y (RR = 0.91, 95% CI 0.61-1.35, P = .62) or NSAID users >60 days per year (RR = 1.54, 95% CI 0.68-3.47, P = .31). There was a statistically significant reduction among aspirin >150/180 pills/y and NSAID users <60 days/y (RR = 0.55, 95% CI 0.44-0.70, P < or = .0001) and an increase among aspirin <150/180 pills/y and NSAID users >60 days/y (RR of 3.43, 95% CI 1.41-8.33, P = .007). CONCLUSIONS: In subgroup analyses useful to formulate hypotheses from a large randomized trial in apparently healthy men, aspirin nonadherence or NSAID use explained the lack of clinical benefit of aspirin on first myocardial infarction that has been attributed to "aspirin resistance." Direct randomized comparisons are necessary in trials designed a priori to test this hypothesis.

Use of aspirin among diabetics in the primary prevention of cardiovascular disease: need for reliable randomized evidence and astute clinical judgment.

BACKGROUND: The American Heart Association Guidelines recommend aspirin for all apparently healthy individuals whose 10-year risk of a first coronary heart disease (CHD) event is >10%. METHODS: The United States (US) Preventive Services Task Force (USPSTF) has recently updated its guidelines to encourage men 45 to 79 years and women 55 to 79 years to use aspirin when the potential benefit outweighs the potential harm. In addition, in some US guidelines, diabetes is considered to be a CHD risk equivalent. RESULTS: Two recently published trials, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD), concluded that aspirin did not reduce risks of CHD. Both JPAD and POPADAD had inadequate statistical power. Reliable randomized evidence is necessary to provide a sufficient totality of evidence about benefits and risks among diabetics. CONCLUSION: At present, astute individual clinical judgments are necessary.

Modest dietary reductions in blood cholesterol have important public health benefits.

Large reductions in blood cholesterol produce major clinical and public health benefits. Based on extrapolations from randomized evidence, assuming no threshold, a 3% to 4% reduction in blood cholesterol would decrease risk of coronary heart disease (CHD) by 12%. If so, treating larger numbers of people at lower risk would yield greater reductions in CHD than treating smaller numbers at higher risk. High- and moderate-risk patients require evidence-based doses of high-potency statins, as adjuncts to dietary management and benefits to individuals are large and easily quantifiable in randomized trials. In low-risk patients, however, dietary modifications contribute to a public health benefit while that benefit to any individual is small. Thus, the hypothesis that modest dietary reductions in blood cholesterol have important public health benefits is easily quantifiable by extrapolation from existing data but impossible to test among randomized individuals, as the sample sizes and costs are prohibitively large.

Benefits and Risks of Nonsteroidal Anti-inflammatory Drugs: Methodologic Limitations Lead to Clinical Uncertainties.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

An update on aspirin in the primary prevention of cardiovascular disease.

BACKGROUND: In 1988, the aspirin component of the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of 22 071 apparently healthy men was terminated early, due principally to a statistically extreme (P<.00001) 44% reduction in the risk of a first myocardial infarction (MI). The Cardio-Renal Drugs Advisory Committee recommended that the US Food and Drug Administration approve professional labeling of aspirin to prevent first MI. The agency did not act on this recommendation because the only other trial, the British Doctors' Trial of 5139 men, showed no significant benefits. Since that time, 3 additional randomized trials (which included men and women) of aspirin in the primary prevention of MI have been published. METHODS: A computerized search of the English literature from 1988 to the present revealed 5 published trials: the Physicians' Health Study (22 071 participants), the British Doctors' Trial (5139), the Thrombosis Prevention Trial (5085), the Hypertension Optimal Treatment Study (18 790), and the Primary Prevention Project (4495). RESULTS: Among the 55 580 randomized participants (11 466 women), aspirin was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15% reduction in the risk of all important vascular events, but had no significant effects on nonfatal stroke or vascular death. CONCLUSIONS: The current totality of evidence provides strong support for the initial finding from the Physicians' Health Study that aspirin reduces the risk of a first MI. For apparently healthy individuals whose 10-year risk of a first coronary event is 10% or greater, according to the US Preventive Services Task Force and the American Heart Association, the benefits of long-term aspirin therapy are likely to outweigh any risks.

Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies.

BACKGROUND: In certain subgroups of patients, prolongation of the QTc interval may increase total and cardiovascular mortality due to life-threatening ventricular arrhythmias and sudden death. Nonetheless, whether modest prolongation of the QTc interval in the general population has clinical importance remains unclear. METHODS: We conducted a literature search from 1990 forward to identify all published prospective cohort studies evaluating the association between prolonged QTc interval and risks of total and cardiovascular mortality as well as sudden death. We reviewed each of the studies individually and then conducted a qualitative overview. RESULTS: The 7 prospective cohort studies identified included 36 031 individuals. There were 2677 (8.7%) individuals with prolonged QTc interval, defined as 440 milliseconds or greater. Whereas 1 study reported no association between prolonged QTc interval and mortality (relative risk, 1.02; 95% confidence interval, 0.70-1.49), the other 6 reported inconsistent associations overall as well as across subgroups defined by various characteristics including age, sex, and comorbidities. The reported associations for both cardiovascular mortality and sudden death were also inconsistent. In the overview, the only consistent findings were for the subgroup of patients with prior cardiovascular disease, in which relative risks ranged from 1.1 to 3.8 for total mortality, from 1.2 to 8.0 for cardiovascular mortality, and from 1.0 to 2.1 for sudden death. Further, in individuals without prior cardiovascular disease, associations were either absent or greatly attenuated; specifically, relative risks ranged from 0.9 to 1.6 for total mortality, from 1.2 to 1.7 for cardiovascular mortality, and from 1.3 to 2.4 for sudden death. CONCLUSIONS: There was no consistent evidence for increased risks of total or cardiovascular mortality or of sudden death, except perhaps for patients with prior cardiovascular disease. In the general population, if QTc interval prolongation is associated with any increase in mortality, that risk is likely to be small and difficult to detect reliably.

Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease.

BACKGROUND: Observational epidemiological studies consistently show that individuals who choose to take high amounts of vitamin E through diet or supplements experience cardiovascular benefits, for which basic research provides plausible mechanisms. However, because the size of the postulated benefit is small to moderate, the confounding inherent in observational studies is as great as the effect size. Before the availability of randomized evidence, about 1 in 4 adults was taking vitamin E supplements in the United States. METHODS: We conducted a computerized search of the English-language literature from 1990 to the present and found 7 large-scale randomized trials of the effectiveness vitamin E in the treatment and prevention of cardiovascular disease. Data were available on myocardial infarction, stroke, or cardiovascular death. RESULTS: Six of the 7 trials showed no significant effect of vitamin E on cardiovascular disease. In an overview, vitamin E had neither a statistically significant nor a clinically important effect on any important cardiovascular event (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.94-1.03) or its components: nonfatal myocardial infarction (OR, 1.00; 95% CI, 0.92-1.09), nonfatal stroke (OR, 1.03; 95% CI, 0.93-1.14), or cardiovascular death (OR, 1.00; 95% CI, 0.94-1.05). CONCLUSIONS: The ORs and CIs provide strong support for a lack of statistically significant or clinically important effects of vitamin E on cardiovascular disease. The use of agents of proven lack of benefit, especially those easily available over the counter, may contribute to underuse of agents of proven benefit and failure to adopt healthy lifestyles.

Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials.

BACKGROUND: Beta-blockers substantially improve survival in patients with chronic heart failure (HF) with left ventricular systolic dysfunction, but concerns about cardiovascular adverse effects may deter physicians from prescribing this therapy. We performed an overview of randomized beta-blocker trials in patients with HF to quantify the risks of these adverse effects. METHODS: Heart failure trials of beta-blockers were identified by electronic searches of the MEDLINE database from 1966 to 2002. The random-effects model was used to combine results from individual trials and calculate estimates of risks associated with therapy. RESULTS: beta-Blocker therapy was associated with significant absolute annual increases in risks of hypotension (11 per 1000; 95% confidence interval [CI], 0-22), dizziness (57 per 1000; 95% CI, 11-104), and bradycardia (38 per 1000; 95% CI, 21-54). There was no significant absolute risk of fatigue associated with therapy (3 per 1000; 95% CI, -2 to 9). beta-Blocker therapy was associated with a reduction in all-cause withdrawal of medication (14 per 1000; 95% CI, -2 to 29) as well as significant reductions in all-cause mortality (34 per 1000; 95% CI, 20-49), HF hospitalizations (40 per 1000; 95% CI, 22-58), and worsening HF (52 per 1000; 95% CI, 10-94). CONCLUSIONS: Although beta-blocker therapy was associated with hypotension, dizziness, and bradycardia, the absolute increases in risk were small, and overall fewer patients were withdrawn from beta-blocker therapy than from placebo. This information should alleviate concerns about prescribing this life-saving therapy to patients with HF.

An application of conditional logistic regression and multifactor dimensionality reduction for detecting gene-gene interactions on risk of myocardial infarction: the importance of model validation.

BACKGROUND: To examine interactions among the angiotensin converting enzyme (ACE) insertion/deletion, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, and tissue plasminogen activator (t-PA) insertion/deletion gene polymorphisms on risk of myocardial infarction using data from 343 matched case-control pairs from the Physicians Health Study. We examined the data using both conditional logistic regression and the multifactor dimensionality reduction (MDR) method. One advantage of the MDR method is that it provides an internal prediction error for validation. We summarize our use of this internal prediction error for model validation. RESULTS: The overall results for the two methods were consistent, with both suggesting an interaction between the ACE I/D and PAI-1 4G/5G polymorphisms. However, using ten-fold cross validation, the 46% prediction error for the final MDR model was not significantly lower than that expected by chance. CONCLUSIONS: The significant interaction initially observed does not validate and may represent a type I error. As data-driven analytic methods continue to be developed and used to examine complex genetic interactions, it will become increasingly important to stress model validation in order to ensure that significant effects represent true relationships rather than chance findings.

The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure.

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.

The need for increased utilization of statins after occlusive stroke.

In registry data, among patients who have survived an occlusive stroke, only about half are treated with statins despite a large and persuasive totality of evidence, which includes large-scale randomized trials. In a comprehensive worldwide meta-analysis of 90,056 participants, statins conferred statistically significant and clinically important reductions in stroke and myocardial infarction, as well as cardiovascular and total mortality. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial of patients with prior stroke or transient ischemic attack, high-potency statins decreased risks of recurrent stroke and major cardiovascular events. In a nonrandomized subgroup analysis, patients who achieved a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) compared to those who achieved <50% had a statistically significant 31% reduction in risk of stroke. Finally, in a comprehensive, worldwide meta-analysis of all trials of cardiovascular disease, patients treated with intensive compared with conventional statin therapy had significantly reduced risks of stroke and myocardial infarction as well as any cardiovascular event or death. Based on this totality of evidence the US federal guidelines as well as those of the American Heart Association/American Stroke Association have been revised to recommend that patients with a prior occlusive stroke should have an optional goal for LDL of 70 mg/dL. All these considerations pose important and timely clinical and public health challenges concerning the need for wider utilization of statins in the treatment of patients with stroke.

The Association of the Metabolic Syndrome with PAI-1 and t-PA Levels.

Background. We used a random sample (n = 2, 495) from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study population to examine the association of the metabolic syndrome (Met S) with plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) antigen levels. Results. The overall prevalence of the Met S was 18%, was dependent on age and gender, and was positively associated with higher antigen levels of both PAI-1 and t-PA. These significant effects were maintained after adjustment for age, gender, BMI, elevated C-reactive protein, smoking status, urinary albumin excretion, and insulin levels. We found no significant interactions between the Met S and other covariates on PAI-1 and t-PA levels. Conclusions. Our study demonstrates that those with the Met S have significantly higher levels of PAI-1 and t-PA antigen, factors known to increase the risk of cardiovascular disease.

Academic perspectives on the United States Food and Drug Administration's guidance for industry on diabetes mellitus.

The United States Food and Drug Administration (FDA) has issued Guidance for Industry, subtitled Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. From an academic perspective, these regulatory requirements provide undue emphasis on the results of phase 2 trials not designed to test hypotheses about clinical cardiovascular events. Phase 2 trials should be considered hypothesis formulating either alone or in their meta-analyses. Thus, this FDA guidance for industry does not adequately emphasize the importance and necessity of well designed and conducted phase 3 trials of sufficient size, dose, and duration to test the hypothesis formulated from the meta-analysis of the phase 2 trials. We believe that the guiding principle about benefits and risks of drugs should be that rational decisions for individual patients and the health of the general public should be based on a sufficient totality of evidence. When that totality of evidence is incomplete, it is appropriate to remain uncertain. We believe phase 2 trials should be performed mainly for proof of concept and dose ranging. To detect reliably the most plausible small to moderate effects of drugs, the totality of evidence must include large scale randomized phase 3 trials. These individual trials must be of sufficient size, dose, and duration as well as achieve high adherence and follow-up. They must also achieve enough clinical endpoints to distinguish reliably between the null hypothesis of no effect and the most plausible alternative hypotheses of small benefit or harm.

Cardiovascular risk associated with interactions among polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems.

BACKGROUND: Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin-angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study. METHODOLOGY/PRINCIPAL FINDINGS: Data from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015). CONCLUSIONS/SIGNIFICANCE: This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed.