Pacemaker mode selection: the evidence from randomized trials

The evidence base for pacing, specifically with regards to outcome-based randomized trials, is only beginning to emerge. At present, the guidelines for pacing in sinus node dysfunction (SND), atrioventricular block (AVB), and vasovagal syncope are largely based on observational, not randomized studies. The findings from observational studies that physiological pacing was associated with reduced mortality, fewer strokes, less heart failure, and less AF when compared with ventricular pacing, were not uniformly supported by the early randomized trials of a relatively small sample size. Thus, it has become increasingly clear that large scale randomized trials are necessary to measure reliably the benefit, if any, of progressively more expensive and complex pacemakers. To provide reliable answers to these important questions, three large multicenter randomized trials in Canada, the United Kingdom, and the United States have been designed and conducted. The present review analyzed the results of completed randomized trials on pacemaker mode selection. To date, > 6,000 patients requiring permanent pacing to prevent bradycardia have been randomized; among these, dual chamber pacing did not prevent stroke or improve survival when compared with ventricular pacing. However, dual chamber pacing led to a moderate reduction of incident and chronic AF, reduced symptoms of heart failure in patients with SND, prevented pacemaker syndrome, and modestly improved quality-of-life. Further, a 5-10% reduction in mortality by atrial-based pacing cannot be excluded based on the results of the analyzed trials. The availability of data from ongoing randomized trials and their meta analysis should complete the totality of evidence during the next several years.     

Is there convincing evidence for the use of chemotherapy alone in patients with limited stage Hodgkin's lymphoma?

Standard practices for patients with stages I and IIA non-bulky Hodgkin's lymphoma have evolved to include combined-modality therapy consisting of two or three cycles of ABVD and radiation therapy to the involved field. Long-term disease control can be expected in more than 90% of patients. However, long-term survival will also be dependent on the occurrence of treatment-related toxicities (late-effects) that include second cancers and cardiovascular events; deaths from these causes will outnumber those due to progressive Hodgkin's lymphoma. Data from randomized trials testing the role of chemotherapy alone are now available. These trials are based on the hypothesis that avoidance of radiation therapy will result in fewer deaths from late-effects, and that long-term survival will be at least comparable and possibly superior. With intermediate periods of follow-up, the results of these randomized trials demonstrate that with chemotherapy alone, disease control is reduced by approximately 5-7%, but this difference has not translated into a survival advantage. While further follow-up is required to evaluate longer term overall survival, current data can be interpreted as showing that a trade-off exists that requires balancing the advantage of superior disease control achieved with inclusion of radiation therapy and minimization of late-effects resulting from use of chemotherapy alone. The balance associated with this trade-off makes chemotherapy alone a legitimate treatment option; patients and clinicians need to be aware of these options in when making treatment decisions.     

Evaluating analgesia: the challenges

Decisions must be made when assigning analgesics, and such decisions involve comparing efficacy and adverse effects. The rules for assessing efficacy by systematic review and by large clinical trials are becoming clearer all the time. It is known, for instance, that trials that are not randomized, are not double-blind, or are too small will exaggerate efficacy. These rules are relatively easy to apply to drug interventions, although there are glaring exceptions, such as in early intra-articular morphine studies. The rules may also be less easy to apply for analgesics available over-the-counter (OTC) if the drugs have not been studied in trials of high quality or if the OTC-recommended doses are below the doses studied in the trials. When there are at least 500 patients studied in trials of high quality, credible efficacy estimates for effective drugs can be derived; more patients are needed for less effective drugs. The number needed to treat and the number needed to harm can be used to compare the efficacy and safety of a treatment with placebo or with other treatments. A recent meta-analysis comparing the number needed to treat for paracetamol 1000 mg and paracetamol 600-650 mg in moderate to severe postoperative pain indicated that paracetamol 1000 mg is likely to be more effective than lower doses. Large data sets allow investigation into dose response, gender differences, and whether particular drugs work better for particular painful conditions. Purists would argue that databases of patient experience should not be used for these efficacy analyses. The rules on how to collect and use evidence on adverse effects are less clearly formulated than they are for efficacy. For safety at or above therapeutic dose, the rules of evidence-gathering are necessarily different, and randomized trials are rarely an adequate or sufficient source. Databases of patient experience, with all the caveats, may be the most reliable data from which to work.     

Does psychosocial intervention improve survival in cancer? A meta-analysis

BACKGROUND: There is growing evidence that positive psychosocial intervention improves the wellbeing of cancer patients. Two meta-analyses conducted to date confirmed a significant small-to-moderate effect on quality of life. Previous randomized trials reported that psychosocial intervention also improved survival. However, more recent trials failed to detect a difference in survival. A systematic review of randomized trials that have examined the effectiveness of psychosocial intervention in cancer patients in terms of survival prolongation was conducted. METHODS: Randomized trials published between 1966 and June 2002 were identified through the databases of MEDLINE, EMBASE, CancerLit, CINAHL, Cochrane Library and reference lists of relevant articles. Relevant data were abstracted. The results of randomized trials were pooled using meta-analyses to estimate the effect of treatment on overall survival at one and four years in all cancer patients and also in breast cancer patients with metastases. RESULTS: Eight trials, which involved a total of 1062 patients (all cancer histologies), were identified. One- and four-year overall survival rates were obtained from eight trials and six trials, respectively. There was no statistically significant difference in the overall survival rates at one and four years [P = 0.6; RR 0.94 (95% CI 0.72, 1.22)] and [P = 0.5; RR 0.93 (95% CI 0.77, 1.13)], respectively. Four trials examined 511 metastatic breast cancer patients. Again, there was no statistically significant difference in the overall survival rates at one and four years [P = 0.3; RR 0.87 (95% CI 0.67, 1.14)] and [P = 0.3; RR 0.91 (95% CI 0.76, 1.10)], respectively. CONCLUSIONS: Psychosocial intervention does not prolong survival in cancer. This meta-analysis can not rule out small effect sizes because of the small number of trials and small trial sizes.     

The value of adjuvant therapy after radical surgery for colorectal cancer.

Extensive efforts to improve survival for patients with colorectal cancer using adjuvant treatments in addition to radical surgery have long been tried but without success. Recent data from several controlled trials have, however, shown positive results. The collected information from several trials using different chemotherapy schedules indicate that overall survival is improved. The extent of this improvement is not properly known although several centres have considered it to be sufficiently large to merit routine use in certain stages. Likewise, the collected information from several trials using perioperative radiotherapy indicates that the proportion of local recurrences are reduced by about 50% but without any major influence on survival. Most evidence favours additional radiotherapy before surgery rather than after. If proper dose planning is utilized, sufficiently high doses can be given preoperatively without increasing postoperative mortality.     

Lung cancer.

Only patients with localized lung cancer benefit from curative resection. Curative radiotherapy is recommended in patients with a resectable tumor in whom surgery is precluded for medical reasons. Adjuvant preoperative or postoperative therapy of any type does not improve the results of surgery except in patients with Pancoast tumor. Therapy for nonlocalized tumors does not affect survival. Radiotherapy has a palliative effect in 50 to 75 per cent of patients presenting with symptoms from either a primary lesion or metastases and should therefore be recommended in symptomatic patients. The palliative effect of chemotherapy is limited in lung cancers other than small cell carcinomas. However, chemotherapy alone or in association with radiotherapy produces remarkable tumor regression and some improvement of survival in small cell carcinoma. The use of immunotherapy in the treatment of lung cancer is still under evaluation.     

Crystalloid, colloid or small volume resuscitation?

Small volume resuscitation fluids are a combination of hypertonic crystalloid with a colloid. SVR fluids have the advantage of logistical convenience in the field situation. Clinical trials point to improved outcome in patients with penetrating trauma injury or traumatic brain injury. HSD may reduce the inflammatory process and has shown improved outcome in trauma patients who require intensive care. Trials so far have been carried out in small numbers of patients and improved survival benefit has only become evident on meta-analysis and sub-group analysis. Further large scale blinded randomized trials are required to confirm the promise of survival advantages.     

Clinical Research in Interventional Pain Management Techniques: The Clinician's Point of View

Abstract: Interventional pain management techniques are considered for patients whose pain proves refractory to conventional treatment. According to the evidence‐based medicine (EBM) guidelines, the highest level of evidence for efficacy and safety of a treatment is generated in high‐quality randomized controlled trials and systematic reviews. A randomized controlled trial is defined as an experiment that determines the influence of an intervention on the natural history of the disease, which means that the comparative group should receive placebo, which is a sham intervention in case of the interventional pain management techniques. The systematic review summarizes in a structured way the results of the available information. When randomized controlled trials are available, observational studies will often be discarded. As new information on a treatment becomes available the perceived value may change, thus determining the survival time of clinical evidence. This survival time is not different when based on randomized or nonrandomized studies. The inclusion criteria are an important component of the randomized controlled trial and are designed to test a treatment in a homogeneous patient population. As interventional pain management techniques are mainly used for the management of spinal pain, it needs to be stressed that there is no gold standard for the diagnosis. This lack of validated standard diagnostic procedures is at the origin of different patient selection criteria, which makes the interpretation of the different randomized controlled trials and the meta‐analyses very difficult. Moreover, the extrapolation of randomized controlled trials with carefully selected patient populations to daily practice is a major problem. Randomized controlled trials in interventional pain management techniques often prove to be underpowered, which can be attributed to the difficulty in motivating patients and the referring physicians to participate in a trial where there is 50% chance of receiving a placebo/sham for intractable pain. Furthermore, the validity of sham intervention as a reflection of the natural course of the disease is questioned. It is stated that any new technique should prove to be at least equally effective as the best available treatment option, which offers the possibility of comparing two groups, both receiving active treatment. The reference treatment may be pharmacological or a rehabilitation program (cognitive behavioral) in which case blinding becomes a problem. It has been demonstrated that large observational studies with a cohort or case–control design do not systematically overestimate the magnitude of the associations between exposure and outcome as compared with the results of randomized controlled trials. There is an urgent need for guidelines on performing prospective cohort trials that should be designed to confirm or refute the anecdotal findings from retrospective studies.     

他汀类药物治疗心房颤动随机对照试验的Meta分析

目的评价他汀类药物抗心房颤动（房颤）的疗效。方法采用Cochrane系统评价的方法,计算机检索PubMed、EMbase、EMB Reviews—Cochrane Central Register of Controlled Trials（2007年第3期）、中国生物医学文献数据库、中文科技期刊数据库,中国期刊全文数据库,检索时间截至2007年9月15日,纳入中外文他汀类药物抗房颤的随机对照试验（RCTo由两名评价者独立评价纳入研究质量、提取资料并交叉核对。采用RevMan4．3软件进行Meta分析。结果共纳入5个RCT,包括470例房颤患者。各研究间存在统计学异质性（I^2=66．8％,P=0．02）,故采用随机效应模型进行合并分析,其结果显示,他汀类药物可减少房颤复发,发生率[RR=0．61,95％CI（0．43,0．88）,P=0．008o敏感性分析显示结果稳定性较好,失安全数为52．91。结论他汀类药物可以有效降低房颤的复发和发生率。但本研究中部分文献质量不高,加之有关他汀类药物预防房颤的RCT文献数量较少,总样本量较小,上述结论尚有待开展大样本、随机、双盲对照试验证实。     

Antihypertensive medications for risk reduction of first and recurrent ischemic stroke

It is increasingly clear that even a small reduction in blood pressure results in a substantial risk reduction of vascular events including ischemic stroke. Recently, several comparative prospective trials of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have demonstrated that, for equivalent reductions in blood pressure, these drugs may confer a greater effect on the prevention of primary and recurrent ischemic stroke compared with other antihypertensive medications. Given this information from prospective randomized trials, it appears that this class of drugs should be the first-line treatment for hypertension in patients at risk of a first or recurrent ischemic stroke. This review will critically assess the scientific basis and rationale of the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in primary and secondary stroke prevention.     

Antihypertensive medications for risk reduction of first and recurrent ischemic stroke

It is increasingly clear that even a small reduction in blood pressure results in a substantial risk reduction of vascular events including ischemic stroke. Recently, several comparative prospective trials of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have demonstrated that, for equivalent reductions in blood pressure, these drugs may confer a greater effect on the prevention of primary and recurrent ischemic stroke compared with other antihypertensive medications. Given this information from prospective randomized trials, it appears that this class of drugs should be the first-line treatment for hypertension in patients at risk of a first or recurrent ischemic stroke. This review will critically assess the scientific basis and rationale of the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in primary and secondary stroke prevention.     

MortalitY in caRdIAc surgery (MYRIAD): A randomizeD controlled trial of volatile anesthetics. Rationale and design

ObjectiveThere is initial evidence that the use of volatile anesthetics can reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalization following coronary artery bypass graft (CABG) surgery. Nevertheless, small randomized controlled trials have failed to demonstrate a survival advantage. Thus, whether volatile anesthetics improve the postoperative outcome of cardiac surgical patients remains uncertain. An adequately powered randomized controlled trial appears desirable.DesignSingle blinded, international, multicenter randomized controlled trial with 1:1 allocation ratio.SettingTertiary and University hospitals.InterventionsPatients (n = 10,600) undergoing coronary artery bypass graft will be randomized to receive either volatile anesthetic as part of the anesthetic plan, or total intravenous anesthesia.Measurements and main resultsThe primary end point of the study will be one-year mortality (any cause). Secondary endpoints will be 30-day mortality; 30-day death or non-fatal myocardial infarction (composite endpoint); cardiac mortality at 30 day and at one year; incidence of hospital re-admission during the one year follow-up period and duration of intensive care unit, and hospital stay. The sample size is based on the hypothesis that volatile anesthetics will reduce 1-year unadjusted mortality from 3% to 2%, using a two-sided alpha error of 0.05, and a power of 0.9.ConclusionsThe trial will determine whether the simple intervention of adding a volatile anesthetic, an intervention that can be implemented by all anesthesiologists, can improve one-year survival in patients undergoing coronary artery bypass graft surgery.     

What have we learned from the current trials?

Even well-conducted randomized controlled trials can only reduce uncertainty, not eliminate it. The trials presented in this article all have gaps, and like many studies, some raise more questions than answers. A summary of the current trials, however, can be presented as follows. For patients with essential hypertension who are at high risk for cardiovascular disease, the use of diuretic therapy (excluding simultaneous use of ACE or CCB) resulted in outcomes at least equivalent to the use of either ACE or CCB without diuretics. Naturally, the dilemma for clinicians is that these drugs are most often used in combination with thiazide diuretics, as indicated by the RENAAL trial where 80% of ARB were used with diuretics in patients with type II diabetes and known nephropathy. The increased risk of heart failure observed with ACE and CCB in that trial may be relevant only to patients in whom diuretics were not also used. The study does raise important awareness, however, that ACE or CCB use without diuretic therapy is no better than diuretic therapy, and may be associated with higher risk of certain outcomes. A substantial number of patients with essential hypertension might achieve adequate blood pressure control with diuretic monotherapy. If so, that certainly has important implications for the cost of medical care in this country. For African Americans with essential hypertension, ACE may have advantages as a component of therapy in comparison with CCBs or beta-blockers, although diuretics should probably be the cornerstone of therapy for them and supported by the Seventh Joint National Committee. For patients with proteinuric renal disease, whether associated with diabetes or hypertension, it should be considered inappropriate to use DHP CCB as monotherapy in any setting, whether as part of a clinical trial or in clinical practice. These drugs should not be considered as ethical placebo arms in trials, most especially in diabetic nephropathy, nor should they be used without an ACE or ARB in patients with proteinuric renal disease in the absence of documented contraindications or intolerance to ACE, ARB, or non-DHP CCB (which are now considered second-line agents for proteinuric renal disease, and are acceptable placebo or comparison arms in clinical trials). For patients with type I diabetes, ACE remain the cornerstone of therapy. Because of recent RENAAL and IDNT trial results, the greatest benefit for slowing progression of renal disease in type II diabetic nephropathy now belongs to ARBs. In contrast, however, the HOPE trial showed that ACE, specifically ramipril, had the greatest evidence for prevention of cardiovascular outcomes in patients with renal insufficiency, regardless of diabetic status. Cardiovascular outcomes were secondary end points in the RENAAL and IDNT trials, and with the exception of heart failure for losartan, no benefits on cardiovascular outcomes were statistically significant. Progression of renal disease has only been studied in a relatively small cohort of Israeli patients comparing enalapril with nifedipine. These gaps lead to a classic dilemma in medical decision-making. Because evidence has shown that patients with elevated serum creatinine (greater than or equal to 1.4 mg/dL) are just as likely to die from cardiovascular disease as they are to reach end-stage renal disease, which outcome should be the focus for clinicians, or for researchers? Using a strictly evidence-based approach, this question can only be answered by yet another large, long, randomized, controlled trial. Given the similarity of actions between the ARB and ACE, it is likely there is considerable overlap of both benefits and side-effects between the two, although ARB may have a lower incidence of cough and hyperkalemia. The decision of which antihypertensive agents to use will have to be tailored carefully to the needs of the patient and careful consideration of both medical and economic factors. Regardless of the choice between an ACE or ARB, however, post hoc analysis of clinical trials [21,47] and observational data clearly indicate that patients with chronic kidney disease, even if considered mild (ie, serum creatinine greater than or equal to 1.4 mg/dL) are at significantly greater risk of cardiovascular morbidity and mortality compared with those with better kidney function. As stated in a recent review by the authors of the HOPE trial [50], "the frequent practice of withholding ACE [or ARB] in patients with mild renal insufficiency is unwarranted," because not only are these patients precisely those who might benefit most from their use, but safety and tolerability are generally excellent. Based on the results of the AASK trial, the authors add the same for the use of ACE inhibitors in African Americans.     

Selective digestive decontamination in patients in intensive care. The Dutch Working Group on Antibiotic Policy

Selective digestive decontamination (SDD) is the most extensively studied method for the prevention of infection in patients in intensive care units (ICUs). Despite 27 prospective randomized studies and six meta-analyses, routine use of SDD is still controversial. In this review, we summarize the available scientific information on effectiveness of SDD in ICU patients. The effects of SDD have been studied in different combinations of the concept, using different antibiotics. Comparison of the individual studies, therefore, is difficult. In most studies, SDD resulted in significant reductions in the number of diagnoses of ventilator-associated pneumonia. However, incidences of ventilator-associated pneumonia in control groups ranged from 5% to 85%. Moreover, these reductions in incidences of ventilator-associated pneumonia in individual studies were not associated with improved patient survival, reductions of duration of ventilation or ICU stay, or reductions in antibiotic use. The numbers of patients studied are too small to determine effects on patient survival. Although two meta-analyses suggested a 20% mortality reduction when using the full concept of SDD (topical and systemic prophylaxis) these results should be interpreted with caution. Formal cost-benefit analyses of SDD have not been performed. SDD is associated with the selection of microorganisms that are intrinsically resistant to the antibiotics used. However, the studies are too small and too short to investigate whether SDD will lead to development of antibiotic resistance. As long as the benefits of SDD (better patient survival, reduction in antibiotic use or improved cost-effectiveness) have not been firmly established, the routine use of SDD for mechanically ventilated patients is not advised.     

Endoscopic repair of groin hernia--what ist evidence-based

The endoscopic techniques of groin hernia repair have developed tremendously over the past 10 years. There are numerous prospective randomized clinical trials comparing conventional techniques of groin hernia repair with endoscopic methods. However, it is difficult to establish a proper meta-analysis of the currently available data due to widely differing study designs. We assessed the currently available prospective randomized clinical trials comparing conventional versus laparoscopic hernia repair. We conclude that based on present data there is a clear advantage for the endoscopic techniques regarding length of hospital stay, postoperative recovery and return to normal activity. The conventional techniques are superior regarding duration of operation and direct cost. Rate of recurrence are comparable in both, endoscopic and conventional approach using mesh prosthesis. Endoscopic techniques are far superior to conventional operation without the use of mesh prosthesis. In patients with recurrent hernia endoscopy offers a major advantage regarding postoperative pain, lenght of hospital stay, return to normal activity and rate of recurrence. We demonstrate these suggestions discussing our own results. Therefore we recomend endoscopic hernia repair in patients with bilateral or recurrent hernia.     

Defining the standard of care in randomized controlled trials of titrated therapies

PURPOSE OF REVIEW: To discuss the appropriate standard of care in randomized controlled trials of titrated therapies in critically ill patients. RECENT FINDINGS: The debate over the appropriate standard of care in randomized controlled trials was sparked by the Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation. In this trial, patients were randomized to either low or traditional tidal volume ventilation, and the investigators reported that low tidal volume ventilation significantly improved survival in patients with acute respiratory distress syndrome. However, it was argued that the control group used in this trial was not reflective of current practice patterns and that the improvement in survival may have been derived from patients in the control group being placed at increased risk. This debate forced intensivists to consider what defines an appropriate standard-of-care control group in randomized controlled trials of titrated therapies. If titrated therapies are to be studied safely, the mechanism behind the titration must be understood and incorporated into the control group. Failure to include a comparator group receiving current practice creates a study design that may jeopardize patient safety because there is no control group representing probable patient outcome outside of the trial. Additionally, randomizing patients to the extremes of a range of care without incorporation of a current practice control group prevents the investigators from making valid recommendations for changing current practice. SUMMARY: The incorporation of current practice patterns into randomized controlled trials of titrated therapies is essential for producing generalizable results and safeguarding patients.     

Clinical review: Timing and dose of continuous renal replacement therapy in acute kidney injury

The optimal management of renal replacement therapy (RRT) in acute kidney injury (AKI) remains uncertain. Although it is well accepted that initiation of RRT in patients with progressive azotemia prior to the development of overt uremic manifestations is associated with improved survival, whether there is benefit to even earlier initiation of therapy is uncertain. Although retrospective and observational studies have suggested improved survival with very early initiation of continuous RRT (CRRT), interpretation of these studies is confounded by their failure to include patients with AKI who recover renal function or die without ever receiving RRT. Several studies have suggested that more intensive delivery of CRRT during AKI is associated with improved survival, although results of trials have been inconsistent. Two large multicenter randomized clinical trials addressing this question are currently underway and should provide more definitive data within the next two years.     

Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies

Introduction

Observational data have suggested that statin therapy may reduce mortality in patients with infection and sepsis; however, results from randomized studies are contradictory and do not support the use of statins in this context. Here, we performed a meta-analysis to investigate the effects of statin therapy on mortality from infection and sepsis.

Methods

We searched electronic databases (PubMed and Embase) for articles published before November 2013. Randomized or observational studies reporting the effects of statin therapy on mortality in patients with infection or sepsis were eligible. Randomized and observational studies were separately pooled with relative risks (RRs) and random-effects models.

Results

We examined 5 randomized controlled trials with 867 patients and 27 observational studies with 337,648 patients. Among the randomized controlled trials, statins did not significantly decrease in-hospital mortality (RR, 0.98; 95% confidence interval (CI), 0.73 to 1.33) or 28-day mortality (RR, 0.93; 95% CI, 0.46 to 1.89). However, observational studies indicated that statins were associated with a significant decrease in mortality with adjusted data (RR, 0.65; 95% CI, 0.57 to 0.75) or unadjusted data (RR, 0.74; 95% CI, 0.59 to 0.94).

Conclusions

Limited evidence suggests that statins may not be associated with a significant reduction in mortality from infection and sepsis. Although meta-analysis from observational studies showed that the use of statins was associated with a survival advantage, these outcomes were limited by high heterogeneity and possible bias in the data. Therefore, we should be cautious about the use of statins in infection and sepsis.     

Coronary stenting and abciximab in primary angioplasty for ST-segment-elevation myocardial infarction

Advances in anti-platelet therapy and improvement of stent deployment techniques have improved the safety and efficacy of stenting in the setting of ST-segment-elevation myocardial infarction (STEMI). However, in randomized trials, routine coronary stenting does not reduce mortality and re-infarction, compared to balloon angioplasty. Further, the benefits in target vessel revascularization seem to be reduced when applied to unselected patients with STEMI. Direct stenting represents an attractive strategy with potential benefits in terms of myocardial perfusion. Future large randomized trials are needed to evaluate whether this strategy has a significant impact on outcome, and to provide a cost-benefit analysis of the unrestricted use of drug-eluting stents in this high-risk subset of patients. The additional use of abciximab reduces mortality in primary angioplasty. Since the feasibility of long-distance transportation has been shown in several randomized trials, early pharmacological pre-treatment may confer further advantages by early recanalization and shorter ischaemic time, particularly in high-risk patients. Further randomized trials are needed to clarify the potential benefits from early abciximab administration and the potential role of small molecules in primary angioplasty for STEMI.     

Coronary revascularization on balance: Robert L. Frye lecture.

The first generation of multicenter randomized controlled trials of coronary artery bypass surgery vs medical treatment in the 1970s found survival advantage only in patients with left main coronary artery disease or with multiple risk factors. Over time, these results have remained reproducible and biologically plausible and continue to be the basis for contemporary guidelines for bypass surgery. Percutaneous coronary intervention (PCI), which became available some 10 years after surgery, was compared with medical treatment in various clinical settings. Patients with stable angina receiving aggressive medical therapy had survival rates comparable to those undergoing PCI in several trials. In the presence of unstable angina, evidence suggests benefit from intervention after stabilization. In the setting of acute myocardial infarction or cardiogenic shock, PCI showed results superior to lytic therapy in centers with large PCI volume. A comparison of the 2 revascularization methods in the 1990s resulted in no overall 7-year survival difference except in patients with treated diabetes in whom bypass surgery prolonged life compared with angioplasty. None of the revascularizations had an effect on the incidence of myocardial infarctions, but importantly, the presence of bypass grafts reduced their fatal impact compared with both medical treatment and PCI. All revascularization trials reported improvement in quality of life, including symptoms, compared with less aggressive therapy. In the pursuit to explain 3 decades of steady decline of cardiovascular mortality in the United States, health economists attempted to model the decline due to availability of intervention by estimates obtained from contemporary randomized prevention and intervention trials. They concluded that, thus far, treatments have made a greater contribution to the decline than has primary prevention. Randomized trials not only contribute to evidence-based clinical practice, but also can reveal underlying biological mechanisms and provide quantitative data to model population trends. Thus, they should be regarded as the basic science of medical therapeutics and population health.