Viability and Outcomes With Revascularization or Medical Therapy in Ischemic Ventricular Dysfunction: A Prespecified Secondary Analysis of the REVIVED-BCIS2 Trial.

Importance: In the Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial, percutaneous coronary intervention (PCI) did not improve outcomes for patients with ischemic left ventricular dysfunction. Whether myocardial viability testing had prognostic utility for these patients or identified a subpopulation who may benefit from PCI remained unclear. Objective: To determine the effect of the extent of viable and nonviable myocardium on the effectiveness of PCI, prognosis, and improvement in left ventricular function. Design, Setting, and Participants: Prospective open-label randomized clinical trial recruiting between August 28, 2013, and March 19, 2020, with a median follow-up of 3.4 years (IQR, 2.3-5.0 years). A total of 40 secondary and tertiary care centers in the United Kingdom were included. Of 700 randomly assigned patients, 610 with left ventricular ejection fraction less than or equal to 35%, extensive coronary artery disease, and evidence of viability in at least 4 myocardial segments that were dysfunctional at rest and who underwent blinded core laboratory viability characterization were included. Data analysis was conducted from March 31, 2022, to May 1, 2023. Intervention: Percutaneous coronary intervention in addition to optimal medical therapy. Main Outcomes and Measures: Blinded core laboratory analysis was performed of cardiac magnetic resonance imaging scans and dobutamine stress echocardiograms to quantify the extent of viable and nonviable myocardium, expressed as an absolute percentage of left ventricular mass. The primary outcome of this subgroup analysis was the composite of all-cause death or hospitalization for heart failure. Secondary outcomes were all-cause death, cardiovascular death, hospitalization for heart failure, and improved left ventricular function at 6 months. Results: The mean (SD) age of the participants was 69.3 (9.0) years. In the PCI group, 258 (87%) were male, and in the optimal medical therapy group, 277 (88%) were male. The primary outcome occurred in 107 of 295 participants assigned to PCI and 114 of 315 participants assigned to optimal medical therapy alone. There was no interaction between the extent of viable or nonviable myocardium and the effect of PCI on the primary or any secondary outcome. Across the study population, the extent of viable myocardium was not associated with the primary outcome (hazard ratio per 10% increase, 0.98; 95% CI, 0.93-1.04) or any secondary outcome. The extent of nonviable myocardium was associated with the primary outcome (hazard ratio, 1.07; 95% CI, 1.00-1.15), all-cause death, cardiovascular death, and improvement in left ventricular function. Conclusions and Relevance: This study found that viability testing does not identify patients with ischemic cardiomyopathy who benefit from PCI. The extent of nonviable myocardium, but not the extent of viable myocardium, is associated with event-free survival and likelihood of improvement of left ventricular function. Trial Registration: ClinicalTrials.gov Identifier: NCT01920048.

Impact of major bleeding and blood transfusions after cardiac surgery: analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial.

BACKGROUND: Prior retrospective studies have identified a relationship between bleeding after cardiac surgery and subsequent mortality. Whether this is attributable to bleeding, anemia, or transfusions is undetermined. METHODS: ACUITY was an international prospective trial of patients with acute coronary syndromes. Coronary artery bypass grafting (CABG) before hospital discharge was performed in 1,491 patients. Major bleeding was adjudicated as CABG- or non-CABG related. The relationship between CABG-related bleeding and 1-year mortality was determined using a time-updated covariate-adjusted Cox model. RESULTS: Coronary artery bypass grafting-related major bleeding after surgery occurred in 789 patients (52.9%); allogeneic blood product transfusions were administered in 612 patients (41.0%), including red blood cell (RBC) transfusions in 570 (38.2%, range 1-53 U), platelet transfusions in 180 (12.1%), and fresh-frozen plasma in 195 (13.1%). One-year mortality occurred in 95 patients (6.4%). Red blood cell transfusion (but not transfusion of platelets or fresh-frozen plasma, CABG-related major bleeding per se, or nadir hemoglobin) was an independent predictor of 1-year mortality, but only after transfusion of ≥4 U (adjusted hazard ratio for death after transfusion of 1-3, 4-6, and ≥7 RBC units = 0.74, 2.01, and 5.22, respectively). Of the 95 deaths after CABG, 23 (24.2%) were attributable to CABG-related RBC transfusions. CONCLUSIONS: In patients with acute coronary syndromes, RBC transfusion of ≥4 U after CABG is strongly associated with subsequent mortality. Future strategies should focus on reducing major hemorrhagic complications and RBC transfusions after CABG.

Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial.

BACKGROUND: Both ischemic and hemorrhagic complications increase mortality rate in acute coronary syndromes. Their frequency and relative importance vary according to individual patient risk profiles. We sought to develop prognostic models for the risk of myocardial infarction (MI) and major bleeding to assess their impact on risk of death and to examine the manner in which alternative antithrombotic regimens affect these risks in individual patients. METHODS AND RESULTS: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13 819 patients with acute coronary syndrome to heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. By logistic regression, there were 5 independent predictors of MI within 30 days (n=705; 5.1%) and 8 independent predictors of major bleeding (n=645; 4.7%), only 2 of which were common to both event types. In a covariate-adjusted, time-updated Cox regression model, both MI and major bleeding significantly affected subsequent mortality rate (hazard ratios, 2.7 and 2.9, respectively; both P<0.001). Treatment with bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor was associated with a nonsignificant 8% increase in MI and a highly significant 50% decrease in major bleeding. Given the individual patient risk profiles and the fact that bivalirudin prevented approximately 6 major bleeds for each MI that might occur from its use, the estimated reduction in bleeding was greater than the estimated increase in MI by bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor for nearly all patients. CONCLUSIONS: Consideration of the individual patient risk profile for MI and major bleeding and the relative treatment effects of alternative pharmacotherapies permits personalized decision making to optimize therapy of patients with acute coronary syndrome. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00093158.

Randomized trial of simple versus complex drug-eluting stenting for bifurcation lesions: the British Bifurcation Coronary Study: old, new, and evolving strategies.

BACKGROUND: The optimal strategy for treating coronary bifurcation lesions remains a subject of debate. With bare-metal stents, single-stent approaches appear to be superior to systematic 2-stent strategies. Drug-eluting stents, however, have low rates of restenosis and might offer improved outcomes with complex stenting techniques. METHODS AND RESULTS: Patients with significant coronary bifurcation lesions were randomized to either a simple or complex stenting strategy with drug-eluting stents. In the simple strategy, the main vessel was stented, followed by optional kissing balloon dilatation/T-stent. In the complex strategy, both vessels were systematically stented (culotte or crush techniques) with mandatory kissing balloon dilatation. Five hundred patients 64+/-10 years old were randomized; 77% were male. Eighty-two percent of lesions were true bifurcations (>50% narrowing in both vessels). In the simple group (n=250), 66 patients (26%) had kissing balloons in addition to main-vessel stenting, and 7 (3%) had T stenting. In the complex group (n=250), 89% of culotte (n=75) and 72% of crush (n=169) cases were completed successfully with final kissing balloon inflations. The primary end point (a composite at 9 months of death, myocardial infarction, and target-vessel failure) occurred in 8.0% of the simple group versus 15.2% of the complex group (hazard ratio 2.02, 95% confidence interval 1.17 to 3.47, P=0.009). Myocardial infarction occurred in 3.6% versus 11.2%, respectively (P=0.001), and in-hospital major adverse cardiovascular events occurred in 2.0% versus 8.0% (P=0.002), respectively. Procedure duration and x-ray dose favored the simple approach. CONCLUSIONS: When coronary bifurcation lesions are treated, a systematic 2-stent technique results in higher rates of in-hospital and 9-month major adverse cardiovascular events. This difference is largely driven by periprocedural myocardial infarction. Procedure duration is longer, and x-ray dose is higher. The provisional technique should remain the preferred strategy in the majority of cases. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00351260.

Patterns of herpes simplex virus shedding over 1 month and the impact of acyclovir and HIV in HSV-2-seropositive women in Tanzania.

OBJECTIVES: Few studies have examined the frequency and duration of genital herpes simplex virus (HSV) shedding in sub-Saharan Africa. This study describes HSV shedding patterns among a sample of HSV-2-seropositive women enrolled in a placebo-controlled trial of HSV suppressive therapy (acyclovir 400 mg twice a day) in Tanzania. METHODS: Trial participants were invited to participate in a substudy involving 12 clinic visits over 4 weeks. At each visit, cervical, vaginal and external skin swabs were taken and analysed for HSV DNA using inhouse real-time PCR. RESULTS: HSV shedding was mainly subclinical (90%; 57/63 shedding days in the placebo arm). The most frequent shedding site was the external skin, but HSV DNA was detected from all three sites on 42% (27/63) of shedding days. In HIV-negative women, HSV DNA was detected on 3% (9/275) of days in the acyclovir versus 11% (33/309) in the placebo arm, while in HIV-positive women, detection was on 14% (23/160) versus 19% (30/155) of days, respectively. CONCLUSIONS: HSV shedding was common, varying greatly by individual. Shedding rates were similar to studies in African and non-African settings. Among HIV-negative women, shedding rates were lower in the acyclovir arm; however, acyclovir did not substantially impact on HSV shedding in HIV-positive women.

Long-term impact of acyclovir suppressive therapy on genital and plasma HIV RNA in Tanzanian women: a randomized controlled trial.

BACKGROUND: Herpes simplex virus (HSV) suppressive therapy reduces genital and plasma human immunodeficiency virus type 1 (HIV-1) RNA over periods up to 3 months, but the long-term effect is unknown. METHODS: A total of 484 HIV-1 and HSV type 2 seropositive Tanzanian women aged 16-35 years were enrolled in a randomized placebo-controlled trial of acyclovir administered at a dosage of 400 mg twice daily. Cervico-vaginal lavage and blood samples were collected at 6 months, 12 months, and 24 months for quantification of genital and plasma HIV-1 RNA and genital HSV DNA. Primary outcomes were detection and quantity of cervico-vaginal HIV-1 RNA at 6 months. RESULTS: At 6 months, there was little difference between the acyclovir and placebo arms for cervico-vaginal HIV-1 RNA detection (88 [ 41 .3%] of 213 vs 84 [ 44 .0%] of 191; odds ratio [OR], 0.90; 95% confidence interval [CI], 0.60-1.33), HSV DNA detection (20 [ 9 .4%] of 213 vs 22 [ 11 .5%] of 191; OR, 0.80; 95% CI, 0.42-1.51), genital HIV or HSV loads, or plasma HIV-1 RNA load. Estimated median adherence was 91%. There was a suggestion of an impact on cervico-vaginal HIV-1 RNA detection among women with estimated adherence 90% (OR, 0.74; 95% CI, 0.50-1.09) when data from all 3 visits were included. CONCLUSIONS: Acyclovir administered at a dosage of 400 mg twice daily is unlikely to be a useful long-term intervention to reduce HIV transmission. The lack of effect on HIV may be attributable to suboptimal adherence or treatment regimen.

Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials.

BACKGROUND: Coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) are alternative treatments for multivessel coronary disease. Although the procedures have been compared in several randomised trials, their long-term effects on mortality in key clinical subgroups are uncertain. We undertook a collaborative analysis of data from randomised trials to assess whether the effects of the procedures on mortality are modified by patient characteristics. METHODS: We pooled individual patient data from ten randomised trials to compare the effectiveness of CABG with PCI according to patients' baseline clinical characteristics. We used stratified, random effects Cox proportional hazards models to test the effect on all-cause mortality of randomised treatment assignment and its interaction with clinical characteristics. All analyses were by intention to treat. FINDINGS: Ten participating trials provided data on 7812 patients. PCI was done with balloon angioplasty in six trials and with bare-metal stents in four trials. Over a median follow-up of 5.9 years (IQR 5.0-10.0), 575 (15%) of 3889 patients assigned to CABG died compared with 628 (16%) of 3923 patients assigned to PCI (hazard ratio [HR] 0.91, 95% CI 0.82-1.02; p=0.12). In patients with diabetes (CABG, n=615; PCI, n=618), mortality was substantially lower in the CABG group than in the PCI group (HR 0.70, 0.56-0.87); however, mortality was similar between groups in patients without diabetes (HR 0.98, 0.86-1.12; p=0.014 for interaction). Patient age modified the effect of treatment on mortality, with hazard ratios of 1.25 (0.94-1.66) in patients younger than 55 years, 0.90 (0.75-1.09) in patients aged 55-64 years, and 0.82 (0.70-0.97) in patients 65 years and older (p=0.002 for interaction). Treatment effect was not modified by the number of diseased vessels or other baseline characteristics. INTERPRETATION: Long-term mortality is similar after CABG and PCI in most patient subgroups with multivessel coronary artery disease, so choice of treatment should depend on patient preferences for other outcomes. CABG might be a better option for patients with diabetes and patients aged 65 years or older because we found mortality to be lower in these subgroups.

Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial.

AIMS: To evaluate the associations of myocardial infarction (MI) and major bleeding with 1-year mortality. Both MI and major bleeding predict 1-year mortality in patients presenting with acute coronary syndrome (ACS). However, the risk of each of these events on the magnitude and timing of mortality has not been well studied. METHODS AND RESULTS: A multivariable Cox regression model was developed relating 13 independent baseline predictors to 1-year mortality for 13 819 patients with moderate and high-risk ACS enrolled in the Acute Catheterization and Urgent Intervention Triage strategy trial. After adjustment for baseline predictors, Cox models with major bleeding and recurrent MI as time-updated covariates estimated the effect of these events on mortality hazard over time. Within 30 days of randomization, 705 patients (5.1%) had an MI, 645 (4.7%) had a major bleed; 524 (3.8%) died within a year. The occurrence of an MI was associated with a hazard ratio of 3.1 compared with patients not yet having an MI, after adjustment for baseline predictors. However, MI within 30 days markedly increased the mortality risk for the first 2 days after the event (adjusted hazard ratio of 17.6), but this risk declined rapidly post-infarct (hazard ratio of 1.4 beyond 1 month after the MI event). In contrast, major bleeding had a prolonged association with mortality risk (hazard ratio of 3.5) which remained fairly steady over time throughout 1 year. CONCLUSION: After accounting for baseline predictors of mortality, major bleeds and MI have similar overall strength of association with mortality in the first year after ACS. MI is correlated with a dramatic increase in short-term risk, whereas major bleeding correlates with a more prolonged mortality risk.

Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis.

CONTEXT: Although an invasive strategy is frequently used in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. OBJECTIVE: To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. DATA SOURCES: Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. STUDY SELECTION: Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. DATA EXTRACTION: The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. DATA SYNTHESIS: Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). CONCLUSIONS: In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.

Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial.

CONTEXT: At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded. OBJECTIVE: To determine 1-year ischemic outcomes for patients in the ACUITY trial. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13,819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005. INTERVENTIONS: Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration. MAIN OUTCOME MEASURE: Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year. RESULTS: Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15). CONCLUSIONS: At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00093158.

Impact of call-to-balloon time on 30-day mortality in contemporary practice.

OBJECTIVE: Studies reporting an association between treatment delay and outcome for patients with ST segment elevation myocardial infarction (STEMI) have generally not included patients treated by a primary percutaneous coronary intervention (PPCI) service that systematically delivers reperfusion therapy to all eligible patients. We set out to determine the association of call-to-balloon (CTB) time with 30-day mortality after PPCI in a contemporary series of patients treated within a national reperfusion service. METHODS: We analysed data on 16 907 consecutive patients with STEMI treated by PPCI in England and Wales in 2011 with CTB time of ≤6 hours. RESULTS: The median CTB and door-to-balloon times were 111 and 41 min, respectively, with 80.9% of patients treated within 150 min of the call for help. An out-of-hours call time (58.2% of patients) was associated with a 10 min increase in CTB time, whereas inter-hospital transfer for PPCI (18.5% of patients) was associated with a 49 min increase in CTB time. CTB time was independently associated with 30-day mortality (p<0.0001) with a HR of 1.95 (95% CI 1.54 to 2.47) for a CTB time of >180-240 min compared with ≤90 min. The relationship between CTB time and 30-day mortality was influenced by patient risk profile with a greater absolute impact of increasing CTB time on mortality in high-risk patients. CONCLUSION: CTB time is a useful metric to assess the overall performance of a PPCI service. Delays to reperfusion remain important even in the era of organised national PPCI services with rapid treatment times and efforts should continue to minimise treatment delays.

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial.

BACKGROUND: Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. METHODS: We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat. FINDINGS: 310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction. INTERPRETATION: Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.

Seven-year outcome in the RITA-2 trial: coronary angioplasty versus medical therapy.

OBJECTIVES: This study was designed to compare the long-term consequences of percutaneous transluminal coronary angioplasty (PTCA) and continued medical treatment. BACKGROUND: The long-term effects of percutaneous coronary intervention need evaluating, especially in comparison with an alternative policy of continued medical treatment. METHODS: The Second Randomized Intervention Treatment of Angina (RITA-2) is a randomized trial of PTCA versus conservative (medical) care in 1,018 patients considered suitable for either treatment option. Information on clinical events, interventions, and symptoms is available for a median seven years follow-up. RESULTS: Death or myocardial infarction (MI) occurred in 73 (14.5%) PTCA patients and 63 (12.3%) medical patients (difference +2.2%, 95% confidence interval -2.0% to +6.4%, p = 0.21). There were 43 deaths in both groups, of which 41% were cardiac-related. Among patients assigned PTCA 12.7% subsequently had coronary artery bypass grafts, and 14.5% required additional non-randomized PTCA. Most of these re-interventions occurred within a year of randomization, and after two years the re-intervention rate was 2.3% per annum. In the medical group, 35.4% required myocardial revascularization: 15.0% in the first year and an annual rate of 3.6% after two years. An initial policy of PTCA was associated with improved anginal symptoms and exercise times. These treatment differences narrowed over time, mainly because of coronary interventions in medical patients with severe symptoms. CONCLUSIONS: In RITA-2 an initial strategy of PTCA did not influence the risk of death or MI, but it improved angina and exercise tolerance. Patients considered suitable for PTCA or medical therapy can be safely managed with continued medical therapy, but percutaneous intervention is appropriate if symptoms are not controlled.

Challenging Issues in Clinical Trial Design: Part 4 of a 4-Part Series on Statistics for Clinical Trials.

As a sequel to last week's paper on the fundamentals of clinical trial design, this paper tackles related controversial issues: noninferiority trials, the value of factorial designs, the importance and challenges of strategy trials, Data Monitoring Committees (including when to stop a trial early), and the role of adaptive designs. All topics are illustrated by relevant examples from cardiology trials.

Design of Major Randomized Trials: Part 3 of a 4-Part Series on Statistics for Clinical Trials.

This paper provides practical guidance on the fundamentals of design for major randomized controlled trials. Topics covered include the choice of patients, choice of treatment and control groups, choice of primary and secondary endpoints, methods of randomization, appropriate use of blinding, and determination of trial size. Insights are made with reference to contemporary major trials in cardiology.

Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.

A cohort of 1792 human immunodeficiency virus (HIV)-positive and 2970 HIV-negative South African miners was observed for 12 months starting in February 1998. All-cause hospitalizations and deaths were significantly associated with HIV infection (respective unadjusted incidence rate ratios, 2.9 and 9.2; respective 95% confidence intervals, 2.5-3.4 and 5.5-16.0). Tuberculosis (TB), bacterial pneumonia, cryptococcosis, and trauma were the major causes of admission for HIV-positive patients, whereas Pneumocystis carinii pneumonia was an uncommon cause (respective admission rates, 8.5, 6.9, 2.2, 6.0, and 0.53 admissions per 100 person-years). Enteritis, bronchitis, urinary tract infections, and soft-tissue infections were also significantly associated with HIV infection. Cryptococcosis caused 44% of deaths among HIV-positive patients. Trauma was the main hazard for HIV-negative men, causing 42% of admissions and 60% of deaths. A broad range of infectious conditions is significantly associated with HIV infection in South African miners. Identification and implementation of effective prophylactic regimens are urgently needed.

Peak flow rate and death due to coronary heart disease: 30-year results from the Northwick Park Heart cohort study.

OBJECTIVE: Numerous studies have reported that chronic obstructive pulmonary disease or impaired lung function are associated with later coronary heart disease (CHD). However, it is unclear if lung function is an independent risk factor, as many of these studies have included only limited measures of other factors associated with CHD. METHODS: In total 2167 men of all ages in the first Northwick Park Heart Study were followed for a median of 30 years. Cox regression models were used to assess the relationship between peak flow rate (PFR) and CHD mortality adjusted for potential confounders measured at baseline. Analyses allowed for missing data, and secondary analyses for repeat measures on some men and competing risks of CHD death. RESULTS: There were 254 CHD deaths with some evidence of an association between PFR and CHD mortality. The adjusted HRs (95% CIs) from the lowest to the highest of four PFR quartiles were 1.53 (1.04 to 2.25), <430 L/min; 1.43 (0.99 to 2.08), 430 - <490 L/min; and 1.31 (0.93 to 1.86), 490 - <550 L/min; compared with the reference group of ≥550 L/min (trend test p=0.025). Other associations with CHD mortality were observed for systolic blood pressure (p<0.0001), body mass index (p=0.0002), smoking status (p=0.015), blood cholesterol (p=0.005), plasma fibrinogen (p=0.001) and high-risk ECG (p=0.021). There were no strong associations for factors V and VIII or platelet count. CONCLUSIONS: After allowing for a range of other risk factors associated with CHD, there was only limited evidence of a relation between PFR and CHD mortality.

Long-term follow-up of elective chronic total coronary occlusion angioplasty: analysis from the U.K. Central Cardiac Audit Database.

BACKGROUND: Chronic total occlusion (CTO) is common, being reported in 18% to 30% of patients undergoing coronary angiography. Percutaneous coronary intervention (PCI) is usually performed to relieve anginal symptoms, but data are emerging to suggest that there may also be a mortality benefit. OBJECTIVES: This study aimed to compare outcomes of patients with successful versus unsuccessful PCI to a CTO. METHODS: We analyzed the U.K. Central Cardiac Audit Database for all CTO PCI cases carried out in England and Wales between January 1, 2005, and December 31, 2009. Vital status in September 2010 was obtained from the Medical Research Information Service. RESULTS: A total of 13,443 patients (78.8% male) had a mean age of 63.5 years and underwent 14,439 CTO procedures. CTO PCI was successful in 10,199 cases (70.6%). During follow-up of 2.65 years (interquartile range: 1.59 to 3.83 years), successful PCI of at least 1 CTO was associated with improved survival (hazard ratio [HR]: 0.72; 95% CI: 0.62 to 0.83; p < 0.001). Complete revascularization was associated with improved survival compared with partial revascularization (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.002) or failed revascularization (HR: 0.61; 95% CI: 0.50 to 0.74; p < 0.001). CONCLUSIONS: Successful CTO PCI was associated with improved long-term survival. The improvement was greatest in patients when complete revascularization was achieved. The identity of the successfully treated occluded vessel was not associated with differences in outcome.

Usefulness of the admission electrocardiogram to predict long-term outcomes after non-ST-elevation acute coronary syndrome (from the FRISC II, ICTUS, and RITA-3 [FIR] Trials).

The aim of this study was to evaluate the independent prognostic value of qualitative and quantitative admission electrocardiographic (ECG) analysis regarding long-term outcomes after non-ST-segment elevation acute coronary syndromes (NSTE-ACS). From the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of Unstable Angina 3 (RITA-3) patient-pooled database, 5,420 patients with NSTE-ACS with qualitative ECG data, of whom 2,901 had quantitative data, were included in this analysis. The main outcome was 5-year cardiovascular death or myocardial infarction. Hazard ratios (HRs) were calculated with Cox regression models, and adjustments were made for established outcome predictors. The additional discriminative value was assessed with the category-less net reclassification improvement and integrated discrimination improvement indexes. In the 5,420 patients, the presence of ST-segment depression (≥1 mm; adjusted HR 1.43, 95% confidence interval [CI] 1.25 to 1.63) and left bundle branch block (adjusted HR 1.64, 95% CI 1.18 to 2.28) were independently associated with long-term cardiovascular death or myocardial infarction. Risk increases were short and long term. On quantitative ECG analysis, cumulative ST-segment depression (≥5 mm; adjusted HR 1.34, 95% CI 1.05 to 1.70), the presence of left bundle branch block (adjusted HR 2.15, 95% CI 1.36 to 3.40) or ≥6 leads with inverse T waves (adjusted HR 1.22, 95% CI 0.97 to 1.55) was independently associated with long-term outcomes. No interaction was observed with treatment strategy. No improvements in net reclassification improvement and integrated discrimination improvement were observed after the addition of quantitative characteristics to a model including qualitative characteristics. In conclusion, in the FRISC II, ICTUS, and RITA-3 NSTE-ACS patient-pooled data set, admission ECG characteristics provided long-term prognostic value for cardiovascular death or myocardial infarction. Quantitative ECG characteristics provided no incremental discrimination compared to qualitative data.