Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. Part 2

9 August, 2011 (16:41) | Cancer | By: Health news

Although effective mass screening of high-risk groups could potentially be of benefit, randomized trials of screening with the use of chest radiography with or without cytologic analysis of sputum specimens have shown no reduction in lung-cancer mortality. Molecular markers in blood, sputum, and bronchial brushings have been studied but are currently unsuitable for clinical application. Advances in multidetector computed tomography (CT), however, have made high-resolution volumetric imaging possible in a single breath hold at acceptable levels of radiation exposure, allowing its use for certain lung-specific applications. Several observational studies have shown that low-dose helical CT of the lung detects more nodules and lung cancers, including early-stage cancers, than does chest radiography.

Therefore, the National Cancer Institute (NCI) funded the National Lung Screening Trial (NLST), a randomized trial, to determine whether screening with low-dose CT, as compared with chest radiography, would reduce mortality from lung cancer among high-risk persons. The NLST was initiated in 2002. In October 2010, the available data showed that there was a significant reduction with low-dose CT screening in the rates of both death from lung cancer and death from any cause. We report here the findings of the NLST, including the performance characteristics of the screening techniques, the approaches used for and the results of diagnostic evaluation of positive screening results, the characteristics of the lungcancer cases, and mortality. A comprehensive description of the design and operations of the trial, including the collection of the data and the acquisition variables of the screening techniques, has been published previously.

Trial Oversight
The NLST, a randomized trial of screening with the use of low-dose CT as compared with screening with the use of chest radiography, was a collaborative effort of the Lung Screening Study (LSS), administered by the NCI Division of Cancer Prevention, and the American College of Radiology Imaging Network (ACRIN), sponsored by the NCI Division of Cancer Treatment and Diagnosis, Cancer Imaging Program. Chest radiography was chosen as the screening method for the control group because radiographic screening was being compared with community care (care that a participant usually receives) in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (ClinicalTrials.gov number, NCT00002540). The NLST was approved by the institutional review board at each of the 33 participating medical institutions.

Participants
We enrolled participants from August 2002 through April 2004; screening took place from August 2002 through September 2007.

Eligible participants were between 55 and 74 years of age at the time of randomization, had a history of cigarette smoking of at least 30 packyears, and, if former smokers, had quit within the previous 15 years. Persons who had previously received a diagnosis of lung cancer, had undergone chest CT within 18 months before enrollment, had hemoptysis, or had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were excluded. A total of 53,454 persons were enrolled; 26,722 were randomly assigned to screening with low-dose CT and 26,732 to screening with chest radiography.

Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening

6 August, 2011 (02:02) | Cancer | By: Health news

Background
The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of lowdose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer.

Methods
From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009.

Results
The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P = 0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P = 0.02).

Conclusions
Screening with the use of low-dose CT reduces mortality from lung cancer.

Lung cancer is an aggressive and heterogeneous disease. Advances in surgical, radiotherapeutic, and chemotherapeutic approaches have been made, but the long-term survival rate remains low. After the Surgeon General’s 1964 report on smoking and health, mortality from lung cancer among men peaked and then fell; among women, the peak occurred later and a slight decline has occurred more recently. Even though the rate of heavy smoking continues to decline in the United States, 94 million current or former smokers remain at elevated risk for the disease, and lung cancer remains the leading cause of death from cancer in this country. The prevalence of smoking is substantially higher in developing countries than in the United States, and the worldwide burden of lung cancer is projected to rise considerably during the coming years.

Bleeding and Other Safety Outcomes. Part 2

2 August, 2011 (18:43) | Heart Attack | By: Health news

The current standard of care for patients after an acute coronary syndrome includes dual antiplatelet therapy, typically with aspirin and clopidogrel. Despite aggressive use of dual antiplatelet therapy, however, patients frequently have recurrent ischemic events. Newer, more potent P2Y12-receptor antagonists provide additional reductions in ischemic events and mortality but at the cost of an increase in bleeding. Thus, patients with a substantial risk of recurrent events have an important unmet need for better secondary prevention. A combination of antiplatelet and anticoagulant agents seems to be an attractive approach. However, such broad antithrombotic therapy may also pose an unacceptable risk of bleeding. In this trial, we enrolled a high-risk patient population, with large proportions of patients who had diabetes, heart failure, or renal insufficiency, as well as a large proportion of patients who did not undergo revascularization for the index event. We hypothesized that this population was most likely to benefit from the addition of an oral anticoagulant agent in addition to standard antiplatelet and other evidencebased therapies. Further investigation is required to determine whether there are other patient populations for which the results may be different or concomitant interventions that might change the risk–benefit profile of the combination of anticoagulation plus antiplatelet therapy in this population.

Three phase 2 clinical trials have investigated the use of new oral anticoagulant drugs in addition to contemporary antiplatelet therapy in patients who have had a recent acute coronary syndrome. When added to antiplatelet therapy, both apixaban and rivaroxaban resulted in doserelated increases in bleeding but also appeared to result in larger absolute reductions in ischemic events than those seen with placebo. The increases in bleeding were smaller and the reductions in ischemic events were more pronounced among patients taking aspirin alone than among those taking aspirin plus clopidogrel. The findings from the APPRAISE-2 trial definitively confirm the increases in bleeding observed in the phase 2 trials of factor Xa inhibitors administered in addition to antiplatelet therapy. Unfortunately, the reductions in ischemic events suggested in the phase 2 trial were not observed in this larger phase 3 trial. Because this trial was stopped early owing to the increase in bleeding events, with fewer events having occurred than the number planned, uncertainty remains regarding the effect of apixaban on ischemic events. The ATLAS-ACS 2 TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51; ClinicalTrials.gov number NCT00402597), which includes a lower-risk population than that in the APPRAISE-2 trial and is evaluating two different doses of another factor Xa inhibitor, is currently ongoing. Whether this trial will have similar results remains to be seen. Meta-analyses of earlier studies with oral vitamin K antagonists combined with aspirin, as compared with aspirin alone, showed that there were reductions in recurrent ischemic events in patients after acute coronary syndromes. In a large, observational analysis that included more than 40,000 patients with myocardial infarction, the use of triple therapy (aspirin, clopidogrel, and a vitamin K antagonist), as compared with aspirin alone, was associated with a rate of bleeding that was increased by a factor of 4, with no significant difference in the rate of survival. Similar increases in bleeding events have been seen in other studies and other clinical settings in which the use of combined antiplatelet and anticoagulant therapy may be considered. The results of the current trial raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding by combining a long-term oral anticoagulant with both aspirin and a P2Y12-receptor antagonist in patients with coronary disease. In summary, we evaluated the addition of apixaban, at a dose of 5 mg twice daily, to standard antiplatelet therapy in patients with an acute coronary syndrome. Treatment with apixaban, as compared with placebo, was associated with a significant increase in the risk of bleeding, without a significant effect on the incidence of recurrent ischemic events.

Bleeding and Other Safety Outcomes

2 August, 2011 (10:13) | Heart Attack | By: Health news

In the on-treatment analysis, the primary safety outcome of TIMI major bleeding occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patientyears), as compared with 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). Among the patients receiving apixaban, as compared with those receiving placebo, there were more events of fatal bleeding (5 vs. 0), intracranial bleeding (12 vs. 3), ISTH major or clinically relevant nonmajor bleeding (117 vs. 45), and total bleeding (679 vs. 305). Patients receiving apixaban received more transfusions than did patients receiving placebo (144 [3.9%] vs. 73 [2.0%]). The findings with respect to the primary safety outcome were consistent among all key subgroups. The increase in bleeding events with apixaban, as compared with placebo, was seen both in patients taking combination antiplatelet therapy (1.3% vs. 0.6%; hazard ratio, 2.27; 95% CI, 1.28 to 4.02) and in patients taking aspirin alone (1.1% vs. 0.1%), although there was only a small number of major bleeding events in the aspirin-only subgroup. The frequencies of serious adverse events and overall adverse events were similar in the apixaban group and the placebo group (24.3% and 59.0%, respectively, in the apixaban group and 24.3% and 57.7%, respectively, in the placebo group). The frequencies of events other than ischemic events and bleeding were either similar in the two groups or lower in the apixaban group than in the placebo group. There were no significant between-group differences in the rates of adverse events related to hepatotoxicity.

In this randomized clinical trial, the oral factor Xa inhibitor apixaban, administered at a dose of 5 mg twice daily in high-risk patients who were taking either aspirin or aspirin plus clopidogrel after an acute coronary syndrome, resulted in a significant increase in bleeding events, including increases in events of fatal and intracranial bleeding, without a significant reduction in recurrent ischemic events. These findings were consistent in all subgroups, including subgroups defined according to antiplatelet therapy (aspirin plus clopidogrel vs. aspirin alone) and according to management of the acute coronary syndrome (revascularization vs. noninvasive management). The increase in bleeding with apixaban led more frequently to discontinuation of the study drug and resulted in the premature termination of the trial — both of which limit the certainty of the conclusions that can be drawn about efficacy.

Study Drug and Antiplatelet Therapies

1 August, 2011 (23:39) | Heart Attack | By: Health news

A total of 7315 of the 7392 patients who underwent randomization (99.0%) received at least one dose of the assigned study drug; 8.5% of the patients were assigned to the reduced dose of apixaban or matching placebo. Of these 7315 patients, 863 of the 3673 patients who received at least one dose of apixaban (23.5%) and 746 of the 3642 who received at least one dose of placebo (20.5%) stopped taking the study drug before the end of the trial (P = 0.002). The median exposure to the study drug was 175 days (interquartile range, 66 to 293) among patients receiving apixaban and 185 days (interquartile range, 75 to 298) among patients receiving placebo. The most common reasons for discontinuation of the study drug were adverse events (8.5% in the apixaban group vs. 6.5% in the placebo group) and withdrawal of consent (5.3% vs. 4.2%). A total of 1310 (21.5%) of the patients who were taking aspirin plus a P2Y12-receptor antagonist at the time of randomization stopped taking the P2Y12-receptor antagonist during the course of the trial, at a median of 39 days (interquartile range, 13 to 108) after randomization; 135 (11.1%) of the patients receiving aspirin alone at randomization started taking a P2Y12-receptor antagonist during the trial, at a median of 14 days (interquartile range, 4 to 93) after randomization.

Efficacy Outcomes
The final number of primary efficacy events was 572, or 61.0% of the initially planned number. In the intention-to-treat analysis, the primary efficacy outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). Similar results were seen in an on-treatment analysis (218 vs. 249 events; hazard ratio, 0.89; 95% CI, 0.74 to 1.06; P = 0.19). There were also no significant differences between the apixaban and placebo groups with respect to any of the secondary efficacy outcomes. The effect of apixaban as compared with placebo was similar among patients receiving combination antiplatelet therapy and among those receiving aspirin alone. The rates of the primary efficacy outcome among patients who were receiving combination antiplatelet therapy were 7.2% in the apixaban group and 7.5% in the placebo group (hazard ratio with apixaban, 0.95; 95% CI, 0.79 to 1.15), and the corresponding rates among those receiving aspirin alone were 9.0% and 9.8% (hazard ratio, 0.92; 95% CI, 0.66 to 1.29) (P = 0.87 for interaction). Similar findings with respect to the primary efficacy outcome were seen in all key subgroups.

Study Drug and Antiplatelet Therapies

29 July, 2011 (17:44) | Heart Attack | By: Health news

A total of 7315 of the 7392 patients who underwent randomization (99.0%) received at least one dose of the assigned study drug; 8.5% of the patients were assigned to the reduced dose of apixaban or matching placebo. Of these 7315 patients, 863 of the 3673 patients who received at least one dose of apixaban (23.5%) and 746 of the 3642 who received at least one dose of placebo (20.5%) stopped taking the study drug before the end of the trial (P = 0.002). The median exposure to the study drug was 175 days (interquartile range, 66 to 293) among patients receiving apixaban and 185 days (interquartile range, 75 to 298) among patients receiving placebo. The most common reasons for discontinuation of the study drug were adverse events (8.5% in the apixaban group vs. 6.5% in the placebo group) and withdrawal of consent (5.3% vs. 4.2%). A total of 1310 (21.5%) of the patients who were taking aspirin plus a P2Y12-receptor antagonist at the time of randomization stopped taking the P2Y12-receptor antagonist during the course of the trial, at a median of 39 days (interquartile range, 13 to 108) after randomization; 135 (11.1%) of the patients receiving aspirin alone at randomization started taking a P2Y12-receptor antagonist during the trial, at a median of 14 days (interquartile range, 4 to 93) after randomization.

Efficacy Outcomes
The final number of primary efficacy events was 572, or 61.0% of the initially planned number. In the intention-to-treat analysis, the primary efficacy outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). Similar results were seen in an on-treatment analysis (218 vs. 249 events; hazard ratio, 0.89; 95% CI, 0.74 to 1.06; P = 0.19). There were also no significant differences between the apixaban and placebo groups with respect to any of the secondary efficacy outcomes. The effect of apixaban as compared with placebo was similar among patients receiving combination antiplatelet therapy and among those receiving aspirin alone. The rates of the primary efficacy outcome among patients who were receiving combination antiplatelet therapy were 7.2% in the apixaban group and 7.5% in the placebo group (hazard ratio with apixaban, 0.95; 95% CI, 0.79 to 1.15), and the corresponding rates among those receiving aspirin alone were 9.0% and 9.8% (hazard ratio, 0.92; 95% CI, 0.66

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. Part 4

29 July, 2011 (14:20) | Heart Attack | By: Health news

Efficacy and bleeding outcomes were analyzed with the use of a Cox proportional-hazards model that included the assigned study group as a covariate and that was stratified according to antiplatelet therapy (single or dual) at baseline. Data on patients who died of noncardiovascular causes were censored at the time of death. A point estimate and two-sided 95% confidence interval for the hazard ratio were calculated for each outcome. Prespecified efficacy and safety analyses were performed in subgroups according to baseline antiplatelet therapy, type of acute coronary syndrome, treatment for acute coronary syndrome, dose of apixaban, region, age, sex, race, body-mass index, degree of renal impairment, number of risk factors, presence or absence of diabetes mellitus, and presence or absence of heart failure. The rates of efficacy and bleeding events are reported as percentages and as events per 100 patient-years. Other categorical variables are reported as percentages. All P values are two-sided. All analyses were per formed with the use of SAS software, version 9.0 (SAS Institute).

Study Participants
A total of 7392 patients underwent randomization between March 17, 2009, and November 18, 2010 (Fig. 1 in the Supplementary Appendix). Patients underwent randomization a median of 6 days (interquartile range, 4 to 7) after the index event of acute coronary syndrome and 2 days (interquartile range, 2 to 4) after discontinuation of parenteral antithrombotic therapy. Among the patients who underwent randomization, 81 (1.1%) withdrew consent and 50 (0.7%) were lost to follow-up for the primary end point during the intended treatment period. The median duration of follow-up from the time of randomization through the last date of contact in the study was 240 days (interquartile range, 132 to 352) among patients assigned to apixaban and 242 days (interquartile range, 131 to 352) among patients assigned to placebo. By design, the trial population had high rates of diabetes, prior myocardial infarction, cerebrovascular and peripheral vascular disease, heart failure or left ventricular dysfunction, and impaired renal function, and a large proportion of the patients had not undergone revascularization for the index event. More than half the patients had three or more protocol-defined high-risk characteristics at the time of enrollment. The index event was a myocardial infarction with ST-segment elevation in approximately 40% of patients, a myocardial infarction without STsegment elevation in 42%, and unstable angina in 18%. More than 52% of the patients underwent coronary angiography, 44% underwent a percutaneous coronary intervention, and 55% had their condition managed medically. At the time of randomization, nearly all the patients (97%) were taking aspirin. The majority of the patients (81%) were receiving aspirin plus a P2Y12-receptor antagonist, predominantly clopidogrel. Most patients were receiving other evidence- based therapies as well, and the rates of these therapies were similar in the apixaban and placebo groups.

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. Part 3

28 July, 2011 (21:27) | Heart Diseases | By: Health news

Investigators were encouraged to practice evidence-based medicine and follow appropriate clinical practice guidelines in managing the care of their patients. The use, choices, and duration of antiplatelet therapy, as well as decisions about the use of other medical treatments and subsequent revascularization procedures, were left to the discretion of the treating physicians.

Study Outcomes
The primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, or ischemic stroke.18 The primary safety outcome was major bleeding, according to the Thrombolysis in Myocardial Infarction (TIMI) definition. Prespecified secondary outcomes included the composite of cardiovascular death, myocardial infarction, ischemic stroke, or unstable angina; the composite of cardiovascular death, myocardial infarction, ischemic or hemorrhagic stroke, or fatal bleeding; and the composite of death from any cause, myocardial infarction, or ischemic or hemorrhagic stroke. Additional efficacy outcomes included the individual components of the primary efficacy outcome, unstable angina, and stent thrombosis. Additional safety outcomes included TIMI major or minor bleeding, major or clinically relevant nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) definitions, and severe or moderate bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) definitions. Data on adverse events other than bleeding were also collected. The primary and secondary efficacy outcomes and the main safety outcome were adjudicated with the use of prespecified criteria by an independent clinical events committee whose members were unaware of the group assignments.

Statistical Analysis
Assuming a recruitment period of approximately 2 years, an average follow-up period of 1.25 years, and a rate of the primary efficacy outcome of 8% per year, we estimated that we would need to enroll 10,800 patients to achieve the desired target of 938 patients with a primary efficacy outcome. With this number of patients with events, we estimated that the study would have 80% power to detect a 20% reduction in relative risk with apixaban as compared with placebo at a one-sided alpha level of 0.005 and 93% power to detect the same reduction in risk at a one-sided alpha level of 0.025. In November 2010, after approximately 7000 patients had been recruited, the independent data monitoring committee recommended that the trial be stopped, owing to an excess of clinically important bleeding events with apixaban in the absence of a counterbalancing reduction in ischemic events. Recruitment was stopped on November 18, 2010. All the patients enrolled in the study were contacted and told to discontinue the study drug and schedule a final follow-up assessment. The trial database was locked on March 23, 2011. The intended treatment period, starting on the day of randomization and ending at the efficacy cutoff date (November 18, 2010), is the basis for the efficacy analyses. The actual treatment period, starting on the date the first dose of study drug was administered and ending 2 days after the last dose of study drug was administered, is the basis for the analyses of safety. A post hoc analysis was performed to assess the primary efficacy outcome during the actual treatment period.

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. Part 2

26 July, 2011 (17:27) | Heart Diseases | By: Health news

Study Design
The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial was a double-blind, placebo-controlled, randomized clinical trial conducted at 858 sites in 39 countries. The study was approved by the institutional review board at each participating site. All participating patients gave written informed consent. The trial was supervised by a steering committee that included representatives from the sponsors (Bristol-Myers Squibb and Pfizer). The data were managed and all analyses were performed at the Duke Clinical Research Institute, Durham, North Carolina. All the authors designed the study, reviewed the data, participated in the analyses, and assume responsibility for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol. The first author wrote the first draft of the manuscript, and all the authors provided comments on subsequent drafts and made the decision to submit the manuscript for publication.
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Study Population
The main inclusion criterion for the trial was an acute coronary syndrome (myocardial infarction, with or without ST-segment elevation, or unstable angina) within the previous 7 days, with symptoms of myocardial ischemia lasting 10 minutes or more with the patient at rest plus either elevated levels of cardiac biomarkers or dynamic ST-segment depression or elevation of 0.1 mV or more. Patients who met this criterion were eligible for the study if their condition was clinically stable and they were receiving standard treatment after the acute coronary syndrome, including aspirin or aspirin plus any P2Y12-receptor antagonist. Eligible patients were also required to have two or more of the following high-risk characteristics: an age of at least 65 years, diabetes mellitus, myocardial infarction within the previous 5 years, cerebrovascular disease, peripheral vascular disease, clinical heart failure or a left ventricular ejection fraction of less than 40% in association with the index event, impaired renal function with a calculated creatinine clearance of less than 60 ml per minute, and no revascularization after the index event.

Randomization and Study Regimen
Patients were randomly assigned, in a 1:1 ratio, to receive apixaban, at a dose of 5 mg twice daily, or matching placebo. Patients with an estimated creatinine clearance of less than 40 ml per minute at the time of randomization were randomly assigned to receive apixaban at a dose of 2.5 mg twice daily or matching placebo. Randomization was performed in a blinded fashion with the use of an interactive voice-response system, in permuted blocks of two, stratified according to site and according to planned long-term use of aspirin or aspirin plus a P2Y12-receptor antagonist. Patients who interrupted the study regimen during the course of the trial were encouraged to resume taking the assigned drug if and when possible.

Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome

26 July, 2011 (14:01) | Heart Diseases | By: Health news

Background
Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.

Methods
We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.

Results
The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.

Conclusions
The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in highrisk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events.

Patients with acute coronary syndromes frequently have recurrent ischemic events despite the use of currently recommended antiplatelet therapy, revascularization procedures as appropriate, and other evidence-based secondary preventive measures. Oral anticoagulation therapy with vitamin K antagonists reduces the incidence of recurrent ischemic events after myocardial infarction but also increases the risk of bleeding when it is added to aspirin or aspirin and clopidogrel. Apixaban, an orally active, selective, direct factor Xa inhibitor, has been shown to reduce the incidence of venous thromboembolism in patients undergoing orthopedic surgery and to prevent thromboembolic events in patients with atrial fibrillation who are not candidates for oral vitamin K antagonist therapy. We previously studied the use of apixaban, at doses of 5 to 20 mg daily, in patients who had had recent acute coronary syndromes and who were receiving aspirin or aspirin plus clopidogrel. Treatment with apixaban resulted in dose-related increases in bleeding events and a trend toward fewer ischemic events.

Considering both ischemic events and bleeding events, the preferred dose was thought to be 10 mg daily. Similar findings were observed with another factor Xa inhibitor, rivaroxaban, in a similar population. We therefore conducted a phase 3 trial to determine whether, in high-risk patients with an acute coronary syndrome, the benefit of apixaban in reducing ischemic events would outweigh the increased risk of bleeding.

Reputation and Precedent in the Bevacizumab Decision. Part 2

23 July, 2011 (23:14) | Health Care | By: Health news

Ultimately, data from confirmatory studies should either permit conversion to regular approval or lead to withdrawal of the indication in question. Hence, accelerated approval is provisional — a medium-term stopover en route to full approval or market withdrawal. There should be a clear end point and, after a reasonable period for confirmatory trials, the sponsor should provide evidence that meets the standard for regular approval. If such evidence emerges, the FDA must convert the drug’s status to regular approval. Otherwise, the FDA must rescind approval. Without a genuine option to withdraw accelerated approval in light of either inadequate or unfavorable confirmatory data, the FDA would have few tools to ensure that companies provide the new, rigorous data they promised to obtain.

Although such adverse decisions may be contested, the integrity of the accelerated approval process and the FDA’s reputation and authority as a public health agency require that it be willing to make and adhere to these difficult decisions. A central question in the bevacizumab dispute concerns whether the standard for conversion of accelerated to regular approval has been met. Genentech argues that progressionfree survival is an acceptable measure of direct clinical benefit in metastatic breast cancer and that confirmatory trials demonstrate that bevacizumab prolongs progression-free survival. Yet the progression-free– survival benefit in confirmatory trials, while statistically significant, was considerably smaller than that seen in E2100. In addition, safety concerns — both new and previously described — have arisen from the recent clinical trials. Genentech further claims that the FDA has switched approval standards for bevacizumab. The agency, however, has consistently maintained that progression-free survival is “not statistically validated as surrogate for survival in all settings” and is “not precisely measured.”4 Therefore, the FDA has full authority to respond to adverse safety and efficacy data by changing medication labeling. Genentech’s second claim, that the possibility of heterogeneity in the treatment effect should justify continued approval, suffers from an absence of data identifying which patient characteristics are associated with clinical benefit. As the FDA’s decision memorandum notes, the mere prospect of efficacy in subgroups of patients, without the ability to identify those subgroups in advance, is inadequate as a rationale for continued approval.

Genentech’s philosophical claim that “conflicting interpretations of data should be resolved in favor of retaining access and choice” represents a departure from federal statute and a bold challenge to the FDA’s mission. In a democratic republic, access and choice represent two among many values. The FDA must also protect scientific rigor, the integrity and legitimacy of federal regulations and guidance, and the public’s health. The agency’s reputation for using science to guide regulatory decisions in the public interest is its most critical institutional asset.

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