Month: September, 2011

Follow-up and Assessment of Outcome. Part 2

25 September, 2011 (01:51) | Hypertension | By: Health news

We tested the primary hypothesis by comparing the rate of the primary end point between the two treatment groups using a two-sided log-rank test. Data from patients who were lost to follow-up or who withdrew consent were censored at the last contact date. Secondary end points were analyzed with the use of the same techniques. The probability of a primary end point by 30 days after enrollment was compared between the two treatment groups with the use of a z test. All analyses were performed in the intention-to-treat population unless otherwise specified. All reported P values are two-sided and have not been adjusted for multiple testing.

Contrary to what we hypothesized, the results of this trial showed that aggressive medical therapy was superior to PTAS with the use of the Wingspan system in high-risk patients with intracranial stenosis, because the rate of periprocedural stroke after PTAS was higher than expected and the rate of stroke in the medical-management group was lower than estimated. The 30-day rate of stroke or death in the PTAS group (14.7%) is substantially higher than the rates previously reported with the use of the Wingspan stent in the phase I trial and in two registries (rates ranging from 4.4% to 9.6%).10,20,25 The higher rate in the current study does not reflect inexperience of the operators, because most of the interventionists who participated in the registries also participated in this trial, and all the interventionists in this trial were credentialed to participate on the basis of evidence of their experience. In addition, the rates of periprocedural stroke did not decline over the course of the enrollment period and did not differ significantly between high-enrolling sites and low-enrolling sites in this trial.
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One possible explanation for the higher rate of periprocedural stroke in this trial as compared with the registries is that all the patients in this study had stenosis of 70 to 99% and recent symptoms, whereas the registries included patients with stenosis of 50 to 99% and symptoms that had occurred more than 30 days before enrollment. Recent symptoms may be a marker for unstable plaque, which could increase the risk of distal embolism during stenting, as has been reported with extracranial carotid stenting. Another explanation for the higher rate of periprocedural stroke in this trial is that the rigorous protocol for evaluating events (i.e., evaluation of all potential end points by neurologists, the adjudication process, and site-monitoring visits) could have resulted in the detection of some milder strokes that may not have been detected in the registries. However, the percentage of primary end-point strokes in the PTAS group that were disabling or fatal (35%; 16 of 46 patients) is higher than the percentage of primary end-point strokes that were categorized as major in the stenting group (21%) or the endarterectomy group (28%) in a recent randomized trial involving patients with extracranial carotid stenosis.

Follow-up and Assessment of Outcome

23 September, 2011 (23:12) | Hypertension | By: Health news

Patients were evaluated at the time of study entry, at 4 days, and at 30 days and have continued to be evaluated every 4 months; patients undergo assessments until 90 days after a primary end point occurs, the patient dies, 3 years of follow-up have been completed, or the close-out visit for the trial is held, which will occur when the last patient enrolled has been followed for 1 year. At follow-up visits, patients are examined by study neurologists who also manage the patients’ vascular risk factors. If a stroke is suspected during the follow-up period, the patient is examined by the study neurologist, and magnetic resonance imaging (MRI) or computed tomography (CT) of the brain is typically performed. Because the treatment assignment is known to the study neurologist, we require that a second site neurologist, who is not aware of the treatment assignments, evaluate any patient who has had a prolonged TIA (lasting more than 1 hour) or mild ischemic stroke (an increase in the patient’s score on the National Institutes of Health Stroke Scale [NIHSS] of <4 points from the score at study entry), since these events may be difficult to classify. (The NIHSS is a 42-point scale that quantifies neurologic deficits in 11 categories, with higher scores indicating more severe deficits.) The assessments of both neurologists are sent for central adjudication.
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All the end points are adjudicated by independent panels of neurologists and cardiologists who are not informed of the treatment assignments. The primary end point is stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period (i.e., angioplasty for symptomatic restenosis in a patient in the PTAS group or placement of a stent in a patient in the medical-management group) or ischemic stroke in the territory of the qualifying artery between day 31 and the end of the follow-up period. Ischemic stroke is defined as a new focal neurologic deficit of sudden onset, lasting at least 24 hours, that is not associated with a hemorrhage on CT or MRI of the brain. Ischemic strokes are further classified by the neurologic adjudicators as being either in the territory or out of the territory of the qualifying artery. Symptomatic brain hemorrhage is defined as a parenchymal, subarachnoid, or intraventricular hemorrhage detected on CT or MRI that is associated with a seizure or with new neurologic signs or symptoms lasting at least 24 hours; it is included as a primary end point only if it occurs within 30 days after enrollment or within 30 days after a revascularization procedure for the qualifying lesion during the follow-up period.
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Statistical Analysis

The mean length of follow-up was designed to be 2 years. In the Warfarin–Aspirin Symptomatic Intracranial Disease trial (WASID; number, NCT00004728),7 the rate of the same primary end point among patients with symptoms within 30 days before enrollment and 70 to 99% stenosis was 29% at 2 years. With adjustment of that rate to account for an estimated 15% relative reduction in risk with aggressive medical management, the projected rate of the primary end point in the medical-management group was 24.7% at 2 years. We estimated that we would need to enroll 382 patients in each group for the study to have 80% power to show a relative reduction of 35% with PTAS in the risk of the primary end point, assuming a 5% crossover rate from the medical-management group to the PTAS group and a 2% loss to follow-up, with the use of a two-sided log-rank test, at a type I error rate of 0.05.

Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis. Part 2

23 September, 2011 (18:17) | Hypertension | By: Health news

The data and safety monitoring board met every 6 months and reviewed monthly reports to monitor the study’s progress and the accumulated data. Two interim efficacy analyses were planned when approximately 33% and 66% of the required primary end points had occurred. There were no prespecified stopping rules for safety.

Study Patients

Eligible patients had a TIA or nondisabling stroke within 30 days before enrollment, attributed to angiographically verified stenosis of 70 to 99% of the diameter of a major intracranial artery. The other eligibility criteria are provided in the study protocol. All the patients gave written informed consent to participate, and patients who did not undergo diagnostic angiography as part of routine care gave consent for angiography as part of the study protocol.


Aggressive Medical Management

The rationale for the medical-management regimen and details on the management of risk factors in the study patients have been published previously.21-23 Medical management is identical in the two groups and consists of aspirin, at a dose of 325 mg per day; clopidogrel, at a dose of 75 mg per day for 90 days after enrollment; management of the primary risk factors (elevated systolic blood pressure and elevated low-density lipoprotein [LDL] cholesterol levels); and management of secondary risk factors (diabetes, elevated non–high-density lipoprotein [non-HDL] cholesterol levels, smoking, excess weight, and insufficient exercise) with the help of a lifestyle modification program. With respect to the primary risk factors, we targeted a systolic blood pressure of less than 140 mm Hg (<130 mm Hg in the case of patients with diabetes) and an LDL cholesterol level of less than 70 mg per deciliter (1.81 mmol per liter). We provide the aspirin, clopidogrel, one drug from each major class of antihypertensive agents, rosuvastatin, and the lifestyle program to the study patients.
PTAS Procedure

PTAS was performed by neurointerventionists who were selected by a committee of experienced neurointerventionists on the basis of their review of procedure notes and outcomes for the 20 most recent consecutive cases of intracranial stenting or angioplasty (if angioplasty had been performed to treat atherosclerosis) performed by the neurointerventionists under consideration. Further details regarding the credentialing process and the monitoring of the interventionists’ performance of PTAS during the trial have been published previously. Patients who were randomly assigned to PTAS were required to undergo the procedure within 3 business days after randomization. Patients who were not taking clopidogrel at a dose of 75 mg each day for at least 5 days before PTAS were given a 600-mg loading dose of clopidogrel between 6 and 24 hours before PTAS. Details of the procedure, which was performed under general anesthesia with the use of the Gateway PTA Balloon Catheter and Wingspan Stent System (both manufactured by Boston Scientific Corporation), and of the care of the patients after the procedure are provided in the protocol.

Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis

21 September, 2011 (18:38) | Hypertension | By: Health news

Atherosclerotic intracranial arterial stenosis is one of the most common causes of stroke worldwide and is associated with a high risk of recurrent stroke. Patients with a recent transient ischemic attack (TIA) or stroke and severe stenosis (70 to 99% of the diameter of a major intracranial artery) are at particularly high risk for recurrent stroke in the territory of the stenotic artery (approximately 23% at 1 year) despite treatment with aspirin and standard management of vascular risk factors. Therefore, alternative therapies are urgently needed for these patients.

Two strategies have emerged for the treatment of high-risk patients: aggressive medical therapy (combination antiplatelet therapy and intensive management of risk factors) and percutaneous transluminal angioplasty and stenting (PTAS). Over the past decade, intracranial PTAS has increasingly been used in clinical practice in the United States and other countries. Currently, the self-expanding Wingspan stent (Boston Scientific) is the only device approved by the Food and Drug Administration (FDA) for use in patients with atherosclerotic intracranial arterial stenosis; it has been available since 2005 for the treatment of patients with 50 to 99% stenosis who have had a TIA or stroke while receiving antithrombotic therapy.
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Because of uncertainty regarding the safety and efficacy of aggressive medical management alone as compared with aggressive medical management plus PTAS with the use of the Wingspan stent system, we began a randomized trial in November 2008 to compare these two treatments in high-risk patients with intracranial arterial stenosis. On April 5, 2011, the trial’s independent data and safety monitoring board recommended that enrollment be stopped because of safety concerns regarding the risk of periprocedural stroke or death in the PTAS group and because futility analyses indicated that there was virtually no chance that a benefit from PTAS would be shown by the end of the follow-up period if enrollment continued. Although follow-up of patients is ongoing, the clinical importance of these findings mandated the reporting of the current results.

Study Design and Oversight
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Details of the trial design have been published previously. This study is an investigator-initiated, randomized, clinical trial funded by the National Institute of Neurological Disorders and Stroke and conducted at 50 sites in the United States. Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided the study devices and supplemental funding for third-party distribution of devices and continues to provide funding for site monitoring and auditing of the study. The Investigator-Sponsored Study Program of AstraZeneca donates rosuvastatin (Crestor) to study patients. Other industry partners are listed at the end of the article. None of the industry partners participated in the design of the trial or in the analysis or reporting of the results.

Medical Devices — Balancing Regulation and Innovation. Part 2

21 September, 2011 (11:46) | Medications | By: Health news

The ASR is a class III device — the FDA’s highest risk classification. Clearance through the 510(k) process is especially inappropriate for such risky devices. Congress envisioned that class III devices would be approved through the more stringent premarket approval (PMA) process, which does require clinical testing, and the Safe Medical Devices Act of 1990 requires that the FDA either use the PMA process for class III devices or reclassify them in a lower-risk category. Despite the clear intent of Congress, high-risk devices continue to slip by this requirement.

On July 20, 2011, the U.S. House Energy and Commerce Subcommittee on Oversight and Investigations held a hearing entitled “Medical Device Regulation: Impact on American Patients, Innovation, and Jobs.” The subcommittee’s chairman, Congressman Cliff Stearns (R-FL), argued that FDA regulation of medical devices is too burdensome, stifles innovation, and drives device manufacturers overseas. But the disastrous outcomes of the use of DePuy ASRs show that rushing untested and potentially dangerous medical devices into the marketplace carries serious risks; our regulators should not be in the business of creating jobs in the manufacture of dangerous devices.

On July 29, 2011, the Institute of Medicine (IOM) released an FDA-commissioned report on the 510(k) clearance process.4,5 The report concluded that it was impossible for 510(k) clearance to assure safety and effectiveness, because it assesses neither, instead establishing only “substantial equivalence” to an existing device. The report therefore recommended that 510(k) clearance be eliminated. In addition, it recommended monitoring medical devices throughout their life cycle, especially during the postmarketing period. Despite its reasonable (and relatively modest) recommendations, the report has been aggressively attacked by the device industry and by politicians from states where device companies are located. In fact, the attacks began even before the report was released, which is highly unusual for an IOM report.

We believe that the IOM report is insightful, judicious, sensible, and long overdue. The 510(k) clearance process was established 35 years ago, and although it may have been a reasonable approach then, it surely is not today. We support the IOM committee’s recommendation that the 510(k) process be replaced with an evaluation of safety and effectiveness. It is important to maintain and encourage innovation in medical devices. But true innovation requires that safety and effectiveness be proven by scientific study in clinical trials.

Unfortunately, the FDA leadership has already suggested that it does not intend to implement this key recommendation of the report, although it may be open to other changes. As the best long-term improvements are contemplated, there are important steps that the agency can take now.

Medical Devices — Balancing Regulation and Innovation

19 September, 2011 (16:01) | Medications | By: Health news

Many Americans benefit from the implantation of medical devices, such as artificial joints and lifesaving defibrillators. Tragically, many also suffer or even die from complications related to medical devices that were never studied in clinical trials before being implanted in patients. As devices have evolved and become more complex, our device-approval system has become incapable of assuring safety and effectiveness. The system we use today was created 35 years ago in an era of much simpler and fewer devices, and it is now outdated.

A recent, but not rare, example provides a cautionary tale about the challenges of ensuring that complex medical devices are both effective and safe. Osteoarthritis of the hip joint is a common and debilitating disorder. Each year, nearly a quarter of a million patients with advanced painful arthritis receive a total hip replacement in the hope that it will restore mobility and improve their quality of life. Conventional artificial hip implants consist of a metal ball inserted into a plastic cup. In 2005, a new metal-on-metal design was introduced in which both components were made from a metal alloy. The design was touted as a major innovation that would improve durability and reduce the risk of hip dislocation — advantages that were especially appealing to younger patients but were never tested.

One metal-on-metal design is the DePuy (Johnson & Johnson) ASR XL Acetabular System, which was introduced into the U.S. market in 2005. The ASR was cleared by a Food and Drug Administration (FDA) process known as 510(k), which refers to the section of the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act that created it. Under that section, the criterion for clearance of a new medical device is that it be “substantially equivalent” to an already-marketed device (a “predicate”); clinical data are not required.

The ASR was constructed by borrowing a metal alloy cup from a different hip device known as the ASR Hip Resurfacing System and retrofitting it onto a standard hip implant. The manufacturer successfully made the case that the re-engineered implant was “substantially equivalent” to a predicate device. Its marketing clearance was therefore based not on clinical trials or other clinical data but on bench testing in a laboratory, which was inadequate to simulate the stresses that would be placed on it in patients’ bodies.

It soon became clear that the device failed at the astonishing rate of at least one in eight. According to a recent report presented at the British Hip Society Annual Conference, 21% of these hips have had to be replaced (revised) by 4 years after implantation, and the revision rate rises to 49% at 6 years, as compared with 12 to 15% at 5 years for other devices. Failure appears to be due to erosion of the metal in the articular surfaces and migration of metallic particles into the surrounding tissues and the bloodstream. Thus, the innovation led to tragedy for many patients. Before it was recalled in 2010, the ASR had been implanted in nearly 100,000 patients, and the result was a public health nightmare.

Enrollment and Randomization. Part 3

19 September, 2011 (14:21) | Heart Diseases | By: Health news

Given the complex clinical circumstances of out-of-hospital cardiac arrest, precise control of the time to the first analysis of cardiac rhythm is difficult to achieve. In our trial, the duration of CPR before the first analysis of rhythm did not fall within the assigned target for 36% of the patients. Although this observation raises the question of quality control in training and trial supervision, the participating EMS agencies were high-functioning services with advanced-level paramedics; in addition, they had collected high-quality patient data before the start of the trial, and they made continuous efforts to reinforce performance targets. Thus, although implementation of the protocol was imperfect, it nonetheless represents the degree of precision with which such therapies are likely to be practiced in the clinical setting of out-of-hospital cardiac arrest. Furthermore, despite this limitation, there was very good separation between the two study groups in the duration of CPR, and a variety of data analyses confirmed the primary finding of no significant difference in the outcome between patients who had early rhythm analysis and those who had later rhythm analysis.

Our results indicate that in most cases, the outcome is similar with as few as 30 seconds and as many as 180 seconds of EMS-administered CPR before the analysis of cardiac rhythm. The exception is the case of cardiac arrest witnessed by EMS responders, which was not evaluated in this study and for which rapid defibrillation remains the standard of care.13 Our results also do not address the strategy of immediate analysis of cardiac rhythm without any preceding CPR, since we deliberately insisted on some CPR for the early-analysis group, in the belief that good patient care required cardiopulmonary support while the defibrillator was being prepared.

Exploratory examination of our data suggests that a strategy of brief CPR and early analysis may be more appropriate than longer CPR and later analysis for patients who have received CPR from a bystander before the arrival of professional responders. Conversely, for patients who have not received CPR from a bystander, there is no approach that is clearly advantageous with respect to the time to analysis of rhythm. The 2010 guidelines of the AHA–ILCOR give little direction as to the preferred period of CPR before analysis of cardiac rhythm. Each EMS system should consider its operational situation when deciding on its strategy for initial EMS-administered CPR. We believe that it is important to administer CPR for some period while the defibrillator pads are being applied and that compressions should be of high quality with minimal interruptions.

In conclusion, in a large clinical trial, we evaluated the timing of the analysis of cardiac rhythm during CPR in patients who had an out-of-hospital cardiac arrest that was not witnessed by EMS personnel. We found no difference in the outcome between the EMS strategy of a brief period of CPR before early rhythm analysis and that of a longer period of CPR before delayed rhythm analysis.

Enrollment and Randomization. Part 2

17 September, 2011 (21:42) | Heart Diseases | By: Health news

In this randomized trial, we tested the hypothesis that patients with an out-of-hospital cardiac arrest might benefit from the administration of CPR by EMS personnel for approximately 3 minutes before the first analysis of cardiac rhythm (with delivery of a defibrillator shock as appropriate). We found that there was no significant difference in the rate of survival with satisfactory functional status between the two EMS strategies of a brief period of CPR with early analysis of cardiac rhythm and a longer period of CPR with delayed analysis of rhythm. Subgroup and adjusted analyses also did not show any significant differences in the outcomes between the two study groups. We further explored the relationship between the rate of survival and the actual time to rhythm analysis and found that outcomes did not improve with increasing time to analysis. This finding suggests that there is no advantage of delaying the analysis of cardiac rhythm during EMS-administered CPR. Indeed, the data suggest that there may be a disadvantage of delaying the rhythm analysis in the subgroup of patients with a first rhythm of either ventricular tachycardia or ventricular fibrillation who have received CPR from a bystander. Overall, our data suggest that the administration of 2 minutes of CPR by EMS personnel before the first analysis of rhythm, which was suggested in the 2005 guidelines of the AHA–ILCOR, is unlikely to provide a greater benefit than CPR of shorter duration.
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The hypothesis that a brief period of initial CPR before analysis of cardiac rhythm could be beneficial is based primarily on the concept that a few minutes of chest compressions may increase myocardial perfusion, thus improving the metabolic state of the cardiac myocytes and enhancing the likelihood of successful defibrillation. Several studies in animals with experimentally induced ventricular fibrillation showed that the outcomes with delayed countershock after a period of chest compressions were better than the outcomes with earlier countershock, whereas other studies failed to show a benefit of CPR before shock. Five previous clinical studies also attempted to evaluate this issue, but all five had limitations involving the design or sample size, and none had findings that were definitive. Cobb et al., in a before-and-after study, showed that the rate of survival increased after the implementation of a policy that required 90 seconds of CPR before analysis of cardiac rhythm when an automated external defibrillator was used. Wik et al. conducted a randomized trial and found no significant difference between the outcomes after immediate defibrillation and those after 3 minutes of basic CPR before defibrillation, but the outcomes in a subgroup with response times exceeding 5 minutes were better after initial CPR than after immediate defibrillation. Randomized trials reported by Jacobs et al. and Baker et al. showed no significant difference in outcomes with early as compared with late defibrillation. Bradley et al. performed an observational analysis and found that CPR by EMS personnel for 46 to 195 seconds before defibrillation was weakly associated with an improved rate of survival.

Enrollment and Randomization

17 September, 2011 (17:31) | Heart Diseases | By: Health news

The first site commenced the run-in phase in June 2007. All the sites stopped enrollment in November 2009, when the data and safety monitoring board recommended that the trial be stopped early because continuing recruitment was unlikely to change the outcome of the study. Of 13,460 patients screened, 10,365 were enrolled, and 10,153 underwent randomization. Of these, 195 were excluded from the data analysis when their cardiac arrest was confirmed to be due to drowning, strangulation, or electrocution, and 25 were excluded because the outcome with respect to the primary end point was unknown. Thus, 9933 patients were included in the primary data analysis.

Characteristics of the Two Study Groups

The early-analysis group comprised more patients than the later-analysis group (5290 vs. 4643) owing to early termination of the trial. The two study groups were evenly balanced with respect to baseline characteristics except that there were small group imbalances in the distribution of patients across sites; however, these would not have any appreciable effect on the results because of the cluster-crossover design, which yields treatment comparisons within clusters. Not all the scheduled cluster crossovers had occurred at the time of termination, although each cluster had crossed over at least once.

The median time to the analysis of cardiac rhythm was 42 seconds (interquartile range, 27 to 80) in the early-analysis group and 180 seconds (interquartile range, 151 to 190) in the later-analysis group. A majority of patients in each group received rhythm analysis within the targeted range for that group: 68% of patients in the early-analysis group received analysis of cardiac rhythm within the targeted range of 0 to 60 seconds and 60% of patients in the later-analysis group received analysis of cardiac rhythm within the targeted range of 150 to 210 seconds.

Primary and Secondary Outcomes

A total of 310 patients in the early-analysis group (5.9%) and 273 patients in the later-analysis group (5.9%) survived to hospital discharge with a modified Rankin score of 3 or less, with a cluster-adjusted difference between later cardiac analysis and early cardiac analysis of −0.2 percentage points. There was also no significant difference between the study groups with respect to any of the secondary outcomes. An analysis adjusted for potential confounders evaluated the effect of study group on survival and showed a difference of −0.3 percentage points (95% CI, −1.3 to 0.7) between later cardiac analysis and early cardiac analysis (P=0.61).

When the outcomes were analyzed on an as-treated basis, the rates of survival with satisfactory functional status were 6.0% among the 3982 patients in whom the analysis of cardiac rhythm was performed between 0 and 60 seconds and 5.9% among the 3115 patients in whom the analysis of cardiac rhythm was performed between 150 and 210 seconds (P=0.97). In an additional exploratory analysis, we evaluated the rate of survival as a function of the actual time to the first rhythm analysis, regardless of the study group. The chance of survival with satisfactory functional status did not improve with increasing time to the first analysis of cardiac rhythm, and among patients with an initial rhythm of ventricular tachycardia or ventricular fibrillation who received CPR from a bystander, the rate of survival tended to decline with increasing time to the first rhythm analysis.

Outcome Measures and Statistical Analysis

15 September, 2011 (18:03) | Heart Diseases | By: Health news

Outcome Measures

The primary outcome was survival to hospital discharge with satisfactory functional status, defined as a score of 3 or less on the modified Rankin scale. This is a validated scale, ranging from 0 to 6, that is commonly used for measuring the performance of daily activities by people who have had a stroke. Lower scores represent better performance; scores of 4 or higher represent severe disability or death. Secondary outcomes were survival to discharge, survival to hospital admission, and return of spontaneous circulation at the time of arrival at the emergency department.

Statistical Analysis

We estimated that with enrollment of 13,239 patients who could be evaluated, the study would have 99.6% power to detect an improvement in the primary outcome from 5.4% with early analysis of heart rhythm to 7.4% with later analysis, assuming a group-sequential stopping rule at a two-sided alpha level of 0.05 with up to three interim analyses (O’Brien–Fleming boundaries). This calculation took into consideration the concurrent ITD portion of the trial, which required the enrollment of 14,154 patients who could be evaluated, in order to have 90% power to detect a 25% difference in the outcome between the two groups in that trial.
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Analyses of the primary and secondary effectiveness outcomes were performed on the basis of a modified intention-to-treat principle with data from eligible patients in whom the cardiac arrest was not due to drowning, strangulation, or electrocution and for whom the primary outcome was known. An independent data and safety monitoring board reviewed the data at prespecified intervals and used a group-sequential stopping rule. The primary analysis compared the outcomes between the groups with the use of the Wald statistic for the treatment group in a generalized linear mixed model. The model included random effects for each of the clusters, accommodated the binary distribution of the outcome variable, and used a linear-link function to estimate an absolute difference in risk.

The between-group difference in the primary outcome, adjusted for baseline characteristics, was calculated with the use of a multiple linear regression model, with robust standard errors to accommodate clustering and the binary distribution of the outcome. Analyses of binary secondary outcomes and subgroup analyses were performed with the use of generalized-estimating-equation models to estimate differences in risk. Mean scores on the modified Rankin scale were compared between the two treatment groups with the use of a linear model.

We conducted further exploratory analyses of the data using kernel density estimators to estimate the distribution of time from the start of CPR to the actual analysis of cardiac rhythm, separately within treatment groups. The association between the primary outcome and the time of cardiac-rhythm analysis was explored with the use of smoothing splines, and confidence intervals were computed with the use of the bootstrap method.

Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest. Part 2

15 September, 2011 (10:02) | Heart Diseases | By: Health news

The protocol was approved by the institutional review or research ethics boards at each participating site. The trial protocol, including the statistical analysis plan, is available at All the authors vouch for the completeness and accuracy of the data and the analyses and for the fidelity of the study to the trial protocol.
Study Setting and Population

The trial was conducted at 150 of the 260 EMS agencies participating in the ROC. The trial agencies were selected because they had the capability to provide advanced cardiac life-support interventions and to record CPR process measures and because they met prespecified quality criteria during an initial run-in phase.

We included all persons 18 years of age or older who had an out-of-hospital cardiac arrest that was not the result of trauma and who were treated with defibrillation, delivery of chest compressions, or both by EMS providers. Persons were excluded if the arrest was witnessed by EMS personnel; if they had a blunt, penetrating, or burn-related injury; if the arrest was due to exsanguination; if they were pregnant; if they were prisoners; if they had an “opt-out” bracelet, indicating that they wished to opt out of the study; if they had “do not attempt resuscitation” orders; if the rhythm analysis was performed by police or a lay responder; or if they received initial treatment by an EMS agency that was not in the ROC. Patients were not required to provide informed consent; according to the regulations of the Food and Drug Administration and the Canadian Tri-Council agreement, this study qualified for exception from the requirements for informed consent because it involved research conducted during an emergency situation.

Each of the 10 participating ROC centers (or sites) was divided into approximately 20 subunits, designated as “clusters,” according to EMS agency or geographic boundaries or according to defibrillator device, ambulance, station, or battalion. Randomization of clusters was stratified according to site. All episodes of cardiac arrest in a cluster were randomly assigned to one CPR strategy; after a set period of time, ranging from 3 to 12 months, all episodes in that cluster were then assigned to the other strategy. All the clusters were assigned to cross over to the other strategy one or more times during the study at fixed intervals; we estimated that approximately 100 patients would be included during each interval.
Study Intervention

Patients in the early-analysis group were assigned to receive 30 to 60 seconds of chest compressions and ventilations (sufficient time to place defibrillator electrodes) before electrocardiographic (ECG) analysis, and those in the late-analysis group were assigned to receive 3 minutes of chest compressions and ventilations before ECG analysis. The assigned intervention was implemented by the first qualified EMS provider to arrive at the scene (defibrillation-capable firefighter, emergency medical technician, or paramedic). The start and stop times for CPR were recorded by the responders, and the information was supplemented by the recording of defibrillator time.

The training of participating EMS providers emphasized uninterrupted chest compressions except for required ventilations, with compressions and ventilations applied in a 30:2 ratio, and specified that advanced airway devices were to be placed with minimal interruptions to compressions. Every 6 months, the EMS providers underwent some retraining that included written reminders, slide presentations, and Web-based modules. All ROC sites implemented high-quality electronic monitoring of the CPR process with the use of defibrillator hardware and software. Adherence to the protocol-specified performance targets and to the requirements for data submission was monitored throughout the study by a study monitoring committee, which provided regular feedback to sites.

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