New Drug to Control High Cholesterol for Statin intolerant patients: NEJM Study

Inhaled Isopropyl Alcohol Superior to Oral Ondansetron as an Antiemetic

Astonishing results from a small, well-designed study may have far-reaching implications.

Though ondansetron is viewed by many as the first-line agent for nausea in the emergency department (ED), there is evidence it doesn’t work in noncancer patients (NEJM JW Emerg Med Aug 2014 and Ann Emerg Med 2014; 64:526). An alternative agent, inhaled isopropyl alcohol, has shown promise (NEJM JW Emerg Med Feb 2016 and Ann Emerg Med 2016; 68:1).

In the current trial, 120 adult ED patients with nausea or vomiting who did not require intravenous access were randomized to inhaled isopropyl alcohol plus 4 mg oral ondansetron; inhaled isopropyl alcohol plus oral placebo; or inhaled saline plus 4 mg oral ondansetron. Isopropyl alcohol was provided in the form of a standard alcohol swab. Patients received a single dose of the oral intervention but could sniff alcohol or saline swabs repeatedly. Nausea was measured on a 100-mm visual analog scale at baseline and 30 minutes.

Mean nausea scores decreased by 30 mm in the alcohol/ondansetron group, 32 mm in the alcohol/placebo group, and 9 mm in the saline/ondansetron group. Rescue antiemetic therapy was given to 28%, 25%, and 45% of each group, respectively. Differences between alcohol and saline groups were statistically significant. Patients in the inhaled alcohol groups also had better nausea control at the time of discharge and reported higher satisfaction with nausea treatment. No adverse events occurred. The mechanism of action is currently unknown.


It is uncommon for us to assign a rating of “Practice Changing” to a small, single-center study, but these results are truly remarkable and are consistent with prior research. For patients not obviously requiring IV therapy, we should treat nausea with repeated inhalations from an isopropyl alcohol swab instead of administering any other drug. And, although this study provides no direct evidence of benefit to patients who do require IV therapy, there would seem to be little downside to trying this simple and safe intervention in that group, too.

Optimal Prevention of Dysplasia Requires Complete Ablation of All Intestinal Metaplasia

This meta-analysis demonstrated that the rate of recurrent dysplasia was doubled when residual Barrett epithelium remained after endoscopic ablation.

Current guidelines suggest that endoscopic ablation be offered to patients with confirmed dysplasia in a segment of Barrett esophagus (BE). The authors of this meta-analysis examined long-term outcomes (almost 13,000 patient follow-up years) after ablation of dysplastic BE, comparing the 86% of patients who had complete remission of intestinal metaplasia with the 14% of patients who had eradication of dysplasia but with persistent metaplasia.

Dysplasia recurred in 5% of those with complete ablation of all metaplasia versus 12% of those who had ablation of dysplasia with persistent metaplasia. The development of high-grade dysplasia or cancer was also twice as likely when metaplasia persisted (3% vs.6%)


This important insight into the management of BE patients after ablation makes it clear that the goal should be complete eradication of all Barrett metaplasia, which decreases the risk for recurrent dysplasia and, more importantly, for developing high-grade dysplasia or cancer. Careful follow-up and retreatment of any persistent metaplasia is part of the eradication process. BE can also recur after ablation, which likewise increases the risk for an adverse outcome. Thus, regular surveillance is mandatory. Finally, earlier study findings suggest that high-dose proton-pump inhibitor therapy is another important component in preventing BE recurrence. This detailed process must be followed if optimal outcomes are to be achieved.


Too Much Oxygen Is Harmful

A meta-analysis shows significantly higher mortality with liberal use of supplemental oxygen in acutely ill patients.


Supplemental oxygen can be a life-saving intervention for patients with hypoxemic respiratory failure; however, emerging evidence suggests that too much oxygen is harmful (NEJM JW Gen Med Dec 1 2016 and NEJM 2016; 316:1583). Small trials have shown excess cardiac arrhythmias, lung injuries, and other complications in hospitalized patients without demonstrated hypoxemia who receive oxygen or whose oxygen administration results in supra-normal partial pressures (i.e., hyperoxemia). Should we be doing more to turn down the oxygen when it’s not needed?

Investigators completed a meta-analysis of 25 randomized trials that included 16,000 acutely ill patients who were treated with either a liberal or a conservative oxygenation strategy. Oxygen targets and supplementation thresholds differed across studies. Median oxygen supplementation levels were fraction of inspired oxygen (FiO2) 0.52 vs. 0.21 (liberal vs. conservative).

Relative risk for death at 30 days was significantly higher in patients who received liberal oxygen (RR, 1.14), although no association was evident between mortality and either peripheral saturation or FiO2. Risk for disability, length of stay, and incidence of hospital-acquired infections, including pneumonia, were similar under both strategies.


All too often, a patient’s oxygen saturation is maintained at 100%. This is not only unnecessary but also probably harmful. It should become part of our practice to turn down the supplemental oxygen until we see oxygen saturations no higher than 95% for most patients and to stop oxygen use as soon as it is not needed. I suspect that we will learn that a target saturation lower than 95% is safe, but for now, avoiding hyperoxemia makes sense.

No Clear Benefit of Prazosin for Sleep-Related Symptoms of PTSD

Figure 1. Change in Scores of Primary Outcome Measures from Baseline.The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician- Administered PTSD Scale (CAPS) item B2 (scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams) (Panel A), the change in Pittsburgh Sleep Quality Index (PSQI) score from baseline to 10 weeks (scores range from 0 to 21, with higher scores indicating worse sleep quality) (Panel B), and the Clinical Global Impression of Change (CGIC) score at 10 weeks (range, 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change from baseline; the CGIC assessed the participant’s ability to function in daily activities and the participant’s sense of well-being) (Panel C). Over the entire 26 weeks, the mean change from baseline on the CAPS item B2 was −2.0 (95% confidence interval [CI], −2.1 to −1.8) with prazosin and −2.1 (95% CI, −2.2 to −1.9) with placebo (P = 0.56); the mean change from baseline on the PSQI was −2.6 (95% CI, −2.9 to −2.3) with prazosin and −2.6 (95% CI, −2.9 to −2.3) with placebo (P = 0.99); and the mean CGIC score was 3.1 (95% CI, 3.0 to 3.2) with prazosin and 3.1 (95% CI, 3.0 to 3.2) with placebo (P = 0.86). I bars indicate 95% confidence intervals.

During my internal medicine residency, I was privileged to be the primary care physician for many veterans. Practicing in a Veterans Affairs (VA) medical center is unique in many ways. Besides the predominantly male population, many patients suffered from mental illnesses with post-traumatic stress disorder (PTSD) as a common culprit. One memorable young patient struggled with persistent sleep disturbance. When a consulting psychiatrist recommended treatment with prazosin, I thought it was a curious choice because alpha blockers sat firmly in my mental buckets of “not great anti-hypertensives” and “helps with urination.” I subsequently learned that alpha-1 antagonists can lower the high adrenergic activity that is thought to drive PTSD symptoms. Further, prazosin crosses the blood-brain barrier quite effectively, and evidence from small randomized clinical trials (RCT) gave us hope that it would work.

Consequently, I read with great interest the results from the PACT trial published in this week’s NEJM. In this largest RCT to date, investigators randomized 304 veterans with PTSD and frequent nightmares from 12 VA centers to receive prazosin or placebo for 26 weeks. During that time, existing therapies were continued but no new pharmacotherapy and psychotherapy could be added.

Unfortunately, the results of this trial did not show any benefit from prazosin for the three primary outcomes: Change from baseline at 10 weeks in the recurrent distressing dream component of the Clinician-Administered PTSD Scale (CAPS; score range, 0–8), the Pittsburgh Sleep Quality Index (PSQI; score range, 0–21), and the absolute score of the Clinical Global Impression of Change (CGIC; score range, 1–7). In general, higher scores indicate worse symptoms for all three scoring systems. The mean between-group differences in the change from baseline for the CAPS recurrent distressing dreams component and PSQI were 0.2 (95% CI, -0.3 to 0.8; P=0.38) and 0.1 (95% CI, -0.9 to 1.1; P=0.80), respectively. The mean difference in the CGIC was 0 (95% CI, -0.3 to 0.3; P=0.96). Of the adverse events, dizziness (34% vs. 21%), lightheadedness (34% vs. 20%), and urinary incontinence (12% vs. 4%) were more common in the prazosin group, and new or worsening suicidal ideation was less common in the prazosin group (8% vs. 15%).

With any clinical trial, the devil is in the detail. The authors offer some possible explanations for the lack of benefit of prazosin, primarily selection bias. At the time of the study, prazosin was already available for off-label use in the VA medical system and was often prescribed as an adjunct to first-line selective serotonin reuptake inhibitors (SSRIs), as with the patient I described above. Therefore, clinicians may have been hesitant to enroll patients with more severe symptoms and risk for clinical deterioration in a randomized trial with the possibility of receiving placebo when prazosin was available outside of the trial. Furthermore, patients treated with trazodone were excluded from the trial because of its alpha-1 antagonist activity, thus removing a population of potential responders.

In an accompanying editorial, Dr. Kerry Ressler from Harvard Medical School reminds us that PTSD is a heterogenous disorder with different manifestations of symptoms. Perhaps not every patient shares the same adrenergic hyperarousal response that is thought to be the driver of nightmares. He encourages the development of better biomarkers to identify the phenotype of patients who may respond to prazosin.

I left the VA before I had the chance to see whether my patient benefited from prazosin, but other patients have told me that prazosin is the only intervention that lets them sleep at night. Although the PACT trial did not show clear efficacy, prazosin may still have therapeutic benefit in select patients.

Does Childhood Kidney Disease Lead to Adult Kidney Failure?

A mother brings her 10-year-old daughter to the family physician for follow-up after successful outpatient treatment of an episode of E. coli pyelonephritis. The mother asks, “Is there a chance that this infection might lead to serious kidney problems when my daughter is older?”

The prevalence of chronic kidney disease has been increasing worldwide, often attributed to the widespread prevalence of urinary tract infections and increasing rates of hypertension and diabetes mellitus. Although many children experience one or more episodes of acute kidney disease that resolve with adequate treatment, the question remains about the long-term risk of progression of childhood kidney disease to chronic kidney disease and end-stage renal disease (ESRD) in adulthood.

In this week’s NEJM, Calderon-Margalit et al. attempt to answer this question in a nationwide cohort study of more than 1.5 million Israeli adolescents who underwent baseline medical examinations before compulsory military service in 1967–1997. Those included in the study had normal kidney function and no hypertension in adolescence. Childhood kidney disease was categorized as congenital anomalies of the kidney and urinary tract, pyelonephritis, and glomerular disease. Data were linked to the Israeli ESRD registry, and Cox proportional hazards models were used to estimate the hazard ratio for ESRD associated with a history of childhood kidney disease.

During a mean follow-up of 30 years, approximately 0.2% of the cohort developed ESRD. Among individuals with a history of childhood kidney disease, approximately 0.75% developed ESRD. Although the absolute risk of developing ESRD was low, multivariable-adjusted analysis showed that a history of any childhood kidney disease was associated with a hazard ratio of 4.19 for developing ESRD in adulthood. Hazard ratios for ESRD were 5.19 for congenital anomalies, 4.03 for pyelonephritis, and 3.85 for glomerular disease. A history of childhood kidney disease was also associated with a younger age of onset of ESRD than no history (mean age, 41.6 vs. 48.6 years).

The authors concluded that a history of childhood kidney disease, even with normal renal function in adolescence, was associated with a four-fold increased risk of developing ESRD in adulthood. This suggests that early identification and intervention to prevent the progression of chronic kidney disease and its complications is needed.

Returning to the mother and her daughter, the physician can explain that although an episode of pyelonephritis can increase the chance of future kidney problems, the risk is low that her daughter would develop chronic kidney disease. However, if she develops symptoms of urinary tract infection in the future, she should get prompt medical care.

Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator



The presence of a cardiovascular implantable electronic device has long been a contraindication for the performance of magnetic resonance imaging (MRI). We established a prospective registry to determine the risks associated with MRI at a magnetic field strength of 1.5 tesla for patients who had a pacemaker or implantable cardioverter–defibrillator (ICD) that was “non–MRI-conditional” (i.e., not approved by the Food and Drug Administration for MRI scanning).


Patients in the registry were referred for clinically indicated nonthoracic MRI at a field strength of 1.5 tesla. Devices were interrogated before and after MRI with the use of a standardized protocol and were appropriately reprogrammed before the scanning. The primary end points were death, generator or lead failure, induced arrhythmia, loss of capture, or electrical reset during the scanning. The secondary end points were changes in device settings.


MRI was performed in 1000 cases in which patients had a pacemaker and in 500 cases in which patients had an ICD. No deaths, lead failures, losses of capture, or ventricular arrhythmias occurred during MRI. One ICD generator could not be interrogated after MRI and required immediate replacement; the device had not been appropriately programmed per protocol before the MRI. We observed six cases of self-terminating atrial fibrillation or flutter and six cases of partial electrical reset. Changes in lead impedance, pacing threshold, battery voltage, and P-wave and R-wave amplitude exceeded prespecified thresholds in a small number of cases. Repeat MRI was not associated with an increase in adverse events.


In this study, device or lead failure did not occur in any patient with a non–MRI-conditional pacemaker or ICD who underwent clinically indicated nonthoracic MRI at 1.5 tesla, was appropriately screened, and had the device reprogrammed in accordance with the prespecified protocol. (Funded by St. Jude Medical and others; MagnaSafe number, NCT00907361.)

The use of magnetic resonance imaging (MRI) poses potential safety concerns for patients with an implanted cardiac device (cardiac pacemaker or implantable cardioverter–defibrillator [ICD]). These concerns are a consequence of the potential for magnetic field–induced cardiac lead heating, which could result in myocardial thermal injury and detrimental changes in pacing properties.1-3 As a result, it has long been recommended that patients with an implanted cardiac device not undergo MRI scanning, even when it otherwise may be considered to be the most appropriate diagnostic imaging method for the patient’s clinical care.4

Over the past two decades, cardiac devices have been designed to reduce the potential risks associated with MRI.5,6 Such devices, if they have been shown to pose no known hazard under certain specified conditions, are labeled “MRI-conditional” by the Food and Drug Administration (FDA) Center for Devices and Radiological Health. However, it is estimated that 2 million people in the United States and an additional 6 million worldwide7 have devices that have not been shown to meet these criteria and are therefore considered “non–MRI-conditional.” At least half the patients with such devices are predicted to have a clinical indication for MRI during their lifetime after device implantation.8

The MagnaSafe Registry was established to determine the frequency of cardiac device–related clinical events and device setting changes among patients with non–MRI-conditional devices who undergo nonthoracic MRI at a magnetic field strength of 1.5 tesla, as well as to define a simplified protocol for screening, monitoring, and device programming for such patients.



The MagnaSafe Registry was a prospective, multicenter study involving patients with a non–MRI-conditional pacemaker or ICD who underwent a clinically indicated, nonthoracic MRI examination at 1.5 tesla. The rationale, design, and protocol have been described previously.9 The protocol, which is available with the full text of this article at, was written after consultation with personnel at the Center for Devices and Radiological Health of the FDA, who requested that thoracic scans be excluded because of a higher perceived risk of adverse outcomes. An investigational device exemption was obtained in April 2009 for the purpose of data collection. All participating centers obtained approval from a local or independent institutional review board.

None of the funders of the study had any role in the design of the study protocol, in the collection or analysis of the data, or in the writing of the manuscript. The authors had full access to the data, performed the analyses, and vouch for the completeness and accuracy of the data and for the fidelity of the study to the protocol.


Patients were included in the registry if they were 18 years of age or older and had a non–MRI-conditional pacemaker or ICD generator, from any manufacturer, that was implanted after 2001,10 with leads from any manufacturer (without implantation date limitation), and if the patient’s physician determined that nonthoracic MRI at 1.5 tesla was clinically indicated (see Tables S1 and S2 in the Supplementary Appendix, available at, for a list of pacemaker and ICD manufacturers and models). The exclusion criteria were an abandoned or inactive lead that could not be interrogated, an implanted device other than a pacemaker or an ICD, an MRI-conditional pacemaker, a device implanted in a nonthoracic location, or a device with a battery that was near the end of its battery life (with a device interrogation display that read “elective replacement indicator”). In addition, pacing-dependent patients with an ICD were excluded because it was not possible to independently program tachycardia and bradycardia therapies for all ICD models at the time of study design. All participants provided written informed consent.


During the first 2 years of the study, the Centers for Medicare and Medicaid Services National Coverage Determination (NCD) stated that a patient with a pacemaker or an ICD was not eligible for coverage for MRI. In March 2011, a change to the NCD was granted that allowed reimbursement for patients enrolled in a prospective registry designed to determine the risk associated with MRI.11


All studies were performed in a 1.5-tesla MRI scanner; there was no vendor restriction (a list of manufacturers and models is included in Table S3 in the Supplementary Appendix). A physician, nurse practitioner, or physician assistant with cardiac device expertise and training in advanced cardiac life support was in attendance. Blood pressure, pulse oximetry, and cardiac rhythm were monitored with an MRI-compatible system from the time of device reprogramming until restoration of baseline values. Further details are provided in the MagnaSafe Protocol section of the Supplementary Appendix.


Figure 1.MagnaSafe Registry Study Flow Chart.

Prescanning device interrogation was performed with the use of a standardized protocol (Figure 1).9 If the patient was asymptomatic and had an intrinsic heart rate of at least 40 beats per minute, the device was programmed to a no-pacing mode (ODO or OVO). Symptomatic patients or those with an intrinsic heart rate of less than 40 beats per minute were determined to be pacing-dependent, and the device was reprogrammed to an asynchronous pacing mode (DOO or VOO). For non–pacing-dependent patients with an ICD, all bradycardia and tachycardia therapies were inactivated before the MRI. Pacing-dependent patients with an ICD were excluded, because not all ICD models allowed for independent inactivation of tachycardia and bradycardia therapies. After the MRI, baseline settings were restored, full device interrogation was repeated, and if necessary, the device was reprogrammed to maintain adequate pacing and sensing. Further details are provided in the MagnaSafe Protocol section of the Supplementary Appendix.


The primary end points, which were assessed during or immediately after the MRI examination, were death, generator or lead failure requiring immediate replacement, loss of capture (for pacing-dependent patients with pacemakers), new-onset arrhythmia, and partial or full generator electrical reset. The secondary end points, which were assessed immediately after the MRI examination and at the final follow-up, were a battery voltage decrease of 0.04 V or more, a pacing lead threshold increase of 0.5 V or more,12 a P-wave amplitude decrease of 50% or more, an R-wave amplitude decrease of 25% or more and of 50% or more,13 a pacing lead impedance change of 50 ohms or more,14 and a high-voltage (shock) lead impedance change of 3 ohms or more.

Patients with any secondary end-point event were required to undergo repeat device interrogation within 7 days, at 3 months (±30 days), and at 6 months (±30 days) after the MRI to determine whether the device settings had returned to baseline. If a secondary end-point event did not occur, a single device interrogation was required at between 3 and 6 months after the MRI (±30 days). Patients who had a primary end-point event were seen in follow-up at the discretion of the supervising physician. Further details and definitions of end points are provided in the Supplementary Appendix.


A case was defined as an instance in which a patient who provided informed consent entered the scanner and underwent MRI of one or more anatomical regions during a single examination session. If the patient returned on a subsequent day for repeat MRI, a separate informed consent was obtained and the data were entered as a unique case.

The mean (±SD) yearly rate of device replacement due to spontaneous malfunction has been estimated to be 0.46±0.22% for pacemakers and 2.07±1.16% for ICDs.15 Using these estimates and assuming a device failure rate during or after MRI of 0, we determined that 1000 cases in which patients had a pacemaker (pacemaker cases) and 500 cases in which patients had an ICD (ICD cases) would be needed to yield a 95% confidence interval of 0 to 0.5% for pacemakers and 0 to 1.0% for ICDs.

Data were analyzed separately for the pacemaker and ICD cohorts with the use of R statistical software, version The decision not to perform statistical comparisons between the pacemaker and ICD cohorts was made before enrollment began. The Wilson score method without continuity correction was used to calculate 95% confidence intervals for single proportions for primary end-point events. The linear association between lead age and each of the secondary end points was assessed with Pearson’s product moment correlation coefficient.



Table 1.Characteristics of the Patients at Baseline and MRI Scanning Information.

From April 2009 through April 2014 at 19 centers in the United States, clinically indicated nonthoracic MRI was performed in a total of 1000 pacemaker cases (818 patients) and 500 ICD cases (428 patients). The baseline characteristics of the patients are shown in Table 1. Follow-up data, which included data from a full device interrogation, were available in 1395 cases (93%) at 6 months. Additional information about the study population is provided in the Supplementary Appendix.


A total of 75% of the MRI examinations were performed on the brain or the spine. The mean time patients spent within the magnetic field was 44 minutes. During the MRI examination, four patients reported symptoms of generator-site discomfort; one patient with an ICD was removed from the scanner when a sensation of heating was described at the site of the generator implant, and the patient did not complete the examination. No patient with generator-site symptoms had the device placed within the “field of view” (the MRI imaging area), had a study end-point event, or reached the specific absorption rate limit set by the FDA for the scanned body site.


Table 2.Primary End Points.

There were no deaths, lead failures requiring immediate replacement, or losses of capture during the MRI examination among patients who were appropriately screened and had their device reprogrammed for imaging (Table 2). In one patient with an ICD who was not pacing-dependent, antitachycardia therapy was left in the active mode during the MRI (a protocol violation). During the post-MRI evaluation, the ICD could not be interrogated, and immediate generator replacement was required. Further details are provided in the Supplementary Appendix.

Four patients had atrial fibrillation and two patients had atrial flutter during or immediately after the MRI (Table S4 in the Supplementary Appendix). Five of these patients had a history of paroxysmal atrial fibrillation and were receiving warfarin; two were receiving antiarrhythmic therapy. Three of the patients returned to sinus rhythm before leaving the MRI environment, and the remaining three patients returned to sinus rhythm within 49 hours. No ventricular arrhythmias were noted.

In six cases (five patients), the patient had partial generator electrical reset; in all six cases, the patients had pacemakers that had been implanted 5.7 to 9.7 years before the MRI (Table S5 in the Supplementary Appendix). Settings in the device memory that were reset included patient and device or lead identification information. No appropriately screened and reprogrammed device underwent a full electrical reset.


Table 3.Measured Changes in Device Setting Values (Post-MRI minus Pre-MRI).

The results with regard to the secondary end points and measured differences between post-MRI and pre-MRI device settings for both pacemakers and ICDs are shown in Table 3 and as a histogram in Fig. S1 in the Supplementary Appendix. A decrease of 50% or more in P-wave amplitude was detected in 0.9% of pacemaker leads and in 0.3% of ICD leads; a decrease of 25% or more in R-wave amplitude was detected in 3.9% of pacemaker leads and in 1.6% of ICD leads, and a decrease of 50% or more in R-wave amplitude was detected in no pacemaker leads and in 0.2% of ICD leads. An increase in pacing lead threshold of 0.5 V or more was detected in 0.7% of pacemaker leads and in 0.8% of ICD leads.

A pacing lead impedance change of 50 ohms or more was noted in 3.3% of pacemakers and in 4.2% of ICDs. For both pacemakers and ICDs, any decrease in pacing lead impedance from baseline occurred in 54% of atrial leads and in 55% of ventricular leads, and any increase occurred in 19% of atrial and 22% of ventricular leads. However, when the change in pacing lead impedance was compared as a continuous variable with the change in P-wave or R-wave voltage or pacing lead threshold, no clinically significant correlations were noted (Table S6 in the Supplementary Appendix).


Among patients who had undergone placement of a new generator or lead within 90 days before the MRI, there were no primary end-point events, and secondary end-point events were limited to a change in pacing lead impedance in 2 of 53 new pacemaker leads and in 1 of 27 new ICD leads. Among patients with leads that had been placed more than 10 years before MRI, there were no primary end-point events, and secondary end-point events were noted in 1 of 31 ICD leads (impedance change of ≥50 ohms) and in 14 of 172 pacemaker leads (1 with a P-wave amplitude decrease of ≥50%, 1 with a pacing threshold increase of ≥0.5 V, and 11 with an impedance change of ≥50 ohms). When the continuous variables of pacing lead threshold change, P-wave amplitude change, R-wave amplitude change, and impedance change were compared separately with the time since lead placement, no clinically significant correlations were found (Table S7 in the Supplementary Appendix).


The maximum number of MRI examinations performed in patients in the MagnaSafe Registry was 11 in one patient with a pacemaker and 7 in one patient with an ICD (Table S8 in the Supplementary Appendix). The median interval between MRIs among patients who underwent more than one MRI examination was 153 days in patients with a pacemaker (range, 3 to 1309 days) and 91 days in patients with an ICD (range, 1 to 1376 days). In the examination of secondary end points, we found no clinically important differences between cases in which the patient underwent a single MRI and cases in which patients had undergone a previous MRI (Table S9 in the Supplementary Appendix).


Table 4.Cases in Which a Secondary End-Point Event Occurred Immediately after MRI or by the Final Follow-up.

Patients whose cardiac device exceeded the limit for a change in setting at the time of the MRI (a secondary end-point event) were asked to return for a repeat interrogation within 7 days and at 3 months and 6 months (pacemakers, 11% of cases; ICDs, 26% of cases). The proportions of cases in which there were persistent changes in device settings at the final follow-up are shown in Table 4. A higher incidence of long-term setting changes was seen with ICDs than with pacemakers. A long-term battery voltage decrease of 0.04 V or more occurred in 4.2% of ICD cases, and a long-term high-voltage lead impedance change of 3 ohms or more occurred in 10.0% of ICD cases.


In this study, we investigated the use of nonthoracic MRI at 1.5 tesla in patients with an implanted non–MRI-conditional cardiac device (pacemaker or ICD). We implemented a specific protocol for device interrogation, device programming, patient monitoring, and follow-up that was designed to reduce the risk of patient harm from MRI effects. In our study, no patient who was appropriately screened and had the device reprogrammed in accordance with our protocol had a device or lead failure. In one case, an ICD that was not properly reprogrammed before the MRI could not be interrogated after the procedure, and immediate generator replacement was required. In six cases, atrial arrhythmias occurred, each lasting less than 49 hours; six partial electrical resets occurred that were detected and corrected during post-MRI reprogramming. Changes in device settings were common, but relatively few exceeded our prespecified threshold criteria for a clinically important change; the most common change was a 3-ohm change in ICD high-voltage (shock) lead impedance (16.4% of cases).

When pre-MRI and post-MRI battery voltage measurements were compared, a small decrease was noted for both pacemakers and ICDs. The radiofrequency energy generated during MRI scanning creates a temporary decrease in battery voltage, which has typically been reported to resolve after several weeks. In our study, all pacemaker voltage decreases of 0.04 V or more had resolved at the last follow-up, although some ICD voltage decreases of 0.04 V or more had not.

At the time that the study was being designed, we did not anticipate the demand for repeat MRI for patients with an implanted cardiac device. If exposure to a strong radiofrequency field resulted in substantial thermal injury at the lead–myocardial interface,1 these patients should be at the greatest risk for a cumulative detrimental change in pacing properties. The only indication of such an effect in our study was a higher rate of high-voltage (shock) lead impedance changes among patients who had had previous MRI than among those who had not had previous MRI (21.5% vs. 14.9%).

Several smaller studies examining the risk associated with MRI in patients with an implanted device have reported varying effects on cardiac device settings.17-31 On the basis of this early experience, position statements recommended caution in the performance of MRI in patients with an implanted cardiac device.32,33 Subsequently, a larger prospective study examined 555 cases of scanning (including thoracic imaging) to assess the risk associated with MRI; no adverse clinical events occurred among the patients who underwent MRI, and the observed setting changes did not require device revision or reprogramming.7

Although it has been suggested that implanted generators and leads may be removed and then replaced to allow for MRI, such procedures may have greater risks than those associated with nonthoracic MRI in the current study. The rate of major complications among patients undergoing generator replacement with or without the placement of an additional transvenous lead was 4 to 15% in a prospective registry.34 In addition, single-center and multicenter studies have shown a rate of major complications associated with elective laser-assisted lead extraction that is in the range of 0.4 to 2%.35-38 Thus, device removal and replacement seem unlikely to be safer than proceeding with scanning for patients with a pacemaker or an ICD who require a nonthoracic MRI, provided a protocol similar to the one used in our study is followed.

The limitations of this study should be considered carefully. This registry represents a heterogeneous experience, with generators and leads from multiple manufacturers and initial as well as repeat examinations at 1.5 tesla. Thus, the results may not be predictive of findings with all device–lead combinations or higher MRI field strengths. Also, because patients younger than 18 years of age and MRI examinations of the thorax were excluded and the number of left ventricular leads was relatively small, it may not be possible to extrapolate the current data to a pediatric population, to patients undergoing MRI of the chest, or to patients with cardiac resynchronization devices. Finally, we excluded pacing-dependent patients with an ICD, because not all such patients had a device that was capable of providing pacing function while allowing for inactivation of tachycardia therapy. Therefore, our method should not be applied to pacing-dependent patients with an ICD unless independent programming of the bradycardia and tachycardia functions is possible.

In conclusion, we investigated the use of nonthoracic MRI at 1.5 tesla in patients with an implanted non–MRI-conditional cardiac device. No patient who was appropriately screened and had the cardiac device reprogrammed according to our protocol had device or lead failure. Substantial changes in device settings were infrequent and did not result in clinical adverse events.

Presented in part as a Late Breaking Clinical Trial at the American Heart Association Annual Scientific Sessions, Chicago, November 15–19, 2014.

Supported by grants from St. Jude Medical, Biotronik, Boston Scientific, and the Hewitt Foundation for Medical Research, and by philanthropic gifts from Mr. and Mrs. Richard H. Deihl, Evelyn F. and Louis S. Grubb, Roscoe E. Hazard, Jr., and the Shultz Steel Company.

Disclosure forms provided by the authors are available with the full text of this article at

Author Affiliations

From the Scripps Research Institute (R.J.R.), the La Jolla Cardiovascular Research Institute (R.J.R., P.D.S.), University of California, San Diego (U.B.-G.), and Scripps Memorial Hospital (S.L.H., G.T.T.), La Jolla, the University of California, Los Angeles, Los Angeles (N.G.B.), and Providence St. Joseph Medical Center, Burbank (R.H.M.S.) — all in California; the Department of Entomology, University of Arizona, Tucson (H.S.C.); Intermountain Medical Center, Salt Lake City (J.L.A., A.E.T.); Inova Heart and Vascular Institute, Falls Church, VA (A.A.); Allegheny General Hospital, Pittsburgh (R.W.W.B.), and Abington Memorial Hospital, Abington (J.V.F.) — both in Pennsylvania; Yale University School of Medicine, New Haven, CT (R.L.); Providence Heart Institute, Southfield, MI (C.E.M.); Oklahoma Heart Institute, Tulsa (E.T.M.); University of Mississippi Medical Center, Jackson (A.L.R.); Medical College of Wisconsin, Milwaukee (J.C.R.); Bassett Medical Center, Cooperstown (J.D.S.), and Advanced Cardiovascular Imaging, Carnegie Hill Radiology, New York (S.U., S.D.W.) — both in New York; Methodist DeBakey Heart and Vascular Center, Houston (D.J.S.); and Baptist Health, Lexington, KY (G.F.T.).

Address reprint requests to Dr. Russo at the Department of Molecular and Experimental Medicine, Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, or at .


Source: NEJM

Monoclonal Antibody in Mild Alzheimer’s Disease

Is solanezumab effective in the treatment of mild Alzheimer’s disease?

Honig et al. conducted a randomized, double-blind, phase 3 trial (EXPEDITION 3), which enrolled only patients who had mild Alzheimer’s disease, defined as a Mini–Mental State Examination score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition), and had biomarker evidence of cerebral beta-amyloid deposition. Patients were randomly assigned to receive intravenous infusions of either solanezumab at a dose of 400 mg or placebo every 4 weeks for 76 weeks. This trial was intended to further investigate the secondary efficacy analyses from two earlier trials.

Clinical Pearls

Q: What is the amyloid beta (Aβ) hypothesis regarding the pathogenesis of Alzheimer’s disease?

A: The neuropathological hallmarks of Alzheimer’s disease include extracellular plaques containing amyloid beta (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, along with synaptic and neuronal losses. The Aβ hypothesis of the mechanism of Alzheimer’s disease proposes that early pathogenesis of the disease results from the overproduction of or reduced clearance of Aβ, leading to the formation of oligomers, fibrils, and neuritic Aβ plaques. Treatments that slow the production of Aβ or that increase the clearance of Aβ may slow the progression of Alzheimer’s disease.

Q: What is solanezumab?

A: Solanezumab, a humanized immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the Aβ peptide, was designed to increase clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses at a stage before the deposition of the fibrillary form of the protein.

Morning Report Questions

Q: Is solanezumab effective in the treatment of mild Alzheimer’s disease?

A: In the trial by Honig et al., the primary efficacy measure was the change from baseline to 80 weeks in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). The trial showed no significant between-group difference at week 80 in the change in score from baseline (change, 6.65 in the solanezumab group and 7.44 in the placebo group; difference, −0.80; P=0.10).

Q: What are some possible explanations for the lack of benefit associated with solanezumab in the trial by Honig et al.?

A: According to the authors, the solanezumab dose that was administered in this trial was associated with a high level of peripheral target engagement, sufficient to reduce free plasma Aβ concentrations by more than 90%. However, this effect did not produce clinical efficacy. Thus, a reduction in peripheral free Aβ alone is unlikely to lead to clinically meaningful cognitive benefits. Second, the dose of solanezumab (400 mg, administered every 4 weeks) may have been insufficient to produce a meaningful effect. Third, the pathological changes in the mild stage of Alzheimer’s disease–related dementia may not be amenable to treatment with a drug targeting soluble Aβ. Fourth, solanezumab was designed to increase the clearance of soluble Aβ from the brain, predicated on the Aβ hypothesis of Alzheimer’s disease — that the disease results from the overproduction of or reduced clearance of Aβ (or both). Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression.

Source: NEJM


To Care Is Human — Collectively Confronting the Clinician-Burnout Crisis

The ethical principles that guide clinical care — a commitment to benefiting the patient, avoiding harm, respecting patient autonomy, and striving for justice in health care — affirm the moral foundation and deep meaning underlying many clinicians’ view of their profession as a worthy and gratifying calling. It is clear, however, that owing to the growing demands, burdensome tasks, and increasing stress experienced by many clinicians, alarmingly high rates of burnout, depression, and suicide threaten their well-being. More than half of U.S. physicians report significant symptoms of burnout — a rate more than twice that among professionals in other fields. Moreover, we know that the problem starts early. Medical students and residents have higher rates of burnout and depression than their peers who are pursuing nonmedical careers. Nor is the trend limited to physicians: nurses also experience alarming rates of burnout.1 Clinicians are human, and it takes a personal toll on them when circumstances make it difficult to fulfill their ethical commitments and deliver the best possible care.

Burnout — a syndrome characterized by emotional exhaustion and depersonalization (which includes negativity, cynicism, and the inability to express empathy or grief), a feeling of reduced personal accomplishment, loss of work fulfillment, and reduced effectiveness — has serious consequences in terms of both human cost and system inefficiency.1 Nothing puts these consequences into starker relief than the devastating rates of suicide among physicians. As many as 400 U.S. physicians die by suicide every year.2 Nearly every clinician has been touched at some point by such a tragedy.

Not only are clinicians’ lives at risk, so is patient safety. Some studies have revealed links between clinician burnout and increased rates of medical errors, malpractice suits, and health care–associated infections. In addition, clinician burnout places a substantial strain on the health care system, leading to losses in productivity and increased costs. Burnout is independently associated with job dissatisfaction and high turnover rates. In one longitudinal study, the investigators calculated that annual productivity loss in the United States that is attributable to burnout may be equivalent to eliminating the graduating classes of seven medical schools.1 These consequences are unacceptable by any standard. Therefore, we have an urgent, shared professional responsibility to respond and to develop solutions.

Indeed, there is broad recognition in the health care community that the problem of clinician burnout, depression and other mental disorders, and suicide has reached a crisis level. There are many existing efforts by individual organizations, hospitals, training programs, professional societies, and specialties to confront the crisis. But no single organization can address all the issues that will need to be explored and resolved. There is no mechanism for systematically and collectively gathering data on, analyzing, and mitigating the causes of burnout. The problem is not lack of concern, disagreement about the severity or urgency of the crisis, or absence of will to act. Rather, there is a need to coordinate and synthesize the many ongoing efforts within the health care community and to generate momentum and collective action to accelerate progress. Furthermore, any solution will need to involve key influencers beyond the health care community, such as information technology (IT) vendors, payers, regulators, accreditation agencies, policymakers, and patients.

We believe that the National Academy of Medicine (NAM; formerly the Institute of Medicine, or IOM) is uniquely suited to take on the coordinating role. Nearly 20 years ago, the IOM report To Err Is Human identified high rates of medical error driven by a fragmented care system. The report spurred systemwide changes that have improved the safety and quality of care.3 Today, we need a similar call to action. To that end, in January 2017, the NAM, in collaboration with the Association of American Medical Colleges (AAMC) and the Accreditation Council for Graduate Medical Education (ACGME), launched a national Action Collaborative on Clinician Well-Being and Resilience.4 The collaborative aims to draw on the relevant evidence base to build on existing efforts by facilitating knowledge sharing and catalyzing collective action.

Since launching the collaborative, the NAM has been overwhelmed by requests from organizations wanting to take part in this work and has therefore issued an open call for network organizations to share information and resources. These network organizations have made formal public commitments to promoting clinician well-being (available on the collaborative’s website5), and they pledge to work with the NAM and others in the network to share knowledge and coordinate efforts. Currently, the collaborative comprises 55 core organizations and a network of more than 80 others, including clinician groups that span many disciplines and specialties, as well as payers, researchers, government agencies, technology companies, patient organizations, trainees, and more.

Four central goals guide the collaborative’s initial work: to increase the visibility of clinician stress and burnout, to improve health care organizations’ baseline understanding of the challenges to clinician well-being, to identify evidence-based solutions, and to monitor the effectiveness of implementation of these solutions. We already know that burnout is driven largely by external factors, rather than by personal characteristics. These factors include work-process inefficiencies (such as cumbersome IT systems), excessive work hours and workloads, work–home conflicts, problems with the organizational culture (such as team dysfunction and management styles that neglect clinician input), and perceived loss of control and meaning at work. Although personal factors unrelated to the clinical environment (such as being young, female, or a parent of young children or teenagers) may also contribute to a greater risk of burnout, the collaborative will focus initially on promoting solutions and progress at organizational, systems, and cultural levels.

The collaborative has organized its efforts into four work streams. The “Research, Data, and Metrics” workgroup is compiling validated survey instruments and evidence-based interventions and identifying benchmarks for gauging progress in supporting clinician well-being. The “Conceptual Model” workgroup has created a comprehensive conceptual model and will establish a shared taxonomy by defining key factors. The “External Factors and Work Flow” workgroup is exploring approaches to optimal team-based care and documentation in the rapidly evolving digital health environment. And the “Messaging and Communications” workgroup is identifying key stakeholders and developing targeted messaging to disseminate available evidence and knowledge and thus inspire action. A key deliverable for the collaborative is an online “knowledge hub” (to launch in 2018) that will serve as a user-friendly repository for available data, models, and toolkits and will provide opportunities for clinicians and other stakeholders to share information and build productive relationships. The NAM encourages all interested organizations and individuals to become involved in the work of the collaborative and to use its products in their own endeavors (for more information, see the project website4).

The health professions are at a critical inflection point. The health system cannot sustain current rates of clinician burnout and continue to deliver safe, high-quality care. But there is reason to be optimistic that the tide is turning. The strong commitment of more than 100 national organizations to the work of the collaborative has made clear that clinician well-being is a growing priority for health care leaders, policymakers, payers, and other decision makers capable of bringing about system-level change. Through collective action and targeted investment, we can not only reduce burnout and promote well-being, but also help clinicians carry out the sacred mission that drew them to the healing professions — providing the very best care to patients.

Source: NEJM

Alzheimer’s drug targeting soluble amyloid falls short in a large clinical trial : NEJM