Breaking News

Measles Alert!

February 20, 2008

measles.jpgCommentary by Rosemary Adamson MD, PGY-2

Be on the look-out for measles! New York City’s Department of Health and Mental Hygiene (DOHMH) issued a measles alert at the end of last November because there were 5 confirmed cases of measles being imported from abroad in 2007 to NYC. The DOHMH wished to raise healthcare provider awareness of measles, especially in travelers. Coming from the UK, this alert is close to my heart, as Britain has been battling with reduced uptake of the MMR vaccine and consequent increased numbers of measles cases for several years. Indeed, one of the imported measles cases came from the UK; the others were from Belgium, China, Israel and Japan. Two of the five cases were US residents and three were foreign nationals. They were a mix of adults and children. However, once measles is imported it becomes a local problem – in 2006 at least 14 cases of measles in Boston were thought to have been caused by spread from a traveler from India. Canada had an annual national average of 10 cases per year from 2002 to 2006 but this year there have been nearly 100 cases of measles in Quebec alone, illustrating the infectivity of this virus.

Measles is an acute viral illness caused by an RNA paramyxovirus. It is highly contagious, infecting non-immune individuals i.e. those who have been neither exposed nor fully immunized. It is important to note that one vaccination is insufficient to develop full immunity. In epidemics, attack rates of 99% have been recorded. The incubation period lasts 6-14 days and individuals become contagious as soon as they develop any symptoms through until a few days after the rash appears. The first symptoms consist of a prodrome of cough, coryza and conjunctivitis (“the 3 Cs”) with fever up to 105ºF. Two or three days later the main illness develops with its characteristic rash and Koplik spots. The rash is maculopapular and erythematous, starting on the face and the working down the body and on to the limbs, including the palms and soles. It may become confluent over the trunk. Koplik spots are small white spots on the mucous membranes of the oropharynx, especially the buccal mucosa, and are pathognomonic, but not always visible. Most cases are relatively benign and resolve spontaneously. Management is entirely supportive as there is no specific treatment for this disease.

Case fatality is due to complications which range from mild to severe and tend to be worse in older patients. They include diarrhea and respiratory tract infections such as bronchitis and otitis media, both of which may require antibiotics, if there appears to be secondary bacterial infection. Another complication is giant cell pneumonia due to direct invasion of the lungs by the measles virus, which is rare, occurring in immunocompromised individuals. Devastating neurological sequelae also may occur. Post-infectious encephalitis occurs in approximately one in every thousand cases. It develops within a few days of the rash and commonly presents with drowsiness, headache and convulsions. Mortality approaches 50% and survivors typically are left with neurological deficits. Subacute Sclerosing Panencephalitis (SSPE) is a fatal condition which can occur many years after measles, more commonly in those who acquired measles under 1 year of age. The New England Journal of Medicine recently published a case report of this complication.

Read more »

A New Path for the ACCORD (The Action to Control Cardiovascular Risk in Diabetes) trial: Does Being Sweeter Save Lives?

February 8, 2008

90px-glukometr_ot.jpgCommentary by Melissa Freeman MD, Endocrinology Section Editor

The ACCORD trial is an ongoing 5-year, North American, randomized study that began in 2001 to evaluate potential interventions to decrease cardiovascular (CV) events in adults living with DM2.  The trial enrolled 10,251 adults, aged 40- 82, with DM2 for 10 or more years, and a history of CV disease or two CV risk factors in addition to DM2. All participants were randomized at enrollment into intensive versus standard glucose control. In addition, participants were also enrolled into one of two additional arms of the study looking at either tight blood pressure control versus standard blood pressure control or treatment of lipids by a fibrate plus statin versus a statin alone.  The intensive blood sugar treatment group aims for an A1C of less than 6% and blood sugars comparable to non-diabetics, achieved by using multiple glucose lowering agents used including metformin, TZD’s, insulin, sulfonylureas, acarbose, and exenatide.  The primary outcome being measured is the occurrence of major CV events after randomization.

The sponsor of the ACCORD trial, The National Heart, Lung, and Blood Institute, has put the brakes on the intensive blood sugar lowering treatment arm due to serious safety concerns expressed by the study’s Data and Safety Monitoring Board. What happened?  After roughly four years, 257 participants in the intensive-treatment group died compared to 203 in the standard treatment group resulting in a 20% higher rate of all-cause death in the intensive glucose lowering group.  Over half of the deaths were from CV causes.  Interestingly, the rate of primary cardiac outcome events (i.e. nonfatal heart attacks) was 10% lower than in the standard group, but the study cites that when heart attacks in this group occurred they were more likely to be fatal. Furthermore, the death rate in the intensive treatment group was lower than the death rate in similar general populations of such adults with DM2.  Still, after risk/benefit comparisons, it was decided that the intensive glucose lowering group posed more harm than good.  The additional arms of the ACCORD study will go on, but all participants will now be treated according to the protocol for standard blood sugar control (A1C 7- 7.9%) with a comparison of outcomes in the participants originally in the intensive blood sugar group to evaluate whether further differences will persist. 

What is the cause of the cited increased mortality?  Neither the medications or the increased number of hypoglycemic episodes have been found to be legitimate culprits.  Was the medical strategy too brave and too intense by going below the current recommendations? Are the participants too high-risk to be generalizable? Did the blood pressure or lipid interventions in this treatment arm confound the results?  Was the study properly designed?  Was more time needed before making conclusions?  In light of this months NEJM article by Gaede et al. showing that tight glucose regulation results not only in CV benefits but in decreased mortality, the current findings in the ACCORD trial must be viewed in the larger context of what is known.  

Still, after a resultant news frenzy that even landed the front page of the NY Times, patients will be asking whether aggressive treatment is right for them.  It may only be a matter of time before A1C’s of 14 will be the new craze.  Nevertheless, at present, it would be premature to say that sweetness saves lives.

Breaking News: A Disappointment for Zetia

January 15, 2008

zetia.jpgCommentary by Alana Choy-Shan MD, NYU Chief Resident

The highly anticipated results of the ENHANCE trial will likely be presented at the American College of Cardiology meeting in March, but the preliminary results already have everyone talking. ENHANCE was a multinational, double-blind randomized controlled trial sponsored by Merck and Schering-Plough (the manufacturers of the combination ezetimibe/simvastatin pill). A total of 720 patients who were heterozygotes for Familial Hypercholesterolemia were randomized to treatment with either ezetimibe/simvastatin 10/80mg or simvastatin 80mg. The primary endpoint was change in mean carotid intima-media thickness (IMT) after two years of treatment. Combination therapy resulted in a change in mean carotid IMT of 0.0111mm versus 0.0058mm with simvastatin alone (p=0.29). LDL levels, which at baseline were approximately 320mg/dL in the two groups, were lowered by 58% with ezetimibe/simvastatin and 41% with simvastatin (p<0.01). Based on these results, the addition of ezetimibe to high dose simvastatin appears to improve LDL levels without a concordant impact on carotid IMT in this population. Though the carotid IMT results are not statistically significant and the study population was a particularly high risk group by virtue of their genetic make-up, the lay press is already reporting that ezetimibe fails to slow atherosclerosis and may actually promote it. Not surprisingly, Merck and Schering-Plough share prices have already fallen – probably not quite the ENHANCEment they were hoping for…

NY Times Link

Schering-Plough Release

Breaking News: FDA Issues New Warnings for Haldol

September 21, 2007

haldol.jpgCommentary by Helen Kourlas, PharmD

On September 17th 2007, the FDA issued an advisory warning healthcare professionals to avoid the use of higher than recommended doses of haloperidol, marketed as Haldol, Haldol Decanoate and Haldol Lactate. In addition to this warning, the FDA also emphasized that the injectable form of haloperidol is only approved to be administered as an intramuscular injection. Common off – label intravenous administration of haloperidol has led to numerous case reports of QT prolongation, Torsades de Piontes (TdP) and sudden death. Seventy three reports of TdP resulted because of haloperidol use, and 8 of the 11 fatal cases were linked to the intravenous administration of haloperidol at various doses. These cases occurred in the absence of predisposing factors, such as electrolyte imbalances, underlying cardiac abnormalities, or the use of medications that are known to prolong the QT interval. Additional cases have also demonstrated a dose-response relationship between the intravenous haloperidol dose and the development of TdP. These events have led the FDA to update the product labeling of haloperidol to include a warning statement alerting healthcare professionals to observe and monitor patients receiving higher than recommended doses of haloperidol as well as patients receiving haloperidol through intravenous administration. Currently, although intravenous administration of haloperidol is a relatively common off label use, this advisory serves as a reminder that injectable haldol is not FDA approved for intravenous administration.

Reference:
Information for Healthcare Professionals. Haloperidol.

Recent Legionella Outbreak in the Bronx

September 20, 2007

legionellapneumophila.jpg

Commentary by Elizabeth Hackett MD, PGY-3

On July 25th, 2007, the NYC Department of Health released an advisory requesting that all New York City physicians maintain a high index of suspicion for Legionnaires’ disease in patients presenting with community acquired pneumonia. This advisory was prompted by 27 cases of Legionella pneumonia reported in the Parkchester neighborhood of the Bronx during the fall of 2006 (zip code 10462 ). This cluster of cases represented an increase in incidence of the disease to 16.6 cases/100,000 in the Bronx, up from 2.3 cases/100,000 citywide.1

This increase in incidence set of an epidemiological quest for a common source for the outbreak, which has yet to be discovered. In order to assist the DOH in discovering and eradicating a source of this outbreak, they are requesting that we remain vigilant in testing for Legionnaires’ disease in our patients. Sputum or brochoalveolar lavage cultures are the preferred method of diagnosing Legionella pneumonia, with BAL being superior. The urine antigen test can be used as an adjunct, but should be accompanied by an attempt to validate the diagnosis by culture.

Legionnaires’ disease, of course, got its name from the 1976 outbreak during the Pennsylvania State American Legion Convention.  221 people were infected in the outbreak, thought to be caused by contaminated water in the hotel’s air-conditioning system, and 34 of them died.  McDade and Shepard, 2 biologists working for the US Centers for Disease Control and Prevention, discovered that the causative agent was small fastidious gram negative rod, which they named after the unfortunate victims.3

This was not the first outbreak of Legionella.  Once the pathogen was identified, antibody testing showed that several outbreaks of pneumonia in the 1950s and 60s were also likely caused by Legionella species.  In fact, it was subsequently discovered that a six-year long epidemic of Legionnaires’ disease was ongoing among British tourists staying at one particular hotel in Spain, which leads me to wonder about the common sense of British tourists.3

Legionella bacteria are naturally occurring aquatic bacteria that grow in warm water, particularly in cooling towers, water heaters and potable-water plumbing.  They are obligate aerobes, and are best grown on BCYEa agar, growing in about 2-5 days in the lab.  There are 49 different Legionella species, 20 of which have been reported to infect humans.  In addition, there are at least 16 different serogroups.  L. pneumophilia serogroup 1 caused the 1976 outbreak and is the cause of seventy to ninety percent of all cases where the bacteria have been isolated.2

Read more »

FDA Black Box Warning on Gadolinium

May 24, 2007

Back in December we reported on the FDA cautioning practioners about the use of gadolinium (an mri contrast agent) in patients with chronic kidney disease.  The FDA is now requesting a black box warning  stating “that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing a debilitating, and a potentially fatal disease known as nephrogenic systemic fibrosis (NSF). In addition, it would state that patients just before or just after liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity.” 

Prior 12/06 post discussing NSF

FDA Request

The HPV vaccine: Recommended in the U.S., but required in Virginia

May 8, 2007

GardasilCommentary By: Marshall Fordyce, PGY-3

Now that the dust has settled in Texas and Virginia, let’s clarify the role of the human papilloma virus (HPV) vaccine in our clinics. An excellent article in last week’s JAMA by its Editor-In-Chief, Dr. Catherine DeAngelis, and Lawrence Gostin, JD, highlights how the recent push for compulsory vaccination – a significant step beyond CDC recommendations – defied precedent and threatened public confidence in our national vaccine policy. Now, after the tussle of aggressive pharmaceutical lobbying and the public outcry that followed, Texas’ executive order to make the HPV vaccine mandatory was overturned and Virginia’s was altered to include wide “opt-out” provisions. This debacle over mandatory vaccination notwithstanding, the importance of the new recommendations has a significant impact on our patients nonetheless.

Last June, when the FDA licensed the first HPV vaccine, the Advisory Committee on Immunization Practices (ACIP, a subset of the CDC) voted to recommend the vaccine to women 9-26 years old. Recent American Cancer Society (ACS) recommendations are very similar, but emphasize that the data best support girls 11 to 12 years old (“should be performed routinely”), and not so much for women 19-26 years old (“can neither be recommended or discouraged.”). These recommendations are given in addition current cervical cancer screening guidelines. Read more »

Don’t Pass the Olives…

April 18, 2007

OlivesThis week, olives from several different companies were found to contain Clostridium Botulinum. No cases of botulism have been reported to date, but this is an opportunity to review the pertinent clinical findings.

Botulism is caused by exposure to the botulinum neurotoxin in clostridium botulinum. There are eight toxin strains identified, 4 are known to cause disease in humans. The toxin is produced only in an anaerobic environment, so bottled or canned food products are a good source of infection. Food may smell putrid when opening the product, but the FDA warns that in this present outbreak, the olives smell and look normal. Read more »

Meeting Perspectives: The 2007 American College of Cardiology Scientific Session

April 5, 2007

ACCCommentary By: Steven Sedlis, MD Associate Professor of Medicine, Chief, Division of Cardiology Manhattan Veterans Administration Medical Center

The 56th annual scientific session of the American College of Cardiology was held in New Orleans on March 24-27.  The site of the meeting had been selected before hurricane Katrina; the ACC re-affirmed its commitment last year when the devastation caused by the storm was still fresh and when future prospects for southern Louisiana were still uncertain. The ACC meeting was by far the largest meeting to have been held at the New Orleans convention center since Katrina; the ACC can be justifiably proud of its role in contributing to the economic recovery of New Orleans. NYU cardiology fellows did their part as well, and led by senior faculty were deeply involved in evidence based investigations of the culinary and festive delights of the “Big Easy”. Word on the street (Bourbon Street that is) has it that alcohol mediated rise in mean cardiology division HDL levels balanced out the massive rise in mean LDL levels resulting from muffuletta, beignet and andouille sausage ingestion.

The major news from the meeting that captured the attention of the media and meeting participants alike were the findings of the COURAGE study.  COURAGE made the front page of the New York Times and was featured as the lead article published on line by the New England Journal of Medicine. This study conducted at 50 US and Canadian centers randomized 2287 patients with chronic stable angina to optimal medical therapy alone or optimal medical therapy combined with percutaneous coronary intervention (PCI). There was no difference in the endpoints of death or non-fatal myocardial infarction at a median follow-up of 4.6 years. There was better control of angina with PCI, but at 5 years 74% of the PCI patients and 72% of the medical patients were free of angina. These findings threaten the economic interests of the device manufacturers and the narrowly defined interests of some interventional cardiologists. Not surprisingly, efforts at spin control began even before the findings were presented at the late breaking trials session on Tuesday morning. For example, there were comments made by some prominent figures in the interventional cardiology community that COURAGE patients were not representative and that the findings could not be generalized. Well, we enrolled 64 patients in the COURAGE study at the Manhattan VA and our COURAGE patients were extraordinarily representative of the types of patients with chronic stable angina who come to our cath lab and that you see in your clinics. The findings of COURAGE are in fact generalizable and the study should have a major impact on the practice of medicine in the United States.

To better appreciate what the findings of COURAGE really mean and to separate the hype from the reality it is important to understand that COURAGE was not intended to be an attack on interventional cardiology. The study was in fact in large part designed and carried out by interventional cardiologists (including me) who were interested in better defining patient populations who would benefit from intervention. It is well established that PCI is of enormous benefit to patients with acute coronary syndrome. Furthermore, PCI provides effective and clinically important symptom relief to patients with very severe angina and coronary anatomy suitable for PCI.  So the first major lesson to take away from the COURAGE study and that is emphasized by the COURAGE investigators is that PCI continues to be a valuable therapeutic option for large numbers of patients with coronary artery disease. This is supported by the data from the study since over 30% of the medical arm patients in COURAGE had to crossover to revascularization to obtain symptom relief.  We just did not know how much benefit (if any) was derived by patients with mild to moderate angina and stable symptoms. Your clinics are full of these types of patients and they are referred for catheterization all the time. We now know that intensive medical therapy is just as good as PCI for these patients. Read more »

First Direct Renin Inhibitor Approved for Hypertension

March 29, 2007

TekturnaCommentary By: Josh Olstein, PGY-3

Earlier this month the FDA approved Tekturna (aliskiren) the first drug in a novel class of antihypertensives that work by directly inhibiting renin. While Novartis has yet to release pricing information, don’t expect to see this new addition on the Bellevue or VA formulary any time soon.

The idea of treating hypertension by blocking the actions of renin has been toyed with by pharmaceutical companies for over twenty years with little success. Aliskiren is the first agent with satisfactory pharmacologic properties to be tested for efficacy in phase III clinical trials. Renin is secreted by the kidney in response to low blood pressure and catalyzes the first and rate-limiting step along the renin-angiotensin system (RAS), the conversion of angiotensinogen to angiotensin I. Over activity of the RAS is known to play a role in the pathology of hypertension, cardiovascular disease, and chronic kidney disease via the actions of angiotensin II. Our current therapeutic options for blocking the actions of the RAS include angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Aliskiren now offers the ability to block the actions of the RAS at its point of origin.

Several industry sponsored randomized, double-blinded, placebo-controlled trials have studied the safety and efficacy of aliskiren for treatment of mild-to-moderate hypertension. One trial published in Circulation compared the blood pressure lowering effects of aliskiren (150mg or 300mg) compared to placebo and irbesartan (150mg). After 8 weeks of treatment, patients receiving aliskiren 150mg or 300mg had significantly larger reductions in both systolic and diastolic blood pressure versus placebo. The average decrease in blood pressure (SBP/DBP) for those taking aliskiren was 11.4/9.3 and 15.8/11.8 for 150mg and 300mg respectively. Reductions in blood pressure were similar between aliskiren and irbesartan however those taking 300mg of aliskiren had significantly lower diastolic blood pressure recordings. Of note, all the trials have shown smaller blood pressure reductions among African Americans than among Caucasian of Asian subjects.

All told, safety data is available for over 6,500 subjects who have participated in various studies of aliskiren. It appears to be generally well tolerated and safe. The most commonly reported adverse effect is diarrhea. Cough and rash have also been noted but have occurred about half as frequently as with ACE-I. Hypotension has been rare but reported and two cases of angioedema have also occurred. Read more »

The COURAGE Trial: PCI is not superior to medical therapy in patients with stable coronary disease

March 27, 2007

ACCCommentary by Cara Litvin, PGY-3

The results of one of the more remarkable studies from the meeting of the American College of Cardiology were presented on Monday, along with the simultaneous early publishing of the study online in the New England Journal of Medicine. As a result the study results captured a front page article in today’s New York Times.

The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial was a randomized trial involving 2287 patients with stable but significant coronary artery disease who were randomized to either undergo PCI (using bare metal stents) or to receive optimal medical therapy alone. The primary outcome of the study was a composite outcome of death from any cause and non-fatal myocardial infarction. During a mean follow up of 4.6 years, there were no significant differences between the PCI group and the medical-therapy group in the primary event rate (19% in the PCI group, 18.5% in the medical therapy group, P=0.62). Secondary endpoints included hospitalization for acute coronary syndrome, stroke, rates of MI and death. All secondary outcomes and individual components of the primary outcomes showed no significant differences between the study groups. Although there was a statistically significant difference in the rate of patients who were free from angina between the study groups at 1 and 3 years, this difference was not significant at baseline or at 5 years of follow-up. 74% of patients who had undergone PCI were angina-free at 5 years, compared with 72% of those who had received medical therapy (P=0.35). Revascularization was performed at the discretion of the patient’s physician due to worsening ischemia or refractory angina, and rates of revascularization were significantly higher in the medical-therapy group (21.1 % versus 32.6%, P<0.001). Read more »

Conflicts of Interest

March 21, 2007

DollarThe debate about the ethically questionable relationship between physicians and the pharmaceutical industry opened up again this morning on the front page of the New York Times. Although the article is heavy on interview and anecdote and a little short on evidence, it is difficult to avoid casting a critical eye on this relationship. The impetus for the article is the new laws in a handful of states requiring drug makers to disclose all payments made to doctors. These laws have made public previously hidden relationships that many doctors have had with the pharmaceutical industry and the article highlights a number of physicians who engage in such relationships. The article opens with a discussion about Dr. Allan Collins the president of the National Kidney Foundation who has received significant criticism over the amount of money he has received from Amgen, the makers of Erythropoietin and Darbopoietin. Multiple doctors and former employees from the pharmaceutical industry are interviewed and quoted extensively regarding the potential bias found in not only in lectures given to doctors but even in the guidelines written to guide decision making. The slant of the piece is clear especially in light of the sections titled Unknown to Most Patients and A Silent Quid Pro Quo. Nevertheless, it is difficult to argue that the influence that the pharmaceutical industry holds over all of us is not problematic. There’s a certain skepticism that flows through many of us when we hear the terms such as pre-hypertension and pre-diabetes likely coined by a pharmaceutical industry hoping to increase the numbers of patients taking prescription drugs. For those physicians interested in the topic there is an excellent website that clearly shares the perspective expressed in the NY Times article: www.nofreelunch.org.

-Sean Cavanaugh, MD Associate Program Director NYU Internal Medicine Residency Program

References:

New York Times Article

Pharmaceutical Company Payments to Physicians: Early Experiences With Disclosure Laws in Vermont and Minnesota Ross.J et. al. JAMA. 2007;297:1216-1223.

Image Courtesy of Wikimedia Commons