Not So Rosi…

May 24, 2007

Commentary by Seagram Villagomez MD, Chief Resident

Since its approval in 1999, nearly 1 million Americans have used the thiazolidinedione (TZD) rosiglitazone (Avandia – GlaxoSmithKline) for the treatment of Type 2 Diabetes.  However, in a drug class which seems plagued by concerns, the safety profile associated with rosiglitazone has been brought to question. Previously, troglitazone (Rezulin) was pulled off the market secondary to hepatoxicity, while muraglitazar was not approved by the FDA given adverse cardiovascular events during early clinical trials.  In a study just released by the New England Journal of Medicine and making headlines across the world, Steven Nissen and colleagues at the Cleveland Clinic demonstrate that rosiglitazone has been associated with an increased risk of myocardial infarction and death from cardiovascular causes.

Nissen et al. conducted a meta-analysis which included searches of published data, as well as publicly available data from the FDA website and GlaxoSmithKline’s clinical trial registry.  Their inclusion criteria consisted of trials whose duration was >24 weeks,  included a randomized control group and had available data on MI and cardiovascular death.  In the end, 42 trials were included in this meta-analysis (including the recently published DREAM and ADOPT Trials).

Approximately 28,000 patients who were predominately white males in their late-50’s with poorly controlled diabetes (A1c = 8.2%) were randomized by these trials between a treatment regimen including rosiglitazone and a control group (any regimen not including rosiglitazone).  Nissen et al. found that the odds ratio for MI was 1.43 ( 95% CI 1.03 to 1.98, p = 0.03) and the odds ratio for death from cardiovascular causes was 1.64 (95% CI 0.98 to 2.74, p = 0.06). However, the total event rates in these combined trials were small. There were 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. 39 deaths from cardiovascular causes occurred in the rosiglitazone group compared to 22 in the control group.

The exact mechanism for the purported increased risk is unknown. The authors speculate it may be secondary to its effects on LDL levels (increasing it by as much as 18%), volume overload, or its effects on reducing hemoglobin levels and thus increased cardiovascular stress.  In comparison, pioglitazone (Actos – Takeda) was shown to have favorable cardiovascular outcomes including MI in previous randomized trials, which is thought to be secondary to reduced effect on the above.

The results presented by Nissen et al. are of concern given a population already at a higher risk for cardiovascular mortality and morbidity. However, this study is not without its flaws.  This study was limited by the use of publicly available trial data and not the raw patient level data obtained by the manufacturer.  The included trials were multiple small ones of short duration and therefore the event rates remained small and a time to event analysis could not be performed.  Trial regimens were not standardized (i.e. dosages and medications) and an exact control group was never determined. Furthermore, these trials in which MIs and cardiovascular deaths were secondary endpoints were not powered to determine significant changes.

Even though the data may be of borderline significance, this report raises many interesting questions concerning the safety and approval of rosiglitazone.  Currently, several larger trials are underway to investigate its effect on cardiovascular events. These trials may provide the information to make clear decisions,  however the tremendous publicity this article has generated may have already altered our practice for better or worse.

Are you telling your patients to stop Avandia based on this new data?

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Mystery Quiz #3-The Answer

May 15, 2007

Before you read the answer you should read the orginal post form last week

The Final Poll Results (26 votes): metastatic disease (26%) , mycobacterial disease (22%) ,fungal disease (22%), bronchiolitis obliterans with organizing pneumonia (boop) (13%), septic emboli (9%) ,vasculitis, e.g. wegener’s (4%), thromboembolic disease (4%), sarcoid (0%)

The patient had granulomatous inflammation on pathology with acid-fast organisms seen. The culture grew mycobacterium avium (MAC). After treatment with azithromycin, ethambutol and rifabutin for eighteen months, the follow-up imaging showed significant clearing of the infiltrates.

CT 3-07

This case highlights one of the imaging patterns that are associated with MAC infection, that is, mostly nodular appearing infiltrates without a predilection for the upper lobes, as seen with reactivation MTB. What was unusual in this case was the rapidity of the disease progression. In other regards, the presentation was typical: mild symptoms that are often difficult to distinguish from the patient’s underlying pulmonary disease, exertional breathlessness, sometimes associated with increased cough and sputum, occasionally associated with systemic symptoms such as weight loss. Read more »

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 »

Mystery Quiz

May 3, 2007

Posted By Robert Smith, MD Associate Professor of Medicine, Division Pulmonary and Critical Care Medicine

The patient is an 81 year old male with severe obstructive lung disease who was referred to the pulmonary service for an abnormal chest x-ray prior to femoral-popliteal bypass surgery.   The patient complained of chronic dyspnea on exertion but specifically denied hemoptysis, increased cough, fever or night sweats.   Initial cxr revealed the following:


A chest ct showed only a spiculated appearing mass in the left upper lobe but was otherwise unremarkable.

A follow-up chest ct done 6 weeks later showed no change in the left upper lobe mass but now revealed additional new findings.

CT 1CT 2

What is your leading diagnosis?

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Is the PPD obsolete?

May 1, 2007

PPDIn February of this year the New York City Department of Health released a new policy paper indicating that they will no longer use the PPD as a screening tool for tuberculosis in their clinics.They have switched to the QuantiFERON-TB Gold, (QFT-G), a blood test. This test is an ELISA, which measures interferon-gamma secretion by t-lymphocytes in response to tuberculosis specific antigens. The test requires heparinized whole blood and must be processed within 12 hours of the blood draw.

The test exposes the patients t-lymphocytes to two proteins. The first is ESAT-6, or early secretory antigenic target-6. The second is CFP10, or culture filtrate protein 10. These two antigens are highly specific to m. tuberculosis. They are NOT found in BCG or in MAC. Therefore, the test has a much higher specificity for exposure to TB than PPD.

Like the PPD, it does not distinguish between latent or active infection. Unlike the PPD, it does differentiate BCG exposure. It also decreases the uncertainty we often find when a patient appears to have active TB but his/her PPD is negative. The CDC reports on three studies looking at sensitivity and specificity of the test. In composite, they describe the specificity between 67% in an immuno-compromised population to 98.1% in a healthy population. Sensitivity ranged 81 to 98% in these same populations. The only documented false positives are prior exposures to M. Kansasii, M. Marinum, or M. szulgai.

In contrast, the PPD has a documented specificity of 49% and sensitivity of 33%.

From a practical and economic point of view, the QFT-G is a huge advance beyond PPD. The test offers a positive or negative result and is not reader dependent. There is never a need for second, or booster, test. The patient does not have to return on a specific date to get the results, and the patient can learn the results over the phone. This will halve the number of necessary clinic appointments in the screened population. The only disappointing factor is the lack of specificity for the immunocompromised population. Still, the results are a vast improvement over those for PPD.

Please refer to the web-site below for the CDC guideline.

-Deborah Shapiro, MD, Attending Physician, Division of General Internal Medicine

Image courtesy of wikimedia commons

Statin Pleiotropy: Unique Roles for a Common Medication

April 26, 2007

AtorvastatinBy: Melissa Freeman, MD, PGY1

For over a decade now, statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have facilitated millions of patients in the management of their atherosclerosis. Statins are known for their ability to reduce hepatic lipoproteins, up-regulate hepatic LDL receptors, and increase apoprotein E- and B-containing lipoproteins. They have become a household name in the genre of lipid-lowering and a touted hero in cardiovascular risk reduction amongst physicians. Excitingly, research has found that statins may be valuable in disease processes outside of their traditional realm.

While studying the specific biological mechanisms statins use to halt atherosclerosis progression, a myriad of in-vitro and some in-vivo beneficial attributes of this drug class surfaced. These discovered benefits have been placed under an umbrella term known as “statin pleiotropy.” Classically, the definition of pleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. As a modern twist, the phrase statin pleiotropy has been created to encompass the non-LDL-mediated effects of statin treatment. One explanation for this pleiotropy includes the fact that mevalonate, the enzyme reaction product of statins, is a precursor of many nonsteroidal isoprenoid compounds besides cholesterol. The products of the mevalonate pathway are essential for wide-ranging cellular functions beyond the scope of this article. Read more »

How Do You Estimate Stroke Risk After a Transient Ischemic Attack?

April 24, 2007

BrainBy: Alana Choy-Shan, MD PGY-3
Transient ischemic attacks (TIAs) are known to be a harbinger of stroke, however it is difficult for physicians to estimate individual stroke risk. Previously, the two systems used to predict short-term risk of stroke after a TIA were the California and ABCD scores. Both scores are based on clinical factors with several key elements in common. However, neither scoring system was devised to predict stroke within 48 hours of TIA, a time period which may be most clinically relevant.

In this study[1] published in the Lancet in January, the creators of the California and ABCD scores tested a new system, called the ABCD2 score. In this scoring system, patients receive points for five factors including: age greater than or equal to 60 years (1 point); first recorded blood pressure after TIA with a systolic greater than or equal to 140mmHg or diastolic greater than or equal to 90mmHg (1 point); clinical features of TIA, unilateral weakness (2 points) or speech impairment without weakness (1 point); duration of TIA, greater than or equal to 60 minutes (2 points) or 10-59 minutes (1 point); and diabetes (1 point). The scoring system was validated in patients recruited from emergency departments, specialty and primary care clinics in California and Oxford. It was found to be a more accurate predictor of stroke than either the California or the ABCD scores. The 2 day risk of stroke after TIA was 0% for patients with an ABCD2 score of 0-1, 1-2% for a score of 2, 0-3% for a score of 3, 2-5% for a score of 4, 3-7% for a score of 5, 4-14% for a score of 6, and 0-50% for a score of 7. Stroke risk at 7 and 90 days was also studied and was found to be higher in patients with higher ABCD2 scores.

Based on these results, the investigators risk-stratified patients based on ABCD2 score. Low risk patients had a score of less than 4, moderate risk patients had a score of 4-5 and high risk patients had a score of 5 or greater. Within the study population, if all patients with moderate or high risk of stroke were hospitalized following a TIA, only 9% of strokes would have occurred outside of the hospital. The authors note that this scoring system should serve as a guide to clinicians, but that the individual characteristics of each patient and the constraints of the health care system will likely dictate whether a patient is hospitalized.

Commentary by Dr. Daniel Labovitz, Director of the NYU Stroke Center:
TIA is a serious diagnosis that demands emergent evaluation and usually requires hospitalization. The study summarized above grew out of a previous study [2] that generated the first empirical scale for assessing risk of cerebral infarct after TIA. The prior study reported a 10.5% risk of stroke within 90 days among 1707 patients diagnosed with TIA by emergency physicians. Strikingly, fully half of those strokes occurred within the first 2 days after the index TIA, yielding a stroke risk similar to that of open-heart surgery. There are two take home messages. First, even though some patients are given the diagnosis of TIA for non-vascular events, the diagnosis carries an extremely high risk of stroke. Second, so much of the risk comes so early that emergent hospitalization for TIA is usually the only practicable way to evaluate and treat possible causes soon enough to make a difference.

1. Johnston SC et. al.Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack.Lancet. 2007 Jan 27;369(9558):283-92.

2. Johnston SC, et. al. Short-term prognosis after emergency department diagnosis of transient ischemic attack. JAMA 2000;284:2901-2906. &_char_set=utf8

Image Courtesy NIH

Quick Thinking Part 4-The Conclusion

April 20, 2007

BellevueWelcome to Quick Thinking. A case is presented in short sections to a faculty expert who will comment on their approach to the patient as the case unfolds. These posts will focus on determining the initial differential diagnoses and diagnostic workups of complicated patient presentations.

Part 1 can be found here.  Part 2 can be found here.  Part 3 can be found here.

Part 3 Case Presentation by Elizabeth Ross, PGY-3:

The patient continued to complain of headache and dizziness and given the patient’s persistent and intermittent fevers he was seen by infectious disease but it was decided not to start antibiotics as there was no clear source of infection.  He subsequently had a tonic-clonic seizure and was transferred to the medical intensive care unit where he was started on prednisone 80mg daily and isoniazid/rifampin/pza/ethambutol (I/R/P/E) for the possibility of both sarcoid and tuberculosis.  Lymphoma was also considered as a possible diagnosis.   A tissue diagnosis was considered essential however neurosurgery felt the lesion was too small and the risk of biopsy too high. He subsequently underwent the following procedures: 

Bronchoscopy with transbronchial needle aspiration of a subcarinal lymph node: benign bronchial epithelial cells and few mature lymphocytes

Liver biopsy: chronic inflammatory changes in portal tracts, portal fibrosis,
no granulomata, no lymphoma

Colonoscopy with biopsies of sigmoid: (because of abdominal catscan showing thickening of sigmoid wall) within normal limits 

Mediastinoscopy with resection of right level 4 node:  lymph node with focally necrotizing granulomas and multinucleated giant cells.  Special stains for acid fast bacilli and fungi negative.


Repeat brain MRI after approximately 3 weeks of both prednisone and I/R/P/E showed marked improvement of infundibular and hypothalamic lesion as well as leptomeningeal abnormal enhancement. This was felt to be consistent with successfully treated tuberculosis or sarcoidosis. 

Commentary: Mitchell Charap, MD Abraham Sunshine Associate Professor of Medicine

The development of seizures made broad treatment a necessity, but in covering with steroids and I/R/P/E, the specific diagnosis may be masked. The finding of necrotizing granulomas on biopsy narrows the differential to tuberculosis (or a fungal infection) and sarcoid. The improvement over two weeks does not help us narrow the differential. If all cultures are negative, then one could consider discontinuing I/R/P/E, but my hunch is that both will be continued.

He was discharged with a diagnosis of tuberculosis or sarcoidosis.   He is still on both prednisone and I/R/P/E.  The plan was to complete the course of anti-tuberculous medications and slowly taper the prednisone over 6 months.


Unfortunately, the decision to treat both sarcoidosis and tuberculosis simultaneously creates problems in that both treatment regimens have toxicities. As a general internist managing this case, I would confer with a specialist (probably a pulmonologist) to help me decide if I can eliminate one of the treatment arms.  My clinical suspicion is that the patient has sarcoidosis, but the presence of necrotizing granulomas make tuberculosis a hard diagnosis to rule out. I would therefore ask the consultant if he/she has a a high  degree of certainty that sarcoidosis is the diagnosis. I would ask if the Kweim-Siltzbach test could add to the level of certainty (of course, the prior administrration of steroids makes this test not very useful). If I do not get a clear-cut answer, I would treat with both regimens until the culture results are available and then base my decision on them.

New Guidelines on the Diagnosis and Treatment of Venous Thromboembolism-Part 2

April 19, 2007

Clotting CascadeCommentary By: Margaret Horlick, MD, PGY-3

New guidelines on the diagnosis and treatment of venous thromboembolism (VTE) were recently jointly issued by the American Academy of Family Physicians and the American College of Physicians. The guidelines are based on a systematic review of the evidence and are published, along with the systematic reviews, in the 2/2007 and 3/2007 issues of the Annals of Internal Medicine.

Part 1-Diagnosis

Part 2 Treatment

The treatment recommendations are summarized as follows:

  1. Low-molecular-weight heparin (LMWH), as opposed to unfractionated heparin, should be used whenever possible for the initial inpatient treatment of DVT; either is an appropriate choice for initial inpatient treatment of PE. The authors note the importance of achieving therapeutic anticoagulation quickly in patients with VTE. In previous trials of unfractionated heparin, this was not accomplished and instead, many patients had both subtherapeutic and supratherapeutic levels. This is contrasted with LMWH with which it is possible to reliably achieve therapeutic anticoagulation quickly. The current evidence, based on systematic reviews, shows that LMWH is at least as effective as unfractionated heparin in the treatment of PE but further trials need to be completed to establish it as the preferred treatment. There is, however, consistent evidence demonstrating both mortality benefit and a lower risk of major bleeding in trials of LMWH as the initial therapy of DVT.
  2. Outpatient treatment of DVT, and possibly PE, with LMWH is safe and cost-effective for carefully selected patients, and should be considered if the required support services are in place. The cited studies for this recommendation had strict inclusion and exclusion criteria; specifically, patients with previous VTEs, thrombophilic conditions or significant comorbid illnesses were excluded, as well as pregnant women and patients unlikely to adhere to outpatient therapy. 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 »

New Guidelines on the Diagnosis and Treatment of Venous Thromboembolism-Part 1

April 12, 2007

800px-parque_del_clot_03.JPGCommentary By: Margaret Horlick, MD, PGY-3

New guidelines on the diagnosis and treatment of venous thromboembolism (VTE) were recently jointly issued by the American Academy of Family Physicians and the American College of Physicians. The guidelines are based on a systematic review of the evidence and are published, along with the systematic reviews, in the 2/2007 and 3/2007 issues of the Annals of Internal Medicine.

According to the reviews, there are 600,000 cases of VTE in the US annually, and the importance of early diagnosis and treatment is underscored by the morbidity and mortality associated with VTE. The authors state that 26% of patients with undiagnosed and therefore untreated PE will have a subsequent fatal embolic event, while another 26% will have a nonfatal recurrent event that can eventually be fatal. DVTs carry their own risk of complication: those proximal to the knee are associated with an increased risk of PE and those located only in the calf veins are associated with the postthrombotic syndrome .

The following summarizes the recommendations on diagnosis:

  1. Validated clinical prediction rules should be used to estimate pretest probability of VTE. The Wells prediction rules for PE and DVT were most frequently evaluated in the literature and have been validated. It is worth noting that these perform better in younger patients without comorbidiites or a history of VTE than they do in other patients.
  2. In patients with a low pretest probability of DVT or PE, obtaining a high-sensitivity D-dimer is a reasonable option. If negative, the test indicates a low likelihood of VTE in these patients. Data quoted in the article state that patients with a low pretest probability of DVT and a negative D-dimer had a 0.5% 3-month incidence of DVT, while the 3 month incidence in patients with intermediate and high pretest probabilities and a negative D-dimer was 3.5% and 21.4%, respectively.
  3. Ultrasound is recommended for patients with intermediate to high pretest probability of DVT in the lower extremities. More specifically, ultrasound has a high sensitivity and specificity for diagnosing proximal DVTs (those located proximal to the knee) in symptomatic patients. Important limitations to this recommendation are that ultrasound is less sensitive both in patients who have DVTs limited to the calf, as well as asymptomatic patients. Contrast venography remains the definitive test to evaluate for DVT.
  4. Patients with intermediate or high pretest probability of PE require diagnostic imaging studies. The gold standard remains pulmonary arteriography; helical CT’s sensitivity is, at the best, 90% with a specificity of 95%. Current multidetector CT technology may have higher sensitivity but further studies will be required to establish this hypothesis.

Next Week: Part 2 Recommendations on Treatment

Qaseem A et al. Current diagnosis of venous thromboembolism in primary care: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2007 Mar 20; 146:454-8.

Image: Parque del Clot, Barcelona, Spain Courtesy of Wikimedia Commons

Does Screening for Lung Cancer Improve Mortality?

April 10, 2007

Spiral CTCommentary By: Anna Dvorak, MDPGY-3

Lung cancer is the number one cause of cancer mortality in both men and women. Screening patients at risk for lung cancer might reduce mortality if it helps find cancers at an early stage while they are still resectable. Randomized studies done in the 1970s showed that screening for lung cancer with chest x-ray did not support this theory. Chest x-rays identified more small tumors, but resecting them did not improve mortality. The question of whether screening with chest CT can improve outcomes remains unanswered.

In October 2006, an observational study in the NEJM looked at screening of asymptomatic high-risk patients with CT. The International Early Lung Cancer Action Program (I-ELCAP) screened 31,000 patients and found 484 cancers. 85% of the cancers detected were stage I, and they estimated an 88% survival amongst these patients.  This is in contrast to the 70% ten-year survival currently seen in patients with stage I lung cancer. They concluded that CT screening could detect lung cancer that is curable. Read more »