Journal Club

Breaking News: The Jupiter Trial

November 12, 2008

jupiter.jpgCommentary by Ilana Bragin MD, PGY-3

This week online in the NEJM, the results of a trial known as Jupiter were presented in an article that will likely change the way we approach cardiovascular health protection. The Jupiter trial attempts to answer this perturbing question: “Why do half of all myocardial infarctions and strokes occur in apparently healthy men and women with levels of LDL that are below currently recommended thresholds of treatment?” The study addresses the biomarker C-reactive protein, an inflammatory marker that has long been linked to an increased risk of adverse cardiovascular events. While cholesterol has been a target for decreasing cardiovascular risk, physicians have known less what to do about elevated CRPs, using it more as a harbinger of trouble, than as an indication for action. Statins have been previously shown to decrease levels of CRP as well as lipids, and the magnitude of the benefit of statin therapy is known to be in part due to its lowering of CRP. However, while we have guidelines for lowering cholesterol, lowering CRP alone has not been a target of therapy. The study, sponsored by AstroZeneca, thus took individuals who did not have elevated LDL by current treatment guidelines, but did have elevated CRP, treated them with a statin, and then monitored them for cardiovascular events.

More specifically, 17,802 patients with low LDL levels <130mg/deciliter and high sensitivity C-reactive proteins 2.0 mg/liter or higher, were randomized to receive either 20 mg of rosuvastatin daily or placebo. Men above the age of 50 and women above the age of 60 with these criteria were eligible. Patients with a history of cardiovascular disease were excluded. Also excluded were patients on hormonal therapy, with evidence of liver disease, with an elevated CK or elevated Cr (Cr>2), patients with diabetes, uncontrolled hypertension, cancer (other than basal or squamous skin cancer) within 5 years of enrollment, uncontrolled hypothyroidism, recent drug or alcohol history, or any patients with inflammatory conditions, such as lupus, severe arthritis, or inflammatory bowel disease as well as anyone taking immunosuppressive medications or long term glucocorticoids.

The study results were impressive. Although the study was designed to be continued for 5 years or until a primary cardiac event; namely myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes; when a prespecified interim efficacy analysis was performed after less than 2 years, the trial was terminated given the markedly beneficial results of the statin.

After 1 year of therapy, as compared with the placebo group, the rosuvastatin group had a 50% lower average LDL and a 37% lower CRP level. At the time of the termination of the study, 142 first major cardiovascular events had occurred in the rosuvastatin group as compared with 251 in the placebo group. Rosuvastatin also decreased the number of deaths from any cause (hazard ratio for the rosuvastatin group, 0.80; 95% CI, 0.67 to 0.97; P=0.02) With Kaplan-Meir estimates, the number of patients needed to treat with rosuvastatin for 2 years in order to prevent one primary endpoint is 95, and if the risk is projected over a 5 year period, the number needed to treat to prevent the occurrence of one primary endpoint, is 25.

Given that few adverse events occurred with the rosuvastatin group (increased physician-reported diabetes was reported in the rosuvastatin group; although there were no significant elevations of fasting blood glucose and only minimal differences in HgA1c), this could significantly impact how we risk stratify patients and subsequently initiate treatment with statins for cardiovascular prevention.

Some questions remain to be addressed. Does this study mean we should test for CRP levels in all patients, even those who have no other cardiovascular risk? Should the test only be initiated in individuals above the age criteria in this trial (men >50, women>60)? And given that cardiovascular disease is such a multifactorial illness (obesity, HTN, smoking, cholesterol, all play a part), how does CRP, when looked at alone without the other risk factors, fit in? Also, the study, in addition to cutting CRP levels, also cut down LDL from low levels to even lower levels—perhaps that effect is greater than the effect of the lower CRP? And lastly, perhaps this study paved the way for looking more at the inflammatory nature of heart disease, and potentially the benefit of other anti-inflammatory medications on lowering heart disease.

Perioperative Beta-blockade: Will POISE Change Management?

September 10, 2008

180px-das_ordinationszimmer_des_chirurgen.jpgCommentary by Michael LoCurcio MD, Michael Janjigian MD and Michael C Brabeck MD, FACP, NYU Division of General Internal Medicine

Cardiovascular complications continue to be a major cause of morbidity and mortality in the perioperative period. Although progress has been made in terms of risk stratification, an effective invasive or pharmacologic intervention that decreases this risk remains elusive. Well designed studies have shown that prophylactic invasive measures are not effective in decreasing this risk, leaving clinicians uncertain as to the best way to maximize the physiology of the patient in the perioperative period.

Enthusiasm for perioperative ß-blockade is based on two landmark studies. About twelve years ago Mangano (1) randomized 200 patients with or at risk for cardiac disease undergoing general noncardiac surgery to atenolol or placebo in the immediate perioperative period and demonstrated a significant reduction in mortality at 6 months (0% vs. 8%), 1 year (3% vs. 14%) and 2 years (10% vs. 21%) favoring atenolol. Subsequently, in the DECREASE trial (2), Poldermans randomized 112 patients with an abnormal dobutamine stress echo undergoing major vascular surgery to bisoprolol or placebo and showed a remarkable decrease in cardiovascular death (3.4% vs. 17%) favoring the ß-blocker group. Both trials were limited by small sample sizes and methodological flaws and these impressive results have not been reproduced in subsequent studies.

Additional trials supporting ß-blockade in the perioperative period have generally been limited to observational and retrospective reviews. Lindenauer (3) analyzed a multicenter administrative database of patients undergoing noncardiac surgery, stratified by the RCRI score, and found an increased risk of death in patients receiving ß-blockers in the lowest risk group with a stepwise decrease in risk actually favoring ß-blockers in patients with an RCRI score of 3 or greater. In DECREASE II (4), Poldermans studied intermediate-risk patients undergoing intermediate-risk surgeries, giving all patients ß-blockers with HR titration, to determine if routine stress testing improved outcomes. While not demonstrating a benefit to routine stress testing, patients with heart rates less than 65 bpm had lower risk than the remaining patients.

A comprehensive systematic review and meta-analysis of published RCT’s of ß-blockers published in the BMJ in 2005 concluded that while ß-blocker use may decrease the incidence of perioperative cardiac events, it did so at the expense of an increased incidence of hypotension and bradycardia requiring treatment(5).

More recently, three randomized trials of patients undergoing vascular surgery (MaVS6 and POBBLE7) and diabetics undergoing noncardiac surgery (DIPOM8) have all shown no benefit to the addition of ß-blockers in the perioperative period.

In October, 2007, the American College of Cardiology/American Heart Association updated its recommendations for perioperative care of patients requiring non-cardiac surgery (9). While acknowledging the lack of robust data, the committee considered the following recommendations to be reasonable for perioperative ß-blockade:

1. Use the RCRI score to determine the patient’s pre-operative risk category.
2. Low risk patients: do not use ß-blockers perioperatively, unless the patient is already taking them.
3. Intermediate risk patients: unclear if ß-blockers are harmful or beneficial.
4. High risk patients facing vascular procedures, especially those with inducible ischemia on pre-operative testing: the perioperative use of ß-blockers is probably beneficial (Class I B).
5. High risk cardiac patients facing intermediate risk surgery: ß-blockers are probably recommended (Class IIa B)
6. Low, intermediate, and high risk patients: continue ß-blockers in the perioperative period if the patient was already on them. (Class I C)
7. Begin ß-blockers several days to weeks before surgery, if possible. Aim for a HR in the low 60’s, and continue for at least one week post-op.
8. Overall, ß-blockers may decrease perioperative cardiac events, but they increase hypotension and bradycardia, which often may need treatment.
9. The use of cardioselective ß-blockers (currently metoprolol or atenolol) in patients with COPD or hyper-reactive airway disease is probably safe.
10. ß-blockers should be started with caution in patients with HF and not at all in patients with second or third degree HB.

Shortly following these recommendations, the results of the much anticipated POISE trial became available (10). In an attempt to further assess the impact of perioperative ß-blockade, the PeriOperative ISchemic Evaluation (POISE) trial randomly assigned 8351 patients undergoing noncardiac surgery to receive long acting metoprolol succinate or placebo starting preoperatively and continued for the next 30 days. This study, the results of which were presented at the American Heart Association meeting in October, 2007, and published online in May in the electronic version of the Lancet, is the largest randomized controlled study to date on the use of perioperative ß-blockers. The results confirmed that the primary endpoint of non-fatal myocardial infarction, cardiac arrest, or death from a cardiovascular cause was decreased in the group treated with metoprolol compared to placebo (5.8% vs. 6.9%, P=0.040). This “benefit,” however, was driven by non-fatal myocardial infarction and was offset by an increase in 30 day overall mortality (3.1 % vs. 2.3%, P=0.032) and increased number of strokes (1% vs. 0.5%, P = 0.005) in the group receiving metoprolol. Hypotension (15% vs. 9.7%, P = 0.0001) and clinically significant bradycardia (6.6% vs. 2.4%, P = 0.03) were also more common in the treatment group. Unexpectedly and somewhat strangely, there appeared to be a statistically significant increase in the number of patients who died from sepsis (27.9% vs. 18.6% of deaths in each group, P = 0.016) in the group receiving metoprolol.

Although the study was well designed and executed (centers in Colombia and Iran were excluded due to concerns of fraudulent data), it is important to note areas of potential bias. Many of the patients included in the study were at relatively low risk for cardiovascular complications and would not be given ß-blockers based on the current ACC/AHA guidelines. Furthermore, the dose of metoprolol was rather high (metoprolol 100 mg extended release tablets were given twice daily or 15 mg intravenously Q6H for those unable able to tolerate oral medication), and were most often started immediately prior to surgery (between 2-4 hours). Patients who were thought to require ß-blockers (and thus may have been most likely to benefit and tolerate the drug) by their doctor were excluded from the study, and patients with a relatively low HR (above 50 bpm) were included in the study. Finally, by pre-specifying ten secondary outcomes and accepting p<=0.05 as statistically significant, the likelihood of a Type I error is substantial.

Will this study change management of the patient in the perioperative period? We think not. The patient population, the dose and the timing of the ß-blockers given in POISE are significantly different than current practice thus making generalization of its results and conclusions problematic. Although POISE does not directly address the issue, it is reasonable to continue ß-blockers throughout the perioperative period in those patients who are already tolerating this type of therapy. The initiation of ß-blockers in the perioperative period should be limited to those with relatively high cardiovascular risk, should be initiated early, if possible, and with the intent to titrate the dose for a goal HR around 60 BPM.

POISE is now being “fast tracked” for publication in Lancet and our expectation is that we have not heard the last about it. The final chapter on the perioperative use of ß-blockade has yet to be written.

1. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. Dec 5 1996;335(23):1713-1720.
2. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. Dec 9 1999;341(24):1789-1794.
3. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. Jul 28 2005;353(4):349-361.
4. Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. Sep 5 2006;48(5):964-969.
5. Devereaux PJ, Beattie WS, Choi PT, et al. How strong is the evidence for the use of perioperative beta blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ. Aug 6 2005;331(7512):313-321.
6. Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. Nov 2006;152(5):983-990.
7. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. Apr 2005;41(4):602-609.
8. Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ. Jun 24 2006;332(7556):1482.
9. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol. Oct 23 2007;50(17):1707-1732.
10. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. May 31 2008;371(9627):1839-1847.

Image of  the surgeon’s consultation room, a painting by Balthasar van den Bossche, courtesy of Wikipedia.

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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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

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 »

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 »

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 »

Does the Overuse of Macrolides Lead to Antibiotic Resistance?

March 12, 2007

MortarCommentary By: Danise Schiliro, PGY-3

Although intuitively we always worry about creating drug resistance when using antibiotics, there is a surprising lack of well done studies that show a clear causal effect of antibiotic use on the development of subsequent drug resistance. A recent study in Lancet may however lead us to re-evaluate our use of macrolides in everyday practice.

Azithromycin and clarithromycin are two of the most commonly used macrolides for treating respiratory infections. Azithromycin has a long half-life, making it convenient for once daily dosing, while clarithromycin has a shorter half-life and needs to be given twice daily for 7 days. Theoretically, shorter drug exposure decreases the chance of developing resistance, and the higher tissue persistence of azithromycin should therefore confer more resistance. However, studies have shown conflicting results. In addition, we know that two different genes are largely responsible for resistance to macrolides in streptococci. The mef gene mediates active drug efflux and confers low to moderate resistance against macrolides. The erm(B) gene confers a high degree of resistance by changing the macrolide binding site on the bacterial ribosome. Read more »

Should patients with Anemia and a Normal Ferritin Undergo Colonoscopy?

February 16, 2007


Commentary By: Joshua Olstein PGY-3

Second only to lung cancer, colon cancer claimed an estimated 55,000 lives in the United States in 2006. In an effort to reduce colon cancer morbidity and mortality, multiple screening tests have been developed to detect early disease among asymptomatic individuals. The 2003 American Gastroenterology Associations guidelines for screening asymptomatic individuals recommended colonoscopy as a preferred method of screening.

Due to a higher risk of colonic neoplasm, patients with unexplained iron-deficiency anemia are not included in these guidelines. However, consensus opinion recommends that these patients be considered for colonoscopy to exclude colonic neoplasm. Patients with anemia who are not iron-deficient represent a group for which risk of colonic neoplasm is not well known and no recommendations exist. These questions were recently addressed in an article authored by Sawhney et al. published in the American Journal of Gastroenterology. Read more »

A drug for NASH that may work?

January 24, 2007

Commentary By: Sandra D'Angelo, PGY-3

Nonalcoholic steatohepatitis (NASH) is a disease in which patients have features of alcoholic hepatitis on liver biopsy without a prior history of significant alcohol consumption and negative hepatitis serologies. It is unclear how prevalent this disease is because most patients with liver function abnormalities do not undergo liver biopsy.  In those that have had a liver biopsy, the prevalence is estimated to be 7-9%.  It is most common in women between the ages of 40-60 and often associated with the metabolic syndrome, obesity, type 2 diabetes mellitus, hyperlipidemia and hypertension.  The pathogenesis of NASH has not been clearly defined; most theorize that the initial process is insulin resistance which later leads to hepatic steatosis.

Unfortunately, there is not enough data available to elucidate the natural history of NASH.  Approximately 8-26 % of patients with NASH progress to cirrhosis.  Most patients with NASH usually have abnormal liver function tests.   Ultimately, a liver biopsy is necessary to confirm the diagnosis.

There are few treatment options available that have been proven effective in NASH.  Refer to the table below for details.  What’s new and exciting is the recent NEJM article entitled, “A Placebo controlled trial of Pioglitazone in subjects with Nonalcoholic Steatohepatitis.”  This proof-of-concept study looks at the role of pioglitazone in patients with NASH. Read more »

Should we recommend mammography screening for women between the ages of 40-50?

December 22, 2006

In a recent article in the Lancet, this question was addressed by a group of investigators led by Sue Moss, Ph.D. from the University of Leeds.  Currently, the  National Cancer Institute, U.S. Preventative Health Services Task Force and the American Cancer Society all recommend screening at a younger age(those between 40-50).  The task force, however, does recommend educating your patients about the potential risks/benefits regarding mammography at a younger age.  Screening women older than 50 has been shown to reduce mortality from breast cancer by about 25%.  Benefit in younger women has been previously suggested in multiple trials.  In fact, a meta-analysis of the trials showed a 15% reduction in breast cancer mortality in these younger women.  However, previous trials have not been specifically designed to study the effect of screening in this particular age group.

In the AGE trial; 160,921 women aged 39-41 were randomly assigned in the ratio of 1:2 to an intervention group of annual mammography to age 48 years to a control group of usual medical care.  The control group would begin yearly screening at age 50-52 as recommend by the NHS in England.   Follow-up at 10 years found a reduction in breast-cancer mortality in the intervention group of 17%, which did not reach statistical significance.   These results are consistent with results from other trials of mammography in this age-group.  The absolute benefit is generally lower than for women older than 50.

Things to consider in this trial:

  • Single view mammography was used after the initial screen, because of concerns about the effect of radiation.  Two-view mammography improve detection rates, reduce recall rates and are the standard of care in the UK.
  • 20% of women in AGE trial did not actually undergo mammograms and 10% missed screening, therefore, the risk reduction was probably underestimated.
  • There was high attrition rate which may have contributed to decreased power of the trial.
  • Screening protocol used was the 1980s protocol which has less sensitivity than modern mammography.

Therefore, based on this paper, it is doubtful that many governing boards in the U.S. will stop recommending yearly screening starting at age 40.  Keep in mind that more modern screening protocols may eventually reveal a more dramatic mortality reduction.  It is important to always discuss the risk of false positives and unnecessary biopsies versus the benefit of early detection of breast cancer.

“Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomized controlled trial”  Lancet 2006; 368” 2053-2060

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* Breast cancer mortality results of the randomised mammography trials in women younger than 50 years.