Monthly Archives: August 2013

Should you screen your patients for lung cancer?

Manser R, Lethaby A, Irving LB, et al. Screening for lung cancer. Cochrane Database Syst Rev. 2013 Jun 21;6:CD001991. doi: 10.1002/14651858.CD001991.pub3. (Review) PMID: 23794187

BACKGROUND: This is an updated version of the original review published in The Cochrane Library in 1999 and updated in 2004 and 2010. Population-based screening for lung cancer has not been adopted in the majority of countries. However it is not clear whether sputum examinations, chest radiography or newer methods such as computed tomography (CT) are effective in reducing mortality from lung cancer.
OBJECTIVES: To determine whether screening for lung cancer, using regular sputum examinations, chest radiography or CT scanning of the chest, reduces lung cancer mortality. SEARCH
METHODS: We searched electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1966 to 2012), PREMEDLINE and EMBASE (to 2012) and bibliographies. We handsearched the journal Lung Cancer (to 2000) and contacted experts in the field to identify published and unpublished trials.
SELECTION CRITERIA: Controlled trials of screening for lung cancer using sputum examinations, chest radiography or chest CT.
DATA COLLECTION AND ANALYSIS: We performed an intention-to-screen analysis. Where there was significant statistical heterogeneity, we reported risk ratios (RRs) using the random-effects model. For other outcomes we used the fixed-effect model.
MAIN RESULTS: We included nine trials in the review (eight randomised controlled studies and one controlled trial) with a total of 453,965 subjects. In one large study that included both smokers and non-smokers comparing annual chest x-ray screening with usual care there was no reduction in lung cancer mortality (RR 0.99, 95% CI 0.91 to 1.07). In a meta-analysis of studies comparing different frequencies of chest x-ray screening, frequent screening with chest x-rays was associated with an 11% relative increase in mortality from lung cancer compared with less frequent screening (RR 1.11, 95% CI 1.00 to 1.23); however several of the trials included in this meta-analysis had potential methodological weaknesses. We observed a non-statistically significant trend to reduced mortality from lung cancer when screening with chest x-ray and sputum cytology was compared with chest x-ray alone (RR 0.88, 95% CI 0.74 to 1.03). There was one large methodologically rigorous trial in high-risk smokers and ex-smokers (those aged 55 to 74 years with >/= 30 pack-years of smoking and who quit
AUTHORS’ CONCLUSIONS: The current evidence does not support screening for lung cancer with chest radiography or sputum cytology. Annual low-dose CT screening is associated with a reduction in lung cancer mortality in high-risk smokers but further data are required on the cost effectiveness of screening and the relative harms and benefits of screening across a range of different risk groups and settings.

Reviewer Comments:

General Internal Medicine-Primary Care(US): I think this Cochrane review is useful as it puts screening for lung cancer in perspective. There may be benefits but there are some caveats. For now, I`m not recommending screening to my patients.

Internal Medicine: I think most clinicians are aware that CXR and sputum cytology have not proven useful for lung cancer screening since the studies addressing these issues were done in the 1970s and 1980s. The CT scan RCT got wide publicity, so again clinicians may be aware of that work. Since there is only one RCT on CT scanning, the systematic review doesn’t really change much.

Respirology/Pulmonology: Cochrane meta-analysis of screening for lung cancer finding benefit for low-dose CT and no benefit for CXR. CXR results already well known. Only 1 low-dose CT trial (NLST) was included, so this study adds no new information. A meta-analysis of low-dose CT is of great interest, but is premature at this time and must await completion of several ongoing RCTs.

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Evidence based review of mammography screening for breast cancer

Gotzsche PC, Jorgensen KJ. “Screening for breast cancer with mammography.” Cochrane Database of Systematic Reviews. 2013 Jun 4;6:CD001877.

BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary.

OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity.

METHODS: We searched PubMed (22 November 2012) and the World Health Organization`s International Clinical Trials Registry Platform (22 November 2012).

SELECTION CRITERIA: Randomized trials comparing mammographic screening with no mammographic screening.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Study authors were contacted for additional information.

MAIN RESULTS: Eight eligible trials were identified. We excluded a trial because the randomization had failed to produce comparable groups.The eligible trials included 600,000 women in the analyses in the age range 39 to 74 years. Three trials with adequate randomization did not show a statistically significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with sub-optimal randomization showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favor of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomization did not find an effect of screening on total cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).Total numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42), as were number of mastectomies (RR 1.20, 95% CI 1.08 to 1.32). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data available in only two trials).
AUTHORS’ CONCLUSIONS:

If we assume that screening reduces breast cancer mortality by 15% and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings. To help ensure that the women are fully informed before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on http://www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials were carried out, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening.

Oncology – Breast:  This publication will undoubtedly be controversial and provocative. Why are the results of this meta-analysis so different from the conclusions and recommendations of other studies? The authors raise good arguments as to the probable lesser benefits of screening in today`s world with better awareness and more effective systemic therapies available; however, in my opinion, it would be premature to dismantle screening programs. The authors state that 50% of “early” breast cancers would never cause problems and lead to overdiagnosis and overtreatment. I am uncertain about the accuracy and evidence supporting this statement.

You Don’t Have To Fast Before A Lipid Panel?!

For years we have dutifully told our patients to only get their lipid levels measured in the fasting state.  We believed that a meal would artificially elevate their levels and lead us to make the wrong treatment decisions.  For diabetes, we measure fasting and 2 hour postprandial blood sugars, but for cholesterol it’s fasting or come back another time.  In fast, we have been trained to ignore a non-fasting result.  Our lab technicians are so well indoctrinated; they dutifully turn away patients who have eaten.

Studies from 2008 and 2009 suggest that we are wrong.

  • In a 2009 JAMA metanalysis of 68 studies involving 302,430 patients without vascular disease, hazard ratios for cardiovascular disease were at least as strong in patients who did not fast as those who did (JAMA 2009 Nov 11;302(18):1993).
  • Two cohort studies from Denmark in 2008 involving 33,391 patients showed that lipid levels varied very little between fasting and non-fasting patients  (Circulation 2008 Nov 11;118(20):2047):
    • Total cholesterol:  -0.2 mmol/L (-7.8 mg/dL) with p < 0.001
    • LDL -0.2 mmol/L (-7.8 mg/dL) with p < 0.001
    • HDL:  -0.1 mmol/L (-3.9 mg/dL) with p < 0.001
    • Triglycerides: 0.3 mmol/L (26.7 mg/dL) with p < 0.001

After reading these studies, I have changed my habits.  It is more important to get the test done, than worry about when my patients ate — and the evidence supports this.

Is clopidogrel (Plavix) plus aspirin better than aspirin alone in stroke and TIA?

Wang Y, Wang Y, Zhao X, et al. “Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.” New England Journal of Medicine. 2013 Jul 4;369(1):11-9.

BACKGROUND:

Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.

METHODS:

In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.

RESULTS:

Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.

CONCLUSIONS:

Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People`s Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).

Comments from clinical reviewers

  • Emergency Medicine: CHANCE trial provides convincing evidence of direct relevance to emergency physicians to support benefit of dual antiplatelet therapy in a subset (~12%) of acute (<24 hours) minor stroke (NIHSS <4) or TIA (ABCD2 >3) patients providing reduced stroke risk with NNT 29 (95% CI 19-54). Although biologically plausible that these benefits could be attained without increased CNS bleeding events, it is unlikely that dual antiplatelet therapy would not increase overall bleeding complications as is observed in ACS trials (increased risk of major bleeding by 38%, as noted in the accompanying editorial). Nonetheless, CHANCE provides compelling evidence to alter emergency medicine management of acute stroke/high-risk TIA in a subset of patients by implementing dual antiplatelet therapy.
  • General Internal Medicine-Primary Care(US): It is very useful to know that dual anti-platelet therapy is effective for preventing stroke after TIA or acute minor stroke. The fact that only around 12% of the population of stroke patients qualified for the therapy, and that follow-up was only 90 days, limits generalizability. Nonetheless, this may be very helpful to patients, particularly in low-resource healthcare settings.
  • Internal Medicine There is pre-existing data that clopidogrel is somewhat superior to aspirin in this setting, and I believe that clopidogrel/aspirin combination was not shown to be superior to clopidogrel alone. Perhaps I’m missing something important, but I’m not sure how new this is.
  • Neurology: This is the first RCT evidence for early dual anti-platelet therapy for preventing stroke after TIA or acute ischemic stroke. The design of the study differs from most previous stroke prevention studies in that this study focuses on early risk within the first 90 days, whereas most stroke prevention studies in the past focused on long-term chronic prevention. The redemonstration of early stroke risk after ischemic stroke or TIA previously observed in observational data and the ability to reduce the early risk are important aspects of the study.
  • Neurology: The paper has good methodology and enough power to answer an important question that is directly relevant to clinical practice. Congratulations!

Vasopressin, steroids, and epinephrine superior to epi alone in ACLS

Addition of Vasopressin Plus Steroids to Epinephrine Increases Survival to Discharge with Favorable Neurologic Outcomes After In-Hospital Cardiac Arrest
ReferenceJAMA 2013 Jul 17;310(3):270, (level 1 [likely reliable] evidence)

The addition of vasopressin and steroids to epinephrine during resuscitation has previously been shown to improve survival following in-hospital cardiac arrest compared to epinephrine alone (Arch Intern Med 2009 Jan 12;169(1):15). A new randomized trial further assessed the efficacy of combined treatment with vasopressin plus steroids in addition to epinephrine in 300 adult patients with in-hospital cardiac arrest.

Patients with in-hospital cardiac arrest requiring epinephrine by European resuscitation guidelines were randomized to vasopressin plus steroids plus epinephrine (VSE) vs. epinephrine alone during resuscitation and were followed until death or hospital discharge. The VSE group received vasopressin 20 units/cycle plus epinephrine 1 mg/cycle for the first 5 resuscitation cycles plus methylprednisolone 40 mg on first cycle. The epinephrine alone group had epinephrine 1 mg/cycle plus normal saline placebo for the first 5 cycles. All patients could receive more epinephrine as needed. Patients in the VSE group who had postresuscitation shock also received hydrocortisone IV 300 mg daily for up to 7 days with gradual taper (patients in the epinephrine group with postresuscitation shock received placebo saline.) Favorable neurologic outcome was defined as a Cerebral Performance Category score of 1 (conscious, alert, and able to work, with possible mild neurologic or psychologic deficit) or 2 (moderate disability, but sufficient cerebral function for independent activities of daily life).

The intention to treat analysis included all patients who received the allocated treatment (Sixteen patients in each group had confirmed return of spontaneous circulation before administration of study treatment and were excluded from analyses.) The rate of survival to discharge with favorable neurological outcome was 13.9% with VSE vs. 5.1% with epinephrine alone (p = 0.02, NNT 12). VSE was also associated with a higher rate of return of spontaneous circulation for at least 20 minutes (83.9% vs. 65.9%, p = 0.005, NNT 6). In a subgroup analysis of 149 patients who had postresuscitation shock, 21.1% of the VSE group and 8.2% of the epinephrine group survived to discharge with good neurologic outcome (p = 0.02, NNT 8). There were no significant differences in the rates of complications, post-arrest morbidity, or causes of death in analysis of 162 patients who survived ≥ 4 hours.

For more information, see the Cardiac arrest topic in DynaMed.