D-dimer for the diagnosis of recurrent DVT
Diagnosing recurrent venous thromboembolic disease of the legs is more difficult than diagnosing a first episode of DVT. Patients who have had an initial DVT are often left with some degree of post-phlebitic syndrome, which can mimic the symptoms of recurrent disease. Duplex ultrasound often remains abnormal after a DVT, making the distinction between recurrent disease and old disease problematic.
D-dimer measurement, which is elevated with thromboembolic events, is quite sensitive for the detection of initial DVT. Although not very specific, its sensitivity is such that a negative D-dimer has good negative predictive value. Since imaging studies are problematic for diagnosing recurrent disease, the D-dimer assay should be quite useful in helping to rule out recurrent DVT. This study from Oklahoma, published in the December 7 Annals of Internal Medicine, investigated the utility of a negative D-dimer assay in excluding recurrent venous thromboembolism.
Three hundred consecutive patients with suspected recurrent DVT had D-dimer levels assessed. Those with negative results (<48 mcg/ml) did not undergo any further diagnostic testing. Those with positive results underwent compression ultrasound imaging. For three months after initial presentation, patients were followed up with imaging studies if there were any symptoms of recurrent DVT or PE, and also clinically at three months.
Of the 300 patients, 166 had positive D-dimer studies; one half of these had negative ultrasound studies, one third had positive studies and the remainder were inconclusive.
Of the 300 patients, 134 (45%) had negative D-dimer studies and did not undergo duplex scanning. In this D-dimer negative group, 11 patients returned for symptoms of recurrent thromboembolism. Of these, there were two cases of documented thromboembolism (one DVT and one PE); 4 patients had negative diagnostic tests and 5 had inconclusive studies. There was one death in the D-dimer negative group, a sudden death, which may have been a myocardial infarction. Thus, the rate of documented recurrent thromoembolism was 2/134 (1.5%). Including the sudden death and the 5 inconclusive studies, the recurrence rate was 8/134 (6%).
As the authors state:
The acceptable upper limit for the incidence of venous thromboembolism on follow-up in patients with a negative D-dimer test result remains a clinical judgment in the individual patient. The prognosis on follow-up in our patients with negative D-dimer test results is similar to the prognosis of patients with negative results on combined impedance plethysmography and fibrinogen leg scanning; it is also similar to the prognosis of patients with negative venography results.
These results, though not conclusive, are certainly useful. D-dimer testing is of utility in excluding a first episode of DVT; it is likely to be much more useful in excluding recurrent DVT, since imaging studies and symptoms are more difficult to interpret in this setting.
One aspect of this article that struck me was how often the authors mentioned the specific name of the D-dimer assay used here. It was named not only in the methods, where it is appropriate, but also in the discussion and even twice in the abstract! In the background paragraph, the authors state that the sensitivity of the [assay] … has been reported to be 96% to 100% in patients with suspected first-episode DVT or symptomatic pulmonary embolism”. And they quote two references. In fact, one of these references is a comparison of 13 assays in the diagnosis of DVT. The method used by the authors here is not among the two that were found to be most sensitive!
December 3, 2004
Better living through electricity?
Atrial fibrillation is associated with increased morbidity and mortality, in part because AF is a marker for other cardiovascular risk factors such as hypertension, valvular disease and left ventricular dysfunction. AF is also deleterious in its own right, due to the rapid, irregular heart rate, loss of atrial systole and atrial thromboembolism. Thus, there is a long history of attempting to restore and maintain normal sinus rhythm through cardioversion and anti-arrhythmic drug therapy.
More recently, several large trials have found no mortality benefit to the rhythm approach over the rate approach (anticoagulating and controlling ventricular rate), and the pendulum has started to swing towards rate control. However, an analysis of one of these trials suggested that there was, in fact, a benefit to sinus rhythm which may have been offset by mortality associated with anti-arrhythmic drug therapy. It is speculated that if sinus rhythm could be maintained without resorting to antiarrhythmics, the rhythm control approach might be beneficial after all. Thus the potential appeal of catheter-based ablation of atrial fibrillation which does not rely so much on anti-arrhythmic drugs.
In today’s NEJM, Hsu et al from Bordeaux, France investigate catheter ablation of atrial fibrillation in congestive heart failure. They studied 58 consecutive patients with at least class II CHF and echocardiographically documented ejection fractions less than 45%, who were undergoing catheter-based ablation of AF. Ejection fraction, symptoms and exercise capacity before and up to one year after the procedure were studied. These patients were also compared to 58 matched controls with normal ejection fractions undergoing the same procedure.
The authors observed substantial improvement in ejection fraction after ablation, from a mean of 36% before the procedure to 57% at one year post-procedure. NYHA class improved from 2.3 to about 1.5. Bicycle ergometer exercise time increased from 11 minutes to 14 minutes (in the control group without CHF, it increased from 14 to 16 minutes).
The authors also looked at their results among patients with adequate vs inadequate rate control before the procedure (average HR 72 vs 103). The ejection fraction improved by 23% in patients with poor rate control and by 17% in those with good rate control. In the absence of structural heart disease, EF increased by 24%; in patients with structural heart disease it increased by 16%.
The authors conclude:
Restoration and maintenance of sinus rhythm by catheter ablation without the use of drugs in patients with congestive heart failure and atrial fibrillation significantly improve cardiac function, symptoms, exercise capacity and quality of life.
I have some reservations about this study. First of all, it is not clear to me how exactly to evaluate a comparison of an ejection fraction in atrial fibrillation (the baseline) with one obtained in normal sinus rhythm. The EF is difficult to measure accurately in fibrillation; furthermore, the decrease in EF in atrial fibrillation which is due in part to tachycardia, in part to the absence of atrial contraction may not exactly reflect the actual decrease in LV contractility. Thus, I am not as impressed by the large increase in ejection fraction as I would have been if the before and after measurements had been taken in sinus rhythm.
Second, the rise in ejection fraction was less among patients with inadequate rate control before the procedure, but the authors do not state how the functional improvements (exercise time and functional status) fared in these two groups. Were they substantially less in those patients with adequate rate control?
Finally, as the authors themselves note, this was not a trial designed to evaluate mortality. But they go on to state that
Since a reduced left ventricular ejection fraction is an important predictor of mortality, the significant improvement in left ventricular function after ablation could be important in improving survival.
I would emphasize the word could here.
Note: there are three other atrial fibrillation articles in this issue. In an editorial, Stevenson and Stevenson summarize nicely the status of catheter ablation for atrial fibrillation and the potential problems and future approaches. Page reviews the approach to newly diagnosed atrial fibrillation. And there is an article on outpatient treatment of recent-onset AF with the “pill-in-the-pocket” approach.
December 1, 2004
Authors’ replies
Dr. Lucy Yardley, corresponding author for the paper on vestibular rehabilitation, has posted comments directly addressing my critiques.
Dr. Robert Belshe, corresponding author of the first of the two NEJM articles on intradermal flu vaccination, emailed several corrections to statements I had made. These are important points.
Dr. Mathew Hotopf, corresponding author of the article on medical decision making competence, posted a detailed reply that greatly clarifies points that I had raised.
November 29, 2004
EUS vs CT for pancreatic cancer
The November 16 Annals has an article from Indiana University comparing endoscopic ultrasound with multidetector CT scanning for the evaluation of suspected pancreatic cancer.
104 patients with suspected non-metastatic pancreatic malignancy underwent both EUS and high-resolution multidetector CT scanning. Of these patients, 41 were managed medically, and 63 underwent surgery. The two modalities were then compared for their accuracy in determining resectability, staging and detection of tumors.
The original hypothesis was that EUS would be better at determining resectability (in particular recognizing unresectable tumors) than CT scanning, and resectability was the study’s primary endpoint. There was no significant difference between the two modalities for this endpoint: resectable tumors were correctly identified by EUS vs CT in 88% vs. 92%. Non-resectable tumors were accurately identified by EUS vs CT in 68% vs 64%. The authors conclude that “if multidetector CT detects a pancreatic mass that seems to be resectable in an appropriate surgical candidate with suspected cancer, preoperative endoscopic ultrasonography does not seem to be necessary unless tissue confirmation of suspected malignancy is desired”.
Secondary endpoints were staging and the actual detection of tumors. In terms of overall staging, endoscopic US was superior to CT scanning, due to better recognition of T3 disease. For nodal staging, there was no significant difference.
Interestingly, EUS was superior to CT scanning in the detection of small tumors. Among the 63 patients who underwent surgery, 53 were found to have cancer. Of these 53, endoscopic ultrasound failed to diagnose 2 tumors less than 25 mm in size; CT scanning missed 10 tumors, 9 of which were less than 25 mm and one greater than 25 mm. Most of these were in the head of the pancreas. The authors do not specifically explain how 10 patients who had no pancreatic masses on CT scanning came to be evaluated for suspected pancreatic cancer, but 4 of them had had biliary stents placed, so presumably biliary obstruction was the presenting symptom for many of these CT-negative cases.
Thus, endoscopic ultrasound was not superior to CT scanning in determining resectability of pancreatic tumors but was superior in picking up small (less than 25 mm) masses that turned out to be cancers at surgery. This study, supported by grants from the American Society of Gastrointestinal Endoscopy, does not make endoscopic ultrasound an obligatory part of the resectability work-up, which was presumably the original intent. It certainly does raise the question of the role of EUS in the work-up of patients with possible pancreatic neoplasms, however, since it was able to pick up small tumors that escaped CT detection.
November 28, 2004
Stretching the flu vaccine?
In this flu-vaccine shortage year, any means of extending the vaccine supply is worth examining. There is evidence that giving vaccines intradermally rather than intramuscularly is more effective. In last week’s NEJM are two articles examining the effect of administering a lower dose of the flu vaccine intradermally. There is also a letter to the editor looking at the effect of simply giving a lower dose of the vaccine by the traditional i.m. route.
In the first study, sponsored by Glaxo SmithKline, 238 subjects were randomized to either a standard 0.5 ml i.m. dose of flu vaccine or a 0.1 ml intradermal dose of a candidate vaccine that was double concentrated (yielding an intradermal vaccine with 40% the concentration of antigen of the standard vaccine). 130 subjects were aged 18-60 years, 108 were over 60 years of age (average age: 69). In the younger group, the antibody responses were almost the same and were adequately protective in the intradermal group. In the group of subjects over 60 years old, the intradermal route yielded antibody titers that were generally lower, significantly lower for one strain and probably only incompletely protective.
In the second study, suppored by NIH grants, 100 subjects 18-40 years of age were randomized to receive either a standard 0.5 ml i.m. dose of a standard flu vaccine, or 0.1 ml of the same vaccine given intradermally. The intradermal route yielded, overall, a similar (for some strains better) antibody response as the i.m. route.
In the letter to the editor, a group from Canada gave healthy volunteers aged 18-40 years old either a full dose or a 1/10 dose of an influenza vaccine by the intramuscular route. Those given the 1/10 dose achieved protective antibody levels (although lower titers for most strains).
These studies indicate that the intradermal route produces better immunogenicity than the i.m. route. This could be used to enhance the immune response in populations that mount a less effective response (such as the elderly). It could also be used to stretch the vaccine supply in case of future shortages, particularly in the younger population. The practical effectiveness of these approaches will depend, at least in part, on FDA approval of different dosages and routes. It seems unlikely that a manufacturer of a conventional influenza vaccine will apply for approval of one-fifth of the dose of that same vaccine, administered intradermally. The Glaxo SmithKline approach of manufacturing a different product is more likely to be financially attractive.
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