Ablation for atrial fibrillation — author’s reply
In my post about the recent NEJM article on ablation for atrial fibrillation, I commented that “… 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 corresponding author of this article, Dr. Pierre Jais, has emailed me this reply:
I would like to thank you for your comments and interesting web site.
I just would like to emphasize that the baseline echographic EF was acquired just after the ablation procedure, in sinus rhythm, to overcome the
limititation you pointed out.Best regards.
Pierre Jais
I went back to the article, to see if I had misunderstood or misstated the methods. The description of the echocardiographic determination of ejection fraction at baseline is as follows:
Patients were routinely admitted two days before the ablation procedure for baseline evaluation. Treatment with oral anticoagulants, taken by all the patients, was stopped on admission, and treatment with all antiarrhythmic drugs, except amiodarone, was stopped for an appropriate period before ablation. Heart rate and rhythm were monitored with the use of 48-hour ambulatory electrocardiography. Transesophageal echocardiography was performed to rule out atrial thrombi, and transthoracic echocardiography was performed to evaluate cardiac structure and function. Echocardiographic measurement of the left ventricular ejection fraction was standardized with the use of Simpson’s biplane method for all patients during the initial hospitalization and subsequent visits.
From the above description, I don’t think it was unreasonable to assume that the initial EF was determined while the patients were still in atrial fibrillation.
Thus, the author’s reply represents a significant clarification.
December 11, 2004
Defibrillators post-MI — a note of caution
The use of implantable cardioverter-defibrillators for the prevention of sudden death in patients who are at high risk for but have not yet had cardiac arrest (primary prevention) is gradually expanding. A number of trials have shown mortality benefit in different populations:
- MADIT: benefit in patients with coronary disease, ejection fraction less than 35%, spontaneous nonsustained ventricular tachycardia and inducible VT with electrophysiologic testing.
- MUSTT: benefit in patients with similar criteria to MADIT, but EF less than 41%.
- MADIT II: benefit in patients with prior MI and EF less than 31%. Important study, since EPS no longer required.
- DEFINITE: patients with non-ischemic cardiomyopathy, VPC’s or NSVT, EF less than 36% had a significant reduction in arrhythmic death but only a trend towards reduction in overall mortality.
- SCD-HEFT (reported but not yet published): benefit in patients with EF ≤ 35%, both ischemic and non-ischemic, particularly in class II rather than class III CHF.
On the negative side, the CABG-PATCH trial, published in 1997, failed to demonstrate any benefit from the implantation of an ICD in patients with ejection fractions under 36% and an abnormal signal-averaged ECG who had just undergone coronary bypass surgery. It has been speculated that active ischemia is an important component of sudden death, and thus patients who had just been revascularized would not benefit as much from an ICD.
Another negative trial has just been published in this week’s NEJM: the DINAMIT trial. In this study from Germany, 674 patients with ejection fractions under 36% who had had an MI less than 40 days previously and demonstrated reduced heart-rate variability or persistent sinus tachycardia (poor prognostic signs related to autonomic system activation), were randomized to therapy with or without an ICD.
Although arrhythmic deaths were significantly reduced by the device, this was almost exactly compensated for by an increase in non-arrhythmic deaths, so the overall death rate was the same in both treatment arms. The authors speculate that in this group of patients, with decreased heart rate variability and a recent MI, the risk of non-arrhythmic, pump-failure death is high, so that ICD therapy ends up converting some arrhythmic deaths to pump failure deaths without affecting the overall outcome.
How do we reconcile these results with the MADIT II trial, in which post-MI patients with reduced LV systolic function benefited from ICD placement? It turns out that most of the MADIT patients had their MI in the remote past. In fact, in a subgroup analysis, the benefit from the ICD was limited to patients whose MI was over 18 months previous to trial entry. This meshes quite well with the data from the current study.
Why remote MI’s should benefit from ICD placement so much more than recent ones is a bit puzzling to me. One possibility is that, as indicated in the CABG PATCH trial, residual ischemia is an important contributor to sudden death risk. In that case, patients with recent MI’s are more likely to have been screened and revascularized when necessary than patients with older events. In MADIT II, patients were not systematically evaluated for ischemia prior to enrollment. Could it be that appropriate screening and treatment of residual ischemia would reduce the potential benefit of defibrillator placement?
December 6, 2004
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.
November 27, 2004
Six articles on postmarketing drug surveillance from JAMA
The pharmaceutical industry and the FDA are being battered by testimony and discussion in the wake of Vioxx. Presumably this will soon die down: news stories appear, flare up and soon fizzle out when their energy (and the public’s interest) is spent. For now, however, the drug surveillance story is still burning bright. David Graham, the gaunt FDA whistle-blower, is enjoying his Warholian fifteen minutes of fame. And this week’s online edition of JAMA pre-publishes six pieces that will appear in next week’s print edition. These articles are about Baycol (cerivastatin), a drug no longer in the news but relevant to the topic. Very briefly summarized:
- The FDA’s Graham et al examine the incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs, an inception cohort study of 252,460 patients treated with various statins and fibrates between 1998 and 2001. The number of patients needed to treat for one year to produce one case of severe rhabdomyolysis was roughly 23,000 for monotherapy with atorvastatin, pravastatin or simvastatin; 3500 for monotherapy with a fibrate, 2000 for monotherapy with cerivastatin, 1500 for fibrate plus a statin other than cerivastatin and only about 10 for fibrate plus cerivastatin.
- Psaty et al discuss the potential for conflict of interest in the evaluation of suspected adverse drug reactions. They discuss the FDA’s regulatory process, noting that: “…the proportion of new molecular entities that are first introduced in the United States has increased from 2-3 % in the early 1980s to 60% in 1998″ and “in contrast to the highly structured premarketing evaluation, postmarketing surveillance has little structure” (and is underfunded).
They describe the information that was publicly available on Baycol, mainly from SADR’s, and contrast this with the information that was available to Bayer but not to the public (which they derive from litigation documents, in which they were expert witnesses for the plaintiffs). They suggest that there was information posessed by the company which should have been made public, but which represented a conflict of interest for Bayer.
The authors argue that, given the speed with which new agents enter the market, the public is at increased risk due to the lack of resources available for post-marketing surveillance and the conflict of interest inherent in the pharmaceutical companies’ positition. This should be dealt with by strengthening the post-marketing surveillance structures and possibly creating an independent agency to deal with this.
- Pierkowski responds to this article on behalf of Bayer, emphasizing that Psaty et al were expert witnesses against Bayer. He argues that both the FDA and Bayer took appropriate actions at the appropriate times.
- Psaty et al then respond to Pierkowski’s points, arguing that whether or not Bayer took appropriate action is less important than whether or not the post-marketing system needs to be dramatically improved.
“While Piorkowski, as an attorney representing Bayer, properly defends some of the company’s specific actions, the purpose of our article was to raise an important public health issue. For us, the cerivastatin-rhabdomyolysis case report served as an illustration. We were primarily concerned to demonstrate how the current postmarketing surveillance system and the current FDA regulations may not, under certain circumstances, be adequate to protect the health of the public.” - Strom reviews the whole post-marketing surveillance system. His manuscript was submitted to JAMA by Bayer. He notes that much data is supplied by the SADR system, but the data itself is, necessarily, of limited quality and must be considered hypothesis generating. It needs to be followed up by appropriate hypothesis testing, which is where the system can and should be improved. He believes that, from a regulatory standpoint, the FDA is up to the task if given the appropriate resources. From a scientific standpoint, other organizations (such as the publicly funded Centers for Education and Research in Therapeutics) need to be developed and strengthened in order to analyze and respond to hypotheses generated from the SADR’s. This cannot be left up to the pharmaceutical industry, given its inherent conflict of interest.
- Finally, in an excellent editorial, JAMA editors Fontanarosa, Rennie and DeAngelis sum it all up nicely. If you only read one of the six articles, I would suggest reading this one. The authors provide the background to the articles published in this issue, and make several suggestions, including decoupling the drug-approval and post-marketing surveillance processes, since “it is unreasonable to expect that the same agency that was responsible for approval of drug licensing and labeling would also be committed to actively seek evidence to prove itself wrong”. They conclude:
“The postmarketing surveillance system requires a long overdue major restructuring. Until that occurs—as indicated by the articles in this issue of JAMA, as epitomized by recent evidence of serious harms from widely used and heavily promoted medications, as demonstrated by the influence of industry over postmarketing data, and as illustrated by the lengths to which some manufacturers will go to protect their interests—the United States will still be far short of having an effective, vigilant, and trustworthy system of postmarketing surveillance to protect the public.”
That being the case, what is the practitioner to do? Assuming that there will continue to be delays before adverse drug effects are discovered and publicized, prudence before prescribing the latest “hot” drugs seems warranted, more than ever. About a year ago, the pharmaceutical rep promoting one of the newer statins asked me when I would be comfortable prescribing this particular medication. I said I would wait at least a year. Now that same representative is reminding me that it’s been a year. I’m still not ready.
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