Drug eluting stents and late thrombosis
Unlike restenosis, which is fairly common, stent thrombosis is a rare but much more dangerous complication after coronary stent placement. It usually occurs before endothelialisation has been completed. For bare-metal stents, this process takes a few weeks; the newer, drug-eluting stents inhibit restenosis by inhibiting fibroblast proliferation, but they also tend to delay the endothelialisation process. For this reason, patients who have had drug-eluting stents are prescribed aspirin and clopidogrel therapy for at least 6 months.
In this week’s Lancet is a Research Letter describing four cases of late stent thrombosis, occurring over a year after stent implantation and shortly after anti-platelet therapy was discontinued for various reasons. Two patients had had both drug-eluting and bare stents implanted; the thrombosis occurred only on the drug-eluting stents. Two of the patients had Cypher sirolimus-eluting stents and two had Taxus paclitaxel-eluting stents.
These numbers are, of course, minute compared to the large number of drug-eluting stents that have been placed, but they presumably represent only some of the actual cases that have occurred. Late stent thrombosis is thus a rare but potentially dangerous complication of drug-eluting stents, when anti-platelet therapy is discontinued.
Since drug-eluting stents reduce the incidence of restenosis significantly, they will continue to be used. Nevertheless, as the accompanying editorial points out, the issue of late stent thrombosis should make us wary of these stents in patients in whom discontinuation of antiplatelet therapy is likely to occur; more data from registries are needed; the duration of antiplatelet therapy may need to be prolonged; and shorter interruption for surgical procedures may need to be considered.
Interestingly, a press release from the Canadian Cardiovascular Congress 2004 that was referred to by EchoJournal indicates work being done on a stent coated with antibodies that attract endothelial cells from the bloodstream. This could conceivably speed up endothelialisation, a very attractive although not-yet-ready-for-prime-time approach.
Many new devices are sure to appear. Given the large sums of money being spent on drug-eluting stents, I find it very interesting that the authors report stent thrombosis in two each of the two main players in the market. A serendipitous coincidence, I assume.
Of course, lowering cardiovascular risk remains the best approach. You don’t need to worry about what kind of stent you’ll be getting if you don’t need a stent.
October 29, 2004
EBM and industry
This week’s BMJ is a theme-based issue on Evidence-Based Medicine. It contains the expected articles on how to judge whether or not EBM is living up to its promise, how best to implement it, and so on. There is one aspect of EBM, however, that is not addressed: its effect on the drug and device industries.
An implicit subtext of the evidence-based movement is that it helps counter the millions of dollars of industry propaganda and hype that wash over us every year. And EBM does, indeed, provide tools to judge drugs and interventions more objectively than we think the industry would like us to. But the drug and device industries have evolved along with (or ahead of) their customers.
Pharmaceutical companies have responded to EBM by carefully designing trials destined to apply to as wide a population as possible, while still obtaining (p<0.05) benefit. Then, armies of drug reps sally forth armed with reprints, while researchers are sent out to spread the gospel of statistical significance. EBM has made us particularly avid of hard data (while relegating clinical significance to a somewhat subordinate role). This emphasis on statistically significant data has been digested by industry and is now used to sell drugs and devices.
Evidence is good. Evidence-based methodologies are better. But they aren’t magic bullets. And EBM is a tool whose use is not restricted to pure and virtuous clinicians. Caveat lector.
October 28, 2004
Another case-control study ?
This week’s JAMA has a cohort study from the Netherlands looking at the risk of community-acquired pneumonia and use of gastric acid–suppressive drugs. The authors used a large, private practice clinical database to investigate a hypothesized linkage between the prescription of proton pump inhibitors or H2 receptor blockers and community acquired pneumonia. In order to adjust for the fact that many patients on these drugs are sicker, or more likely to have certain diseases, the authors performed a nested case-control examination that looked at recent acid-suppression therapy compared with previously discontinued therapy, adjusting for a large number of factors and diseases (such as age, sex, indication for the therapy, presence of diabetes, copd and stomach cancer).
The unadjusted relative risk of pneumonia for patients who had been prescribed acid-suppressant therapy vs. those who had not was quite high (4.5). In the matched, adjusted case-control cohort of recent therapy vs. past therapy, the adjusted odds ratio was 1.63, much lower, but still significant.
I believe it is impossible to properly adjust for all the reasons why pneumonia patients might have been prescribed acid-suppressant therapy shortly before getting pneumonia. Some of the factors that the authors controlled for are surely valid, but there are likely to be others. Even an individual practitioner’s style and personality could be linked with both the likelihood of prescribing these drugs and that particular patient population’s risk for pneumonia. Adequate adjustment is just not possible.
After multiple case-control and cohort studies showed significant cardiovascular benefit from estrogen replacement therapy, properly randomized trials demonstrated that this was not the case, forcing an incredible about-face. One would think that the estrogen replacement scandal would have put a major brake on performing and publishing these sorts of studies, yet they seem be flourishing. Has nothing been learned?
October 25, 2004
Vestibular rehabilitation for dizziness
In the October 19 issue of Annals of Internal Medicine is a study from the UK of the effectiveness of primary care-based vestibular rehabilitation for chronic dizziness. Primary care patients with a history of labyrinthine dizziness that had lasted at least two months were randomized in a single blind fashion to receive nurse-taught vestibular rehabilitation exercises or usual care; after three months the patients who had received the usual care were crossed-over to vestibular rehabilitation.
The rehabilitation exercises consisted of increasingly aggressive maneuvers designed to stress the vestibular system and provoke dizziness (such as turning the head with eyes open, then closed). These exercises were to be done once or twice daily. The details of the vestibular rehabilitation, and a detailed patient handout explaining the exercises, are available at the Annals website. Patients were evaluated using various questionnaires and forms, and with a device that measured postural stability.
The results indicated that patients did indeed improve more with the vestibular rehabilitation than without.
I found the results of this study to be frustrating. There are two things that I would have liked to find out: what percentage of patients in each group felt, say, “cured or almost completely cured” or “very substantially better” and whether or not there was any difference in the number of falls in either group. The authors bombard us with data, but do not answer these simple questions directly.
I am happy to hear that the Vertigo Symptom Scale was 13.3 in the usual care group and only 9.88 in the rehabilitation group. I am delighted that the Dizziness Handicap Inventory went from 35.88 to 31.09. I am impressed that the Short Form-36 (physical functioning) was 25.95 vs. 27.14. But what does all this mean? The authors do state that 67% of the treated group reported clinically significant improvement, compared with 38% of the usual care group, but what exactly constitutes clinically significant improvement? Did any of these patients actually fall, before or during the study? Nothing about this issue.
Since so many of my older patients complain of unsteadiness on their feet, I would love to recommend exercises to help them. Most likely, vestibular rehabilitation would be helpful and effective. But it would be nice to have some simpler, more comprehensible data about it. I understand that tables full of statistically significant numbers are necessary to get published, but it should be possible to sneak in a patient’s actual assessment of treatment efficacy somewhere.
October 24, 2004
Review of antiplatelet therapy
In this week’s JAMA are several articles dealing with stroke, stroke prevention and antiplatelet therapy. Tran and Anand review oral antiplatelet therapy in cerebrovascular disease, coronary artery disease and peripheral arterial disease. They looked at trials involving antiplatelet therapy in patients with documented vascular disease (stroke, TIA, coronary disease, peripheral arterial disease). Some of the main points that emerged are:
- In patients with vascular disease, antiplatelet therapy leads to a risk reduction for vascular events of 20-30% vs. placebo.
- Aspirin vs. plavix: The CAPRIE trial compared 325 mg of aspirin to 75 mg clopidogrel in almost 20,000 patients. Plavix was modestly superior to aspirin overall, with a risk reduction of 8.7%. The cost of plavix is much greater than that of aspirin, however, and the benefit is less than the benefit achieved by either drug alone over placebo (in the 20-30% range); the authors of this review suggest that, in most cases, either drug may be used for initial, secondary prevention.
- Aspirin plus plavix: Greater bleeding risk. Not more effective than clopidogrel alone in the setting of stroke/TIA (MATCH trial); more effective than aspirin alone in unstable coronary syndrome patients; more studies ongoing in other CAD patients; recommended in patients after unstable angina and after percutaneous coronary interventions (aspirin indefinitely; clopidogrel for 12 mos, possibly longer).
- Persantine (dipyridamole): One large trial of extended-release dipyridamole (ER-DP) in patients with stroke or TIA showed benefit of aspirin plus ER-DP above either drug alone. The theory is that ER-DP is superior to short-acting dipyridamole, which is the basis for the combination drug Aggrenox (aspirin plus ER-DP), but the evidence is based on this one trial, and other trials are still ongoing. No evidence yet for effectiveness in CAD patients, and theoretical concern about deleterious coronary vasodilation, particularly with short-acting dipyridamole.
- Treatment failures on monotherapy (recurrent events): In general, patients on aspirin add or switch to clopidogrel; patients on clopidogrel add aspirin, but several variants depending on types of events. See article for details.
I found this review to be quite helpful. It applies mainly to the non-acute-coronary-syndrome patients. Another article in the same issue of JAMA deals with ACS patients in greater detail.
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