Our old friend,the efficacy-effectiveness phenomenon (EEP) can be found in the drug eluting stent (DES) controversy.The NEJM electronic issue hit the ether on 2/14/07 presenting 4 meta-analyses, two editorials and the well publicized Swedish registry study which alarmed cardiologists and patients. Subscribers also could listen to an audio segment in which Dr. Steve Nissen of Cleveland Clinic debated Dr. Donald Baim of Boston Scientific. Nissen recommended that a RCT be done to compare DES with bare metal stents while Dr. Baim announced that a trial was already underway to compare DES with coronary artery bypass surgery (CABG).The DES which seemed to have solved the problem of early stent restenosis stand accused of leading to late stent thrombosis and increased coronary events-trading short term gain for long term harm. Data and conflicting interpretations and opinions fly back and forth.
The term EEP refers to the often striking differences in outcomes that occur when an intervention shown to be very efficacious and safe in a RCT is applied to a broader group of patients as the intervention moves from the very controlled world of a trial to the more chaotic settings of real clinical practice.
Some of the difference is due to the fact that the intervention is now being used to treat patients who may vary in many important-and outcome determining-ways from the treatment group in the trial. A recent article in the Archive of Internal Medicine suggest that a more subtle mechanism may be at work as well.Results may also be less impressive when the intervention is applied to patients with the identical characteristics as the treatment group in the trial an effect speculated by the Archives article authors to be due at least in part to general greater care in their treatment and more uniform and consistent application of other generally accepted and recommended aspects of care. Further. there may well be differences in trial subjects related to the fact that they agree to be in a trial.
Safety issues are more likely to become evident in the observational data that accumulate as the intervention becomes widely used. RCTs are relatively small and generally recognized not to be the method of choice to determine if less common side effects occur. Observational data as they accumulate develop much more statistical power for short term effects and because observation can continue much longer the longer term outcomes become evident.So we clearly need to rely on observational data but the rub occurs in interpretation of the data. The groups that are compared in observational data are not randomized and while various statistical techniques are applied to try and compensate for the biases that plaque non-randomized comparisons there is a thick messy residue of doubt and controversy. The techniques seem an attempt to make observational data more like controlled trials which of course they aren't.
When DES were approved by the FDA the striking fact impacting the minds of interventional cardiologist was that the restenosis rate ( the main problem with bare stents) was about 20% and that seen in the DES trials for the coated stents was about 10%. Of course, cardiologists were anxious to apply that technology to their coronary artery patients and very quickly DES took over and by a year after approval about 80% of the percutaneous interventions involved use of DES. Not only were they applied to patients who were exactly like those in the trials ( basically short lesions and large arteries in a non acute setting) but also to patients with more complicated lesions and those in the middle of an acute coronary syndrome.
From a mechanistic point of view, it seems that the addition of drugs to the stents worked to prevent the over-exuberant growth of intimal cells onto the stents causing early restenosis ( in the six month time frame) but also may have overdone it in some patients leading to inadequate neointimal coverage of the DES and late thrombosis of the stent. Some cardiologists have suggested that the late thrombosis event coincided with stopping Plavix and have suggested continued use of Plavix for three or more years rather than the one year now commonly recommended.
The FDA's position seems to be that for the on label indications for DES, there appears to be no real issue with late thrombosis and that there is an increased risk of late thrombosis in patients with more complicated lesions and those with renal disease and diabetes. . How long to take anti-platelet drugs is an unsettled question as is the use of DES in patients whose coronary artery disease features do not confrom with the current on-label indications.
When a RCT is published and publicized and the results appear to be really great the best advice may be -as Bob Dylan said- "don't speak too soon, the wheel's still in spin"
addendum: 3/23/07.I have revised the next to last paragraph as somehow the original published version was garbled .