Banning Anticoagulation in Stroke or Consequence of Poor Study Design
To the Editor:
We read with great interest the review from H.P. Adams1 who critically re-evaluates individual aspects of well-known and often-discussed studies on anticoagulation in acute stroke. These studies do not exhibit a net benefit of anticoagulant use with regard to the criteria safety, mortality, morbidity, prevention of stroke recurrence and late outcome. The author emphasized the differences among the individual studies with regard to sample sizes, time-to-start of therapy (extending up to 48 hours after stroke onset), protocols for dosages and controls of anticoagulants used and the route of administration leading to a distinct criticism of major meta-analysis published. In addition, prominent shortcomings such as the missing baseline brain imaging studies in the dominating IST and CAST trials and the lack of any efforts to differentiate among stroke subtypes with gross under representation of embolic mechanisms are mentioned. However, despite these shortcomings, H.P. Adams concludes that he sees no indication for anticoagulation in acute stroke and suggests the future role of anticoagulants will be very limited.
In our view this conclusion is premature and not accepted by many “stroke experts” in institutions where advanced diagnostic techniques and neuro-monitoring are available. So far the albeit limited data available from these trials reveals statistically significant advantages of anticoagulation in the prevention of deep venous thrombosis, pulmonary embolism, as well as of early recurrent stroke. It is likely that a supposed increase in risk of bleeding complications is biased by restrictions of IST and CAST which do not reflect standards of acute stroke management in major European and North American hospitals. These standards include high-quality brain and vascular imaging (CCT, MRI, ECD, TCD), cardial diagnostics (ECG-monitoring, TTE and TEE) and monitoring of blood pressure, metabolic and relevant coagulation blood parameters performed within days after stroke onset by trained neuroradiologists, cardiologists, angiologists, and stroke unit teams. Such techniques have been shown to be able to reduce symptomatic hemorrhagic transformation and bleeding complications in patients treated with rtPA in acute stroke trials even if the time window was extended beyond 3 hours.2 They may similarly improve the benefit/risk ratio for early anticoagulation in acute stroke.
Thus we share the careful considerations of the author toward the shortcomings and results of the existing studies on anticoagulation although we disagree with his conclusion: adapting to the risk of downhill skiing with modern technology combined with training resulted in both breathtaking records and a substantial reduction in the “complication” rate of this discipline. Similarly potential risks of anticoagulation should be minimized by appropriate selection and monitoring of patients treated with definitely more sophisticated protocols than are needed for standard aspirin recommendation. Recent therapy concepts both in the United States and Canada3,4 as well as our country surveyed in 33 dedicated stroke centers, mostly university hospitals,5 reflect a pathophysiologically driven, widespread careful use of anticoagulation in selected patients and the use of heparinoids for the prevention of deep vein thrombosis in most immobilized patients. In all patients individual therapy decisions are dynamically adapted by a quick stroke workup based on stroke etiology, size of the infarction, history of anticoagulation disorders, and actual bleeding risks from patient premorbidity, etc, which were all not considered in IST and CAST.
In our view the author‘s conclusion to the many legitimate points of criticisms could better have resulted in formulation of timely study concepts stratifying risk and benefit of anticoagulant use in acute stroke by employing criteria such as time window, imaging criteria, and stroke etiology.
Adams HP. Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke. 2002; 33: 856—861.
Röther J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, et al, for the Kompetenz- netzwerk Schlaganfall Study group. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke <6 hours. Stroke. 2002; 33: 2438–2445.
Al Sadat A, Sunbulli M, Chaturvedi S. Use of intravenous heparin by North American neurologists: do the data matter? Stroke. 2002; 33: 1574–1577.
Daffertshofer M, Grips E, Dempfle CE, Hennerici M. Heparin in der Akutphase des ischämischen Schlaganfalls: Datenlage und klinische Realität. Nervenarzt. In press.
I thank the Editor for asking me to respond to the letter by Grips et al who apparently disagree with my interpretation of and conclusions about the data from recent clinical trials of anticoagulation for treatment of patients with acute ischemic stroke. An exchange of ideas about anticoagulation in the treatment of stroke is welcomed. Unfortunately, the letter contains incorrect information. Grips et al are incorrect in their statement that I see no indication for anticoagulation for treatment of patients with recent stroke. In my review, I stated that “anticoagulants do have a role in management of some patients with recent stroke as a measure to prevent deep vein thrombosis and, presumably, pulmonary embolism.”1 However, the focus on my review was the issue is whether emergent administration of anticoagulants improves neurological outcomes, halts neurological worsening, or prevents early recurrent stroke. When these standards are used, definitive data that these medications are effective do not exist.
As reflected by the article by Al-Sadat et al,2 physicians continue to prescribe anticoagulants. This is not surprising because physicians often are slow to change their practices. However, Grips et al should not construe this survey’s data as proof for the utility of emergent anticoagulation. In the era of evidence-based medicine, physicians should evaluate the strength of information supporting the use of any medication—even those time-honored medications such as heparin. Recent clinical trials do not provide any definitive data that emergent anticoagulation is useful in improving outcomes of patients with acute ischemic stroke. These data are much more compelling than personal beliefs and nothing in the letter of Grips et al refutes this information.
Al-Sadat et al2 concluded that further research is needed on how the results of negative clinical trials affect physician behavior. The best way to influence physicians is to provide the necessary and correct data to them in an educational format. That was the mission of my article. In addition, the development of guidelines by professional groups can help change physicians’ opinions. I note that the opinions in the recent guidelines authored by a panel of experts appointed by the American Stroke Association and the American Academy of Neurology are similar to those contained in my independent review.3
Because the current data do not support the use of emergency anticoagulation, the burden now is on the advocates of this therapy to provide convincing information from well-designed clinical trials. I encourage Grips et al to conduct such a prospective trial that includes the high level of technology that they recommend. The trial would need to include a number of steps to ensure the validity of the data from the ancillary diagnostic studies that they propose using. In addition, the trial also should meet the modern requirements of clinical research including randomization, blinding, careful ancillary management, and an adequate sample size to avoid false-positive and false-positive results. I would welcome new data showing the usefulness of anticoagulation in treatment of patients with stroke. I am very willing to change my view about emergency anticoagulation given credible data.
Adams HP Jr. Emergent use of anticoagulation for treatment of patients with ischemic stroke. Stroke. 2002; 33: 856–861.
Al-Sadat A, Sunbulli M, Chaturvedi S. Use of the intravenous heparin by North American neurologists: do the data matter? Stroke. 2002; 33: 1574–1577.
Coull BM, Williams LS, Goldstein LB, et al. Anticoagulants and antiplatelet agents in acute ischemic stroke: Report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Neurology. 2002; 59: 13–22.