Letters to the Editor
Additional Letters to the Editor Available Online:
Childhood Sexual Abuse and Chronic Daily Headaches David G. McCollum, M.D.; reply by Morris Maizels, M.D.
Reconsideration of the Smallpox Vaccination Administration Site Christopher J. Salgado, M.D., Samir Mardini, M.D., and Hung-Chi Chen, M.D.
Appropriate Indications for Administration of tPA
to the editor: I would like to clarify some of the recommendations from the article, "Transient Ischemic Attacks: Part I. Diagnosis and Evaluation,1" that appeared in American Family Physician. The authors advocate early referral to the emergency department for evaluation and potential treatment with tissue-type plasminogen activator (tPA). They also place this recommendation in their algorithm (Figure 11). Transient ischemic attack (TIA) is not an indication for tPA administration; only confirmed strokes have received this indication. In fact, rapidly improving symptoms, as can occur with TIAs, are a contraindication to the administration of tPA.
Further, there has been much discussion about the role of tPA in patients who have suffered a stroke. Many authorities often quote a 30 percent reduction in disability with this intervention. For the record, the National Institute of Neurological Diseases and Stroke (NINDS) study group demonstrated a 12 percent absolute reduction in disability (number needed to treat [NNT] = 8).2 The 30 percent figure that often is quoted (including in the Advanced Cardiac Life Support provider manual3) is relative risk reduction, which is a statistic that is commonly employed to exaggerate the benefits of an intervention. Further, it is always important to point out the harm associated with tPA administration in stroke patients. NINDS demonstrated a 6 percent deterioration caused by intracranial hemorrhage (NNT = 16). The use of tPA in the community hospital setting has been demonstrated to be fraught with problems.4
I agree with the current conclusions of the Cochrane Collaboration: "The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a [license] exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given."5
REFERENCES
1. Solenski NJ. Transient ischemic attacks: part I. Diagnosis and evaluation. Am Fam Physician 2004;69:1665-74.
2. Tissue plasminogen activator for acute ischemic stroke. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333: 1581-7.
3. Cummins RO, Field JM, Hazinski MF, Babbs CF, American Heart Association. ACLS provider manual. Dallas, Tex.: American Heart Asssociation, 2001:202.
4. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med 2002;162:1994-2001.
5. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2005;(1):CD00213.
in reply: I thank Dr. Dachs for his interest in the article.1 We are in agreement that a patient with an accurately diagnosed resolved transient ischemic attack (TIA), defined by the current criteria (transient cerebral ischemic deficit lasting for at least one hour) or by the traditional definition (lasting for at least 24 hours), is not a candidate for tissue-type plasminogen activator (tPA) in the nonacute setting. At the time of an acute cerebral ischemia event, to which the algorithm pertains, the evaluating physician has no way of predicting if the deficit will clear or if it will remain permanent, and, therefore, this presentation could be a TIA or a stroke. For this reason, it is appropriate to evaluate a patient who presents with acute symptoms lasting less than 180 minutes for treatment with intravenous tPA regardless of whether the patient ultimately is diagnosed with a TIA or stroke. The National Institute of Neurological Diseases and Stroke (NINDS) trial for tPA in acute stroke contained a placebo limb and a treatment limb that consisted of potential TIAs and stroke patients. It is not appropriate to wait for patients to clear their symptoms of TIA in the acute setting because "time is brain." As Dr. Dachs points out, rapidly improving symptoms or signs may indicate resolution of the cerebral ischemia, in which case the risks of intravenous tPA outweigh the benefits. Interestingly, there are data to suggest that although patients might be excluded at the time of initial evaluation for intravenous tPA on the basis of "mild or significantly improving neurologic symptoms," 32 percent of such patients in one study were deemed dependent at discharge (or deceased).2
My article1 was a review of the evaluation and treatment of TIA and not of the evaluation or treatment of acute stroke. The points that Dr. Dachs makes about the administration of tPA for acute stroke are well addressed in a previous article in American Family Physician.3 This article3 states "that the use of tPA in community hospitals is feasible and safe as long as the American Heart Association (AHA) guidelines and NINDS protocol are followed."4 The use of tPA for acute ischemic stroke according to strict guidelines has been endorsed by the AHA Stroke Council [now the American Stroke Association] and the American Academy of Neurology. The U.S. Food and Drug Administration approved tPA 11 years ago, and after more than a decade of experience and use, intravenous tPA remains endorsed by these and other related foundations and academies.
REFERENCES
1. Solenski NJ. Transient ischemic attacks: part I. Diagnosis and evaluation. Am Fam Physician 2004;69:1665-74.
2. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001;56:1015-20.
3. Benavente O, Hart RG. Stroke: part II. Management of acute ischemic stroke. Am Fam Physician 1999;59:2828-34.
4. Tanne D, Kasner SE, Mansbach H, Binder JR, Verro P, Scott PA, et al. Intracerebral hemorrhage after intravenous t-PA for hyperacute ischemic stroke in clinical practice: rate and predictors. Cerebrovasc Dis 1998;8(suppl 4):48.
Use of Dipyridamole in Patients with Recent Stroke or TIA
to the editor: Dr. Solenski's review1 of treatment options for transient ischemic attack (TIA) discusses the additive benefits of combination therapy with aspirin and extended-release dipyridamole (Persantine), compared with placebo or aspirin alone, as noted in the European Stroke Prevention Study 2 (ESPS-2).2 However, Dr. Solenski raises a concern that the "expected similar benefits for reducing myocardial infarction and vascular death were not observed."1 This concern is misplaced because a trial limited to stroke patients would not be expected to show such benefits.
ESPS-2 only enrolled patients with recent ischemic stroke or TIA2. Such patients are overwhelmingly more likely to have a recurrent stroke than a myocardial infarction during the two-year follow-up period of the trial.3 Although a nonsignificant trend toward reduction of myocardial infarction in favor of aspirin and combination therapy was seen in ESPS-2,2 there were simply too few myocardial infarction endpoints to draw any firm conclusion. This paucity of myocardial infarction endpoints in stroke patients has occurred in other antiplatelet trials. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,4 patients enrolled after a stroke were seven times more likely to have a stroke than a myocardial infarction during the follow-up period. More strikingly, the recent Management of Atherothrombosis with Clopidogrel in High-risk Patients (MATCH) with Recent Transient Ischemic Attack or Ischemic Stroke trial enrolled patients with recent stroke and TIA, 73 percent of whom would be presumed to have a high risk of cardiac events caused by diabetes or previous myocardial infarction. Even in this population, ischemic stroke was five times more likely as an endpoint than myocardial infarction.5
Patients with a recent stroke or TIA are at exceedingly high risk for a recurrent ischemic stroke. Preventing myocardial infarction in these patients is important, but recurrent stroke prevention is paramount, at least for the first two years. In this context, the concern about combined aspirin/extended-release dipyridamole raised by Dr. Solenski should not prevent the use of this therapy in patients with recent stroke or TIA.
REFERENCES
1. Solenski NJ. Transient ischemic attacks: part II. Treatment. Am Fam Physician 2004;69:1681-8.
2. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13.
3. Albers GW. Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients? Neurology 2000;54:1022-8.
4. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39.
5. Diener HC, for the MATCH investigators. Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischemic attack or ischemic stroke. Paper presented at: 13th European Stroke Conference; May 13, 2004; Mannheim, Germany.
Author disclosure: Dr. Bernstein has received honoraria from Boehringer Ingelheim Pharmaceuticals and Bristol-Myers Squibb Company.
in reply: I appreciate the opportunity to address Dr. Bernstein's letter and thank him for his interest in our article.1 The European Stroke Prevention Study 2 (ESPS-2) consisted of a large cohort of 6,602 patients randomized into four treatment groups with more than 1,600 patients enrolled in each limb. Primary endpoints were stroke, death, and stroke and death together. Transient ischemic attack (TIA) and other vascular events were secondary endpoints. More than 33 percent of the patients in each limb had known ischemic heart disease, and an additional 8 percent in each limb had known cardiac failure at the time of enrollment. This calculates to more than 500 patients with known ischemic heart disease enrolled in each limb of the study. An unknown number of patients likely had undiagnosed ischemic heart disease, potentially raising the true number of patients with cardiac ischemia. Patients were followed on treatment with the study drug for two years. A total of 167 patients experienced myocardial infarction during this time with no statistically significant difference between the study limbs, particularly between patients receiving aspirin and those receiving placebo. There are strong data showing that even low-dose aspirin given over short periods of time is cardioprotective.2 For example, in a cohort of patients with silent ischemia, there is significant benefit from taking low-dose aspirin (75 mg per day) as seen in a randomized, double-blind, placebo-controlled trial.3 The group randomized to aspirin had significantly less myocardial infarctions or death at three months compared with the placebo group (4 versus 21 percent, respectively) and also at 12 months (9 versus 28 percent, respectively). Therefore, the effect of acetylsalicylic acid on preventing myocardial infarction in this relatively large cohort of patients would be expected. However, I agree that myocardial infarction was a secondary outcome point and that the trial was not designed to evaluate this. Secondary outcome points still should be analyzed critically because they may provide important data in understanding the representative nature of the patient population being tested. I strongly agree with Dr. Bernstein that outcomes for the evaluation of stroke therapies are most accurately determined if stroke alone is chosen as the primary endpoint, as was eloquently argued by Dr. Albers.4 As pointed out in Dr. Albers' article, long-term follow-up studies have found that after a stroke or TIA, patients have a greater risk of dying of a cardiac event than of a stroke.5,6 This suggests that data on myocardial infarction in the context of the medication being tested for secondary stroke prophylaxis should continue to be critically analyzed as a secondary outcome point.
REFERENCES
1. Solenski NJ. Transient ischemic attacks: part I. Diagnosis and evaluation. Am Fam Physician 2004;69:1665-74.
2. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
3. Nyman I, Larsson H, Wallentin L. Prevention of serious cardiac events by low-dose aspirin in patients with silent myocardial ischeamia. The Research Group on Instability in Coronary Artery Disease in Southeast Sweden. Lancet 1992;340:497-501.
4. Albers GW. Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients? Neurology 2000;54:1022-8.
5. Cartlidge NE, Whisnant JP, Elveback LR. Carotid and vertebral-basilar transient cerebral ischemic attacks. A community study, Rochester, Minnesota. Mayo Clin Proc 1977;52:117-20.
6. Prencipe M, Culasso F, Rasura M, Anzini A, Beccia M, Cao M, et al. Long-term prognosis after a minor stroke: 10-year mortality and major stroke recurrence rates in a hospital-based cohort. Stroke 1998;29:126-32.
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