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BRIEF COMMUNICATIONS: Richard Dubinsky and Sue-Min Lai Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample Neurology 2006; 66: 1742-1744 [Abstract] [Full text] [PDF]

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Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample

Tobias Kurth, Peter U. Heuschmann, Alexander M. Walker, and Klaus Berger.   (22 September 2006)

Mortality of stroke patients treated with thrombolysis

Matthew L. Flaherty, Brett Kissela, Pooja Khatri, Univ. of Cincinnati College of Med.   (22 September 2006)

Reply from the Authors

Richard M. Dubinsky, Sue M. Lai, Dept of Preventive Medicine and Public Health University of Kansas Med. Ctr.   (22 September 2006)

Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample 22 September 2006
Tobias Kurth, Division of Preventive Medicine, Brigham and Women's Hospital 900 Commonwealth Ave East, Boston MA 02215-1204, Peter U. Heuschmann, Alexander M. Walker, and Klaus Berger. Send Correspondence to journal: Re: Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample tkurth{at}rics.bwh.harvard.edu Tobias Kurth, et al.	Dubinsky and Lai found a 1.9-fold increase in the relative risk (RR) of mortality associated with treatment with tissue-type plasminogen activator (tPA) among patients with ischemic stroke. [1] We believe that several methodological issues impact the interpretation of the results. First, Dubinsky and Lai could not adjust for the confounding effect of stroke severity, which may partly have overestimated the association between tPA and mortality. [2,3] Moreover, they did not account for the individual hospital’s experience in treating stroke patients with tPA. The number of thrombolyses performed at a hospital is inversely related to in- hospital mortality. [3] Second, to report a single RR for the association between tPA and mortality across a very heterogeneous patient population is problematic. In our analyses of a German stroke registry, there was a subgroup of patients with very poor prognosis in whom tPA appeared to have been given as a last resort, and in whom tPA was associated with a poor outcome. The estimated RR of mortality associated with tPA changed dramatically when different adjustment methods were used that did or did not account for the tPA treatment effect among patients with poor prognosis. [4] For example, we found an 11-fold increased risk in mortality when we estimated what would have happened had every ischemic stroke patient been treated with tPA versus none. In contrast, the comparison between the experience of tPA-treated patients and the calculated outcomes had those same patients not been treated showed no association with mortality. Dubinsky and Lai present a RR that was estimated from a logistic regression that did not specify a covariate- treatment interaction term. [1] We also found an intermediate effect estimate (RR=1.93) when we used a similar logistic regression model. [4] Because the effect of tPA on mortality varies so much between different patient groups, reporting a single RR from a logistic regression model does not produce a clinically meaningful result for this particular example. A recent study showed that utilized that same data-base as Dubinsky and Lai and found similar mortality and intracerebral hemorrhage rates. [2] The authors come to a divergent conclusion that the observed rates are similar to the rates reported from prospective trials and large observational studies [3,5] and that thrombolysis has a safety profile similar to that observed in large clinical trials. [2] References 1. Dubinsky R, Lai SM. Mortality of stroke patients treated with thrombolysis: analysis of nationwide inpatient sample. Neurology. 2006;66:1742-4. 2. Bateman BT, Schumacher HC, Boden-Albala B, et al. Factors associated with in-hospital mortality after administration of thrombolysis in acute ischemic stroke patients: an analysis of the nationwide inpatient sample 1999 to 2002. Stroke. 2006;37:440-6. 3. Heuschmann PU, Kolominsky-Rabas PL, Roether J, et al. Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. JAMA. 2004;292:1831-8. 4. Kurth T, Walker AM, Glynn RJ, et al. Results of multivariable logistic regression, propensity matching, propensity adjustment, and propensity-based weighting under conditions of nonuniform effect. Am J Epidemiol. 2006;163:262-70. 5. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. 2003;34:2847 -50. Disclosure: Dr. Kurth has received investigator-initiated grants from Bayer AG, McNeil Consumer & Specialty Pharmaceuticals, and Wyeth Consumer HealthCare for studies evaluating the risk and benefit of analgesics. He is a consultant to i3 Drug Safety and has recieved an honorarium from Organon for contributing to an expert panel. Dr. Heuschmann has received an honorarium for a lecture from Solvay. Dr. Walker's drug safety group has conducted sponsored research for every major pharmacuetical manufacturer over the past decade. Dr. Berger has received an investigator-initiated research grant for an epidemiologic migraine study from a consortium formed by Allmiral, Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Boots Healthcare, Glaxo-Smith-Kline, Janssen, McNeil, MSD Sharp & Dohme, and Pfizer, and has received a research grant to study quality of life in Parkinson Diease from Hoffmann-LaRoche.
Mortality of stroke patients treated with thrombolysis 22 September 2006
Matthew L. Flaherty, University of Cincinnati College of Medicine 231 Albert Sabin Way, MSB Room 5060, University of Cincinnati College of Med, Cincinnati, OH, 45267, Brett Kissela, Pooja Khatri, Univ. of Cincinnati College of Med. Send Correspondence to journal: Re: Mortality of stroke patients treated with thrombolysis matthew.flaherty{at}uc.edu Matthew L. Flaherty, et al.	We disagree with the conclusions of the recent report by Drs. Dubinsky and Lai on mortality and hemorrhage risk after thrombolysis for acute ischemic stroke. [1] The authors used the Charlson index to adjust for medical comorbidities among stroke patients identified in the National Inpatient Sample (NIS) but they could not adjust for stroke severity, likely the most important factor influencing outcome after stroke. [6] The landmark NINDS rt-PA Stroke Trial demonstrated a reduction in morbidity but not in mortality among patients treated with thrombolysis. [7] However, patients treated with rt-PA have (on average) more severe strokes than patients not treated with thrombolysis. [8] (This effect is also documented in our unpublished, population-based data). Mild or rapidly improving stroke symptoms are often cited by clinicians as reasons rt-PA is not administered. Without an index of stroke severity, mortality rates for NIS patients receiving thrombolysis cannot be meaningfully compared to NIS patients not receiving thrombolysis, nor to other randomized studies, cohort studies, or population-based reports. We are further puzzled by the concluding statement of Dr. Dubinsky’s abstract, "US community experience in the use of thrombolysis has higher rates of complications and mortality than in controlled clinical trials." [1] The intracranial hemorrhage rate among rt-PA treated patients from the NIS was lower than among rt-PA treated patients in the NINDS rt- PA Stroke Trial (4.2% vs. 6.4%). [1,7] The mortality rate was also lower in the NIS although the time frame reported was not comparable (in-hospital mortality of 10.1% in the NIS vs. 3-month mortality of 17% in the NINDS rt -PA Stroke Trial). [1,7] A meta-analysis of open-label studies of rt-PA administered using the NINDS rt-PA Stroke Trial protocol showed hemorrhage rates and mortality comparable to the trial data. [5] Patients in the meta- analysis had a median baseline NIH Stroke Scale score equivalent to patients in the NINDS rt-PA Stroke Trial (14). [5,7] Finally, the use of procedure code 99.10 to identify patients treated with rt-PA is suspect. Because this code provided no additional revenue to hospitals before approval of the new DRG 559, it was sporadically used in rt-PA treated patients (showing a sensitivity of only 50% in one study), and it cannot be assumed that its application was randomly distributed among patients. [8] We agree that the translation of results from clinical trials to clinical practice is important but methodological issues make the study by Dubinsky and Lai unhelpful. References 6. Frankel MR, Morgenstern LB, Kwiatkowski T, Lu M, Tilley BC, Broderick JP, Libman R, Levine SR, Brott T. Predicting prognosis after stroke: a placebo group analysis from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial. Neurology 2000;55:952-959. 7. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581-1587. 8. Johnston SC, Fung LH, Gillum LA, Smith WS, Brass LM, Lichtman JH, Brown AN. Utilization of intravenous tissue-type plasminogen activator for ischemic stroke at academic medical centers: the influence of ethnicity. Stroke 2001;32:1061-1068. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 22 September 2006
Richard M. Dubinsky, University of Kansas Medical Center, Dept. of Neurology 3599 Rainbow Blvd, Mail Stop 2012, Kansas City, KS 66160, Sue M. Lai, Dept of Preventive Medicine and Public Health University of Kansas Med. Ctr. Send Correspondence to journal: Re: Reply from the Authors rdubinsk{at}kumc.edu Richard M. Dubinsky, et al.	We appreciate the comments of Dr. Kurth et al and Dr. Flaherty et al. The purpose of our study was to determine the community wide utilization of thrombolysis and in hospital mortality. [1] The main limitation of our study was the lack of a measure of stroke severity and we acknowledged that this has a major effect on the decision to use thrombolysis and on survival. However, the rate of utilization of thrombolysis, morbidity and mortality in this nationwide sample are important to determine the utilization and potential benefit. Co-morbidities (including those due to atherosclerosis) were controlled for by the Charlson index, a validated tool used to examine mortality in similar datasets. [9] The mortality associated with thrombolysis varies between community studies and controlled clinical trials and is dependent on the length of follow- up. In a meta-analysis of controlled trials the mortality was 8.6% within seven to ten days, which is lower than what we have reported with a similar follow-up. [10] Our report of a ~20% sample of all US hospitalizations found a rate similar to that reported in Germany [11] but less than what was reported in community hospitals in Cleveland. [12] We did not control for hospital experience, due to changes in hospitals selected for the NIS from year to year. A recent study, using the NIS, controlled for hospital volume of strokes and of thrombolysis, reported that these did not predict morality. [2] Their results were similar to ours. Case ascertainment is a major source of bias in community studies. There is a potential for under and for over reporting. In the only study comparing chart abstraction to an administrative database the specificity of thrombolysis was 50% (17/34 cases) while the sensitivity was 100%. [8]However, the results of this study of convenience samples of 30 consecutive stroke admissions from 42 academic medical centers involved in a quality improvement project on stroke therapy can’t be generalized to judge the accuracy of the NIS. While we may have missed some cases, we eliminated many that were most likely miscoded, based on age, type of admission, and co-morbidities. There is no reason to suspect that any missed cases would alter our results. The recent implementation of a DRG for stroke thrombolysis will aid research in the effects of thrombolysis in community hospitals. This will help to determine if the benefit seen in controlled clinical trials can be extended to community experience with thrombolysis. References 9. Charlson M, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies. Development and validation. J Chronic Dis 1987;40:373-383. 10. Wardlaw J, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke (Cochrane Review). Chichester, UK: John Wiley & Sons, Ltd, 2003 14 March 2003. 11. Heuschmann PU, Berger K, Misselwitz B, Hermanek et al. Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality: the German Stroke Registers Study Group. Stroke 2003;34:1106-1113. 12. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283:1151-1158. < Disclosure: The authors report no conflicts of interest.