Thrombolytic Trials Research Articles

“Two per cent isn’t a lot, but when it comes to death it seems quite a lot anyway”: patients’ perception of risk and willingness to accept risks associated with thrombolytic drug treatment for acute stroke

Background:Thrombolytic drugs to treat an acute ischaemic stroke reduce the risk of death or major disability. The treatment is, however, also associated with an increased risk of potentially fatal intracranial...

A 50-Year Research Journey From Laboratory to Clinic

Prior important research is not always cited, exemplified by Oswald Avery's pioneering discovery that DNA is the genetic transforming factor; it was not cited by Watson and Crick 10 years later. My first laboratory research (National Institutes of Health 1950s) resulted in the clinical development of transseptal left heart catheterization. Laboratory studies on cardiac muscle mechanics in normal and failing hearts led to the concept of afterload mismatch with limited preload reserve. At the University of California, San Diego in La Jolla (1968) laboratory experiments on coronary artery reperfusion after sustained coronary occlusion showed salvage of myocardial tissue, a potential treatment for acute myocardial infarction proven in clinical trials of thrombolysis 14 years later. Among 60 trainees who worked with me in La Jolla, one-third were Japanese and some of their important laboratory experiments are briefly recounted, beginning with Sasayama, Tomoike and Shirato in the 1970 s. Recently, we developed a method for cardiac gene transfer, and subsequently we showed that gene therapy for the defect in cardiomyopathic hamsters halted the progression of advanced disease. Cardiovascular research and medicine are producing continuing advances in technologies for gene transfer and embryonic stem cell transplantation, targeting of small molecules, and tissue and organ engineering.

Comparison of Mechanical Embolectomy and Intraarterial Thrombolysis in Acute Ischemic Stroke within the MCA: MERCI and Multi MERCI compared to PROACT II

Intraarterial thrombolysis and mechanical embolectomy have been studied for endovascular treatment of stroke. The MERCI and Multi MERCI trials of mechanical embolectomy with or without adjuvant intraarterial thrombolysis demonstrated effective recanalization, but with a higher mortality compared with control patients in the PROACT II trial of intraarterial thrombolysis. Differences in trial design may account for this mortality difference. We identified patients in the MERCI and Multi MERCI trials who would have been eligible for PROACT II. Rates of good outcome (mRS < or =2) and mortality at 90 days were compared, adjusting for differences in baseline NIHSS score and age. Sixty-eight patients enrolled in MERCI and 81 enrolled in Multi MERCI were eligible for PROACT II. In both unadjusted and adjusted analyses, PROACT II-eligible embolectomy patients showed a trend toward better clinical outcomes compared to the PROACT II control arm (adjusted, MERCI 35.4% [p = ns], Multi MERCI 42.8% [p = 0.048], PROACT II control, 25.4%). In both unadjusted and adjusted analyses, mortality rates did not significantly differ between embolectomy patients and PROACT II control patients (adjusted analysis, MERCI 29.1%, Multi MERCI 18.0%, PROACT II control, 27.1%). Compared with the PROACT II treatment group, embolectomy groups showed similar rates of good outcome and mortality. Differences in mortality and proportion of good outcome between the MERCI/Multi MERCI trials and the PROACT II trial are explained by differences in study design and baseline characteristics of patients. Mechanical embolectomy and IA thrombolysis may each be reasonable strategies for acute stroke; a randomized trial is necessary to confirm these results.

“I don’t like that, it’s tricking people too much…”: acute informed consent to participation in a trial of thrombolysis for stroke

Background:Informed consent is regarded as a contract between autonomous and equal parties and requires the elements of information disclosure, understanding, voluntariness and consent. The validity of informed consent for critically...

Effectiveness and cost effectiveness of thrombolysis in patients with acute pulmonary embolism

Acute pulmonary embolism is a common, life-threatening, cardiopulmonary disorder with a high mortality rate within the first 3 months of diagnosis. As prompt anticoagulation is the mainstay of therapy in patients with pulmonary embolism, the clinical utility and cost effectiveness of systemic thrombolysis is debated. Pulmonary embolism with cardiogenic shock and hypotension is characterized as 'massive' in nature and an accepted indication for thrombolysis, although catheter-directed embolectomy with or without local lytic therapy is preferred in centers with appropriate experience. Acute right ventricular dysfunction is a poor prognostic indicator in patients with pulmonary embolism. The most recent randomized controlled trial of systemic thrombolysis in patients with submassive pulmonary embolism and right ventricular dysfunction found that, compared with heparin alone, alteplase and heparin reduced the risk of clinical deterioration requiring treatment escalation, but did not reduce the risk of death. Subsequently, a formal cost effectiveness concluded that alteplase and heparin was slightly less effective and marginally more expensive than heparin alone in this patient population. Current evidence does not support the use of thrombolytic agents in most hemodynamically stable patients with right ventricular dysfunction. However, improved methods of risk stratification may help to identify subgroups of patients at high risk of death that might benefit from systemic thrombolysis.

The smoker’s paradox after successful fibrinolysis: reduced risk of reocclusion but no improved long-term cardiac outcome

In smokers treated with fibrinolysis for ST-elevation myocardial infarction (STEMI) a paradoxical beneficial short-term outcome has been reported. This was attributed to favorable clinical and angiographic baseline variables and a better response to fibrinolysis. During follow-up infarct artery reocclusion is an important prognosticator. We studied the effects of smoking on reocclusion and long-term cardiac outcome after successful fibrinolysis. In the Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis trials (APRICOT-1 and -2) 499 STEMI patients with an open infarct artery <48 h after fibrinolysis received randomized antithrombotic treatment until 3-month follow-up angiography. Five-year clinical follow-up was complete. Current smokers (317 patients, 64%) had favorable clinical (age 54 vs. 60 years, P < 0.01) and angiographic (single vessel disease 61% vs. 49%, P = 0.02) baseline characteristics. Reocclusion rates were 21% (67/317) in smokers versus 32% (59/182) in non-smokers (P < 0.01). Five-year infarct-free cardiac survival did not differ: 82% vs. 85%. Reocclusion (HR 2.41, 95%CI 1.05-5.56, P = 0.04) independently predicted cardiac mortality. Smoking was independently associated with a reduced risk of reocclusion (OR 0.58, 95%CI 0.37-0.91, P = 0.02), but not with improved 5-year cardiac outcome (HR 1.34, 95%CI 0.79-2.25, P = ns). After successful fibrinolysis, smoking is independently associated with a more than 40% reduced risk of reocclusion, which is an independent predictor of adverse outcome. However, even with more favorable baseline characteristics smokers did not have improved 5-year cardiac outcome in this low-risk population.

Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke.

BackgroundIntravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit.Trial proceduresPatients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24–48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0–2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol).Trial registrationISRCTN25765518

Sustained coronary patency after fibrinolytic therapy as independent predictor of 10-year cardiac survival: Observations from the Antithrombotics in the Prevention of Reocclusion in COronary Thrombolysis (APRICOT) trial

Whether late coronary patency after myocardial infarction has prognostic impact independent of left ventricular function remains a matter of debate. Reocclusion rates in the first year after fibrinolysis vary between 20% and 30%. Of all reocclusions, about 30% present as clinical reinfarction, associated with a 2-fold-increased risk of mortality. The clinical impact of reocclusion that presents without reinfarction has not been studied; but an association has been demonstrated with impaired contractile recovery of left ventricular function, the strongest prognosticator of long-term outcome. We therefore studied the impact of 3-month coronary patency after successful fibrinolysis on 10-year cardiac survival. In the APRICOT-1 trial, 248 ST-elevation myocardial infarction patients with an open infarct artery 24 hours after fibrinolysis had 3-month repeated angiography. Ten-year clinical follow-up was complete in 99.6%. The reocclusion rate was 29% (71/248). Of these reocclusions, 24% presented as clinical reinfarction (17/71). Cardiac survival at 10 years was 73% in patients with a reoccluded infarct artery and 88% in patients with sustained patency (P < .01). This difference was also present in patients in whom reocclusion was only detected as a result of systematic repeated angiography, that is, in the absence of reinfarction or ischemic symptoms between angiograms (70% vs 86%, P < .03). Multivariable analysis identified sustained patency at 3-month angiography as independent predictor of 10-year cardiac survival (hazard ratio 2.10, 95% CI 1.10-4.02) together with left ventricular ejection fraction. Sustained infarct artery patency in the first 3 months after successful fibrinolysis is a strong predictor of 10-year cardiac survival, independent of left ventricular function. Notably, this also holds true when reocclusion occurs without signs of clinical reinfarction or recurrent ischemia. Therefore, future preventive strategies should also focus on "clinically silent" reocclusions. Additional studies on better antithrombotic regimens and the combination with a routine invasive strategy early after successful fibrinolysis are warranted.

Pathophysiology of ischaemic stroke: insights from imaging, and implications for therapy and drug discovery

Preventing death and limiting handicap from ischaemic stroke are major goals that can be achieved only if the pathophysiology of infarct expansion is properly understood. Primate studies showed that following occlusion of the middle cerebral artery (MCA)--the most frequent and prototypical stroke, local tissue fate depends on the severity of hypoperfusion and duration of occlusion, with a fraction of the MCA territory being initially in a 'penumbral' state. Physiological quantitative PET imaging has translated this knowledge in man and revealed the presence of considerable pathophysiological heterogeneity from patient to patient, largely unpredictable from elapsed time since onset or clinical deficit. While these observations underpinned key trials of thrombolysis, they also indicate that only patients who are likely to benefit should be exposed to its risks. Accordingly, imaging-based diagnosis is rapidly becoming an essential component of stroke assessment, replacing the clock by individually customized management. Diffusion- and perfusion-weighted MR (DWI-PWI) and CT-based perfusion imaging are increasingly being used to implement this, and are undergoing formal validation against PET. Beyond thrombolysis per se, knowledge of the individual pathophysiology also guides management of variables like blood pressure, blood glucose and oxygen saturation, which can otherwise precipitate the penumbra into the core, and the oligaemic tissue into the penumbra. We propose that future therapeutic trials use physiological imaging to select the patient category that best matches the drug's presumed mode of action, rather than lumping together patients with entirely different pathophysiological patterns in so-called 'large trials', which have all failed so far.

Acute Ischaemic Stroke in Patients Aged 80 Years and Older

Ischaemic stroke is a devastating disease in the elderly with 30-50% 90-day mortality. Thrombolysis for stroke is potentially life saving and disability sparing in this group but the number of elderly patients studied in clinical trials, particularly those aged > or = 80 years, has been small. Indeed, < 50 patients aged > 80 years have been treated in clinical thrombolytic trials of ischaemic stroke. However, there is no evidence of a differential treatment effect by age. Multiple cohort studies have suggested that the risk of symptomatic intracerebral haemorrhage among octogenarians is no different from that in younger patients. Thrombolysis can be safely offered to acute ischaemic stroke patients aged > or = 80 years, although robust data from randomized clinical trials are relatively scarce.

In Vitro Evaluation of Dual Mode Ultrasonic Thrombolysis Method for Transcranial Application with an Occlusive Thrombosis Model

A recent clinical trial of transcranial low-frequency ultrasound-mediated tPA thrombolysis (LFUT) showed cerebral hemorrhages associated with high spatial peak pulse average intensity (I SPPA), wide beam and long pulse duration. We developed an alternative approach to LFUT wherein diagnostic power M-mode Doppler (PMD) ultrasound is combined with LFUT, with a goal of increased safety. The effectiveness of such a dual mode ultrasonic thrombolysis (DMUT) was explored in vitro. The DMUT system emitted PMD (2 MHz) and LFUT (550 kHz) beams in alternating fashion from a small 12 mm diameter probe. The LFUT had a low I SPPA (2 W/cm 2) and a short pulse duration (55 μs). Occlusive clots made in plastic tips from bovine plasma and thrombin were placed in flow models pressurized to 800 mH 2O, with 600 IU/mL monteplase injected upstream. Recanalization times were then compared among three groups: the control (monteplase alone), PMD (monteplase + PMD) and DMUT (monteplase + PMD + LFUT). The capability of the DMUT device to monitor recanalization was demonstrated by observing with Doppler the degree of flow of a blood-mimicking fluid in the vicinity of the clot. Recanalization times were 37.9 ± 22.9, 38.9 ± 12.4 and 18.5 ± 8.0 min, respectively, for the control, PMD and DMUT. There were significant differences between DMUT and the control ( p = 0.0004) and between DMUT and PMD ( p = 0.0004). Recanalization flows were clearly detected. It is anticipated that this DMUT method presents a safer and more efficient approach than normal LFUT. (E-mail: furuhata@jikei.ac.jp)

Does MR Imaging Improve Precision in Stroke Thrombolysis Trials?

Summary: On the basis of these data, it appears that MR imaging can assist in measuring the effect of thrombolytic therapy. This has immediate application to laboratory and clinical trials of experimental treatment. The application of this imaging approach to routine patient care will depend on the still unknown value of predicting the infarct size and the ischemic penumbra in choosing therapy for patients with this difficult problem.

Thrombolytic therapy for acute ischemic stroke

The treatment of acute stroke changed dramatically since the publication of the NINDS trail for IV rt-PA for acute stroke. While this was not the first trial, it was the first positive trial. Subsequently there has been an explosion in acute treatment modalities since the NINDS trial showed that acute stroke treatment is feasible. The following chapter reviews the thrombolysis trials, the inclusion and exclusion criteria of intravenous and intra-arterial use of pharmacologic and mechanical thrombolysis in acute ischemic stroke. Also discussed are the new pharmacotherapies and mechanical devices that will hopefully expand the treatment window and make thrombolysis safer and more effective.

Mismatch and Defuse

See related article, pages 1826–1830. The goal of acute stroke evaluation is to determine not only stroke type (ischemic versus hemorrhagic) and localization (anatomical and vascular), but perhaps more importantly, to determine reversibility (presence of an ischemic penumbra that may be salvaged with acute therapy). Traditionally, neurologists have relied on history and neurological examination to provide much of this information. However, long experience has demonstrated that the neurological examination is imperfect at best in determining lesion localization and grossly limited in its ability to provide insights into the presence of penumbral tissue. This is evidenced by the only modest correlations between National Institutes of Health Stroke Scale (NIHSS) score and perfusion-weighted imaging lesion volume.1,2 The last decade has seen a striking growth in neuroimaging techniques that provide important real-time information about acute stroke pathophysiology. In the mid-1990s the advent of diffusion-weighted imaging revolutionized the role of MRI in acute stroke evaluation. Not …

Rescue angioplasty for failed thrombolysis in older patients: Insights from the REACT trial

Background Thrombolysis remains the first-line therapy in a substantial proportion of patients presenting with ST elevation myocardial infarction. The optimal treatment for patients in whom there is failure of reperfusion following thrombolysis is unclear. The Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis (REACT) trial demonstrated, in 427 randomly assigned patients with failed reperfusion following thrombolysis, that event-free survival rates were significantly improved with rescue angioplasty compared with either repeat thrombolysis or conservative treatment. However, the safety and efficacy of rescue angioplasty among older patients remains uncertain. Methods and results We aimed to determine whether rescue angioplasty was safe and effective in an older population, by evaluating the primary and secondary clinical outcomes among the 105 patients ≥ 70 years of age in the REACT trial. We observed an increased overall 6-month event rate among older patients. The relative benefit of rescue angioplasty versus repeat thrombolysis or conservative treatment was maintained, and the absolute benefit actually increased in this older age group compared with the study population as a whole. There was no adverse impact of advanced age on bleeding complications. Repeat thrombolysis was no more effective than conservative therapy. Conclusions Rescue angioplasty is the preferred management strategy for failed thrombolysis, even for patients ≥ 70 years of age.

Lack of experience of intravenous thrombolysis for acute ischaemic stroke does not influence the proportion of patients treated

Objectives: To determine the eligibility of patients with ischaemic stroke admitted to the 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, for intravenous thrombolysis; to identify the...

Reperfusion in Acute Myocardial Infarction: How is the Future Shaping up?

Current evidence from several clinical trials indicates that primary angioplasty in patients with acute myocardial infarction (AMI) appears superior reperfusion therapy to immediate thrombolysis, even when transfer to an angioplasty center is necessary. Thus, organization of ambulance systems and adequate angioplasty facilities appears to be the key issue in providing the most effective contemporary reperfusion therapy for AMI. Furthermore, on-site primary coronary angioplasty in high-risk AMI patients at hospitals with no cardiac surgery on-site is nowdays considered safe, effective, and faster than angioplasty after transfer to a surgical facility. Randomized trials have demonstrated the superiority of primary angioplasty with stent implantation over balloon angioplasty alone in the treatment of AMI, including patients with diabetes. Stent use has been associated with significant decreases in length of stay, major adverse cardiovascular events, and in-hospital mortality. Finally, because of the risk of stent thrombosis, the issue of whether drug-eluting stents are safe or even more beneficial than bare-metal stents in patients with AMI, as in other non-AMI patient groups, remains uncertain, although preliminary data seem to favour the use of drug-eluting stents. I N T R O D U C T I O N Acute myocardial infarction (AMI) has been associated with thrombotic occlusion of a coronary artery as early as in 1793 when an autopsy was performed on Sir James Hunter, a famous surgeon who died suddenly following a violent argument with hospital administrators in London. The term “acute coronary thrombosis” was well established in medical literature and its connotation was reaffirmed following the seminal study of DeWood et al in 1980. Thrombolytic agents were discovered in the 1950s and, following long debates about their clinical benefits, they entered clinical routine in 1986. However, it is now evident that although fresh thrombus represents the major pathological finding in acutely occluded coronary arteries, it is found in less than 70% of the cases. This is in keeping with the current success rates of thrombolytic trials that, even with the use of aggressive protocols, result in restoration of normal coronary flow (TIMI 3) in only 60 to 70% of the cases. It seems that a considerable proportion of AMI might be due to spontaneous dissection and/or severe intramural EDITORIAl Department of Cardiology, Athens Euroclinic, Athens, Greece, & St Thomas’ Hospital, London, England HOSPITAL CHRONICLES 2007, 2(4): 143–150

Review of the Current Status of Intra-Arterial Thrombolysis for Treating Acute Cerebral Infarction: a Retrospective Analysis of the Data from Multiple Centers in Korea

ObjectiveThe purpose of the study was to review the current status of intra-arterial (IA) thrombolysis in Korea by conducting a retrospective analysis of the data from multiple domestic centers.Materials and MethodsThe radiologists at each participating institution were asked to fill out case report forms on all patients who had undergone IA recanalization due to acute anterior circulation ischemia. These forms included clinical, imaging and procedure-related information. A central reader analyzed the CT/MR and angiographic results. The rates of successful recanalization, hemorrhagic transformation and functional outcome were obtained. The univariate analyses were performed together with the multivariate analysis.ResultsWe analyzed the data from 163 patients, and they had been treated at seven institutes. The initial imaging modalities were CT for 46 patients (28%), MR for 63 (39%), and both for 54 (33%). Various mechanical treatment methods were applied together in 50% of the patients. Radiologically significant hemorrhage was noted in 20/155 patients (13%). We found various factors that influenced the recanalization rate and the occurrence of significant hemorrhagic transformations. The favorable outcome rate, reported as modified Rankin Scale ≤ 2, was 40%, and the mortality rate was 11%. The factors that predicted a poor functional outcome were old age (p = 0.01), initially severe neurological symptoms (p < 0.0001), MR findings of a wide distribution of lesions (p = 0.001), involvement of the basal ganglia (p = 0.01), performance of procedures after working hours (p = 0.01), failure of recanalization (p = 0.003), contrast extravasation after the procedure (p = 0.007) and significant hemorrhagic transformation (p = 0.002). The subsequent multivariate analysis failed to show any statistically significant variable.ConclusionThere was a trend toward increased dependency on MR imaging during the initial evaluation and increased usage of combined pharmacologic/mechanical thrombolysis. The imaging and clinical outcome results of this study were comparable to those of the previous major thrombolytic trials.

Acute stroke: we have the treatments and we have the evidence – we need to use them

Despite huge global burden, stroke disease has traditionally received little attention in the general medical press. We review a series of four acute stroke research articles published in a themed issue of the Lancet. Claiborne-Johnston and coworkers presented a scoring system to stratify risk of stroke following transient ischaemic attack. Chalela and colleagues demonstrated that magnetic resonance imaging is superior to computed tomography in detecting acute ischaemic stroke and that fears of missing intracranial haemorrhage are unfounded. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke – Monitoring Study) group reported positive experience of translating acute stroke thrombolysis trials into routine clinical practice in Europe, and the PROSIT (Project on Stroke Services in Italy) group studied acute effects of admission to a dedicated stroke unit. The message from all of these reports is that evidence-based, successful management of acute stroke is possible, and that investment in health infrastructure and changing mind sets of health practitioners to improve stroke care will deliver benefits.

Intravenous thrombolysis in stroke patients of ≥80 versus &lt;80 years of age—a systematic review across cohort studies

elderly stroke patients were excluded or underrepresented in the randomised controlled trials of intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) applied within 3 h. Cohort studies comparing intravenous rtPA in stroke patients of >/=80 versus <80 years of age were limited by small sample sizes and yielded conflicting results. Thus, we performed a systematic review across all such studies. a systematic literature search (PubMed; Science Citation Index) was performed to retrieve all eligible studies. Two reviewers independently extracted data on 'death', 'favourable 3-month outcome (modified Rankin Scale </=1)' and 'symptomatic intracranial haemorrhage (sICH)'. Across studies, weighted odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated. six studies were included [n = 2,244 patients; 477 (21%) aged >/=80 years]. Significant differences in baseline characteristics to the disadvantage of older patients were present in all studies. Compared with younger patients, older patients had a 3.09-time (95% CI = 2.37-4.03; P < 0.001) higher 3-month mortality and were less likely to regain a 'favourable outcome' (OR = 0.53; 95% CI = 0.42-0.66; P<0.001). The likelihood for 'sICH' (OR = 1.22; 95% CI = 0.77-1.94; P = 0.34) was similar in both age groups. intravenous rtPA-treated stroke patients of >/=80 years of age have a less favourable outcome than younger ones. Imbalances in predictive baseline variables to the disadvantage of the older patients may contribute to this finding. Compared with the younger cohort, rtPA-treated stroke patients aged >/=80 years do not seem exceedingly prone to sICH. Thus, there is scope for benefit from thrombolysis for the older age group. Hence, to obtain reliable evidence on the balance of risk and benefit of intravenous rtPA for stroke patients aged >/=80 years, it is safe and reasonable to include such patients in randomised placebo-controlled trials.