Trial of Tissue Plasminogen Activator for Mortality Reduction in Acute Myocardial Infarction

Wilcox, Robert G.; Olsson, C.; Skene, A. M.; Lippe, G von der; Jensen, Gorm; Hampton, John R.

doi:10.1016/s0140-6736(88)92656-6

Cited by 1,035 publications

(165 citation statements)

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“…However, the events leading to such attack can be alleviated by suitable thrombolytic treatment with tissue plasminogen activator, urokinase, or streptokinase. Unfortunately these often induce acute thrombotic reocclusion (Chesebro et al, 1987;Verstraete et al, 1985;While et al, 1989;Wilcox et al, 1988). Although the mechanism of reocclusion is not known, the possible role of thrombus-bound thrombin, which is still active, has been proposed (Francis et al, 1983;Agnelli et al, 1991), indicating the need for potent and specific pharmacological agents.…”

mentioning

confidence: 99%

Design of Potent Bivalent Thrombin Inhibitors Based on Hirudin Sequence: Incorporation of Nonsubstrate-Type Active Site Inhibitors

Tsuda¹,

Cygler²,

Gibbs³

et al. 1994

Biochemistry

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Hirudin from medicinal leech is the most potent and specific thrombin inhibitor from medicinal leech with a K, value of 2.2 x M. It consists of an active site blocking moiety, hirudin'-48, a fibrinogen-recognition exo-site binding moiety, hir~din~~-~~, and a linker, hir~din~~-~~, connecting these inhibitor moieties. Synthetic inhibitors were designed based on the C-terminal portion of hirudin. The bulky active site blocking moiety, was replaced by small nonsubstrate-type active site inhibitors of thrombin, e.g., dansyl-Arg-(D-pipecolic acid). The linker moiety was replaced by o-amino acids of (12-aminododecanoic acid)-(4-aminobutyric acid), and hirudi~P-~~ was used as a fibrinogen-recognition exo-site binding moiety in most of the inhibitors. The crystal structure of the inhibitor in complex with human a-thrombin showed that dansyl, Arg, and D-pipecolic acid of the active site blocking moiety occupy S3, S1, and S2 subsites of thrombin, respectively, and were therefore designated as P3, P1, and P2 residues.The use of dansyl-Arg-(D-pipecolic acid) improved the affinity (KJ of the inhibitor 10-100-fold (down to 1.70 x lo-" M) compared to that of the similar compounds having D-Phe-Pro-Arg as their substratetype inhibitor moiety (K = 10-9-10-10 M). The linker connected to P2 residue eliminated the scissile peptide bond. The inhibitor was also stable against human plasma proteases. Further inhibitor design revealed that the toxic dansyl group could be replaced by 4-tert-butylbenzenesulfonyl group and 1-or 2-naphthalenesulfonyl group for in vivo studies. In addition, the replacement of hir~din~~-~~ with [TY~~~,-

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mentioning

confidence: 99%

Design of Potent Bivalent Thrombin Inhibitors Based on Hirudin Sequence: Incorporation of Nonsubstrate-Type Active Site Inhibitors

Tsuda¹,

Cygler²,

Gibbs³

et al. 1994

Biochemistry

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“…In other trials, a higher incidence of reinfarction than among controls was reported after thrombolytic therapy,8"12'1516 except in one trial. 17 In another trial, the reinfarction rate after alteplase was higher than that in the present study (18.1% at 1 year).18 In that trial, aspirin was started only 8-10 days after myocardial infarction, whereas reinfarctions tend to occur earlier (Table 1).…”

Section: Reinfarctionmentioning

confidence: 45%

Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. One-year follow-up. The European Cooperative Study Group.

et al. 1992

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BACKGROUND The European Cooperative Study Group conducted two randomized trials in patients with suspected myocardial infarction to assess the effect of 100 mg single-chain recombinant tissue-type plasminogen activator (rt-PA, alteplase) on enzymatic infarct size, left ventricular function, morbidity and mortality relative to placebo (alteplase/placebo trial) and to assess the effect of immediate percutaneous transluminal coronary angioplasty (PTCA) in addition to alteplase (alteplase/PTCA trial). One-year follow-up results are reported. METHODS AND RESULTS In the alteplase/placebo trial, 721 patients with chest pain of less than 5 hours and extensive ST-segment elevation were allocated at random to 100 mg alteplase or placebo (double-blind) over 3 hours. In the alteplase/PTCA trial, 367 similar patients received alteplase and subsequently were allocated at random to immediate coronary angiography and angioplasty of the infarct-related vessel or control. All patients received aspirin and intravenous heparin. In the alteplase/placebo trial, mortality during the first year was reduced by 36% with alteplase (from 9.3% to 5.6%; difference, -3.7%; 95% confidence interval, -7.5% to 0.2%). Revascularization was performed more frequently after alteplase, and more patients in the alteplase group were in New York Heart Association functional class I or II. Reinfarction tended to occur more frequently after alteplase than after placebo. In the alteplase/PTCA trial, reinfarction was less common after immediate PTCA, and revascularization procedures were less frequent. However, this benefit was offset by a high rate of immediate reocclusion and early recurrent ischemia and by higher mortality at 1 year (9.3% versus 5.4%; difference, 3.9%; 95% confidence interval, -1.5% to 9.2%) in the invasive group. In a multivariate analysis of 1,043 hospital survivors, mortality after discharge was related to coronary anatomy, left ventricular function, age, and previous infarction but not to initial treatment allocation. Reinfarction after hospital discharge tended to be more common after alteplase and related to coronary anatomy. CONCLUSIONS Benefit from treatment with alteplase, heparin, and aspirin is not diminished at 1 year. Routine immediate PTCA does not confer additional benefit. Prognosis after hospital discharge mainly is determined by coronary anatomy and residual left ventricular function and is unrelated to initial treatment assignment.

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“…In our experience at Chiba Hokusoh Hospital, 8 of 81 patients with AAD also had ACS (9.88%), which is more frequent than previously reported, indicating that only 0.26% of patients with ACS are diagnosed with AAD. 14 Sullivan et al 1 and Spittell et al 2 found that the rate of correctly diagnosing AAD in the ER was 40-60% and 62%, respectively.…”

Section: Diagnosis Of Aadmentioning

confidence: 99%

Diagnostic Score to Differentiate Acute Aortic Dissection in the Emergency Room

Shirakabe

Hata

Yokoyama

et al. 2008

Circ J

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cute aortic dissection (AAD) and acute coronary syndrome (ACS) are life-threatening cardiovascular emergencies that can be difficult to differentiate in the emergency room (ER), particularly if ACS is complicated with AAD, in which case the clinical signs of AAD may be overlooked. The diagnosis in the ER will affect the choice of treatment and, therefore, prognosis.Electrocardiography, cardiac ultrasonography, and myocardial markers can diagnose ACS, but the clinical symptoms and signs of AAD can be confusing. Enhanced computed tomography (CT) is valuable for diagnosis when AAD is suspected in the ER, although the rate of correct diagnosis has been reported as 40-74%. 1,2 Because AAD progresses to fatal complications within the first 48 h, mortality rates increase at the rate of 1-2% per hour. Other reports have indicated a 9-39% perioperative mortality rate for type-A AAD. [3][4][5] Thus, the correct differential diagnosis of AAD and ACS in the ER is critical 6,7 and the goal of the present study was to establish a diagnostic standard (ERAAD score) by clarifying information that is specific to AAD. Methods Study DesignStudy 1 In order to define the features of AAD and ACS we evaluated 131 patients with AAD or ACS who were admitted between April 2001 and March 2002. The clinical information included age, gender, presence of back pain, systolic and diastolic blood pressures (BP), serum creatine kinase level, ST-T segment changes on electrocardiograms (ECG), mediastinum thoracic ratio (MTR; Fig 1) and cardiothoracic ratio (CTR) on chest X-rays, and aortic regurgitation (AR) and aortic diameter on cardiac ultrasonograms, as well as history of smoking, hypertension, hyperlipidemia or diabetes mellitus. We scored the total number of indexes specific to AAD for each patient to obtain the ERAAD score. J 2008; 72: 986 -990 (Received October 20, 2007; revised manuscript received January 8, 2008; accepted January 17, 2008 Circ

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Trial of Tissue Plasminogen Activator for Mortality Reduction in Acute Myocardial Infarction

Cited by 1,035 publications

References 5 publications

Design of Potent Bivalent Thrombin Inhibitors Based on Hirudin Sequence: Incorporation of Nonsubstrate-Type Active Site Inhibitors

Design of Potent Bivalent Thrombin Inhibitors Based on Hirudin Sequence: Incorporation of Nonsubstrate-Type Active Site Inhibitors

Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. One-year follow-up. The European Cooperative Study Group.

Diagnostic Score to Differentiate Acute Aortic Dissection in the Emergency Room

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