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CLINICAL STUDIES |
From the Texas Tech University Health Sciences Center Schools of Pharmacy (Dr. Tsikouris, Mr. Ziska, Mr. Fike) and Medicine (Dr. Suarez, Dr. Meyerrose, Dr. Smith), Lubbock, Texas.
Address for reprints: James P. Tsikouris, PharmD, Assistant Professor of Pharmacy Practice, Texas Tech University School of Pharmacy, 3601 4th Street, Suite 1C162, Lubbock, TX 79430.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Myocardial infarction • plasminogen activator inhibitor • ACE inhibitor
Activation of the renin-angiotensin system and, specifically, angiotensin-II stimulates production of plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of the endogenous fibrinolytic, tissue plasminogen activator (t-PA).7 Elevated PAI-1 levels may contribute to recurrent thrombosis after an index AMI.8,9 More important, lower PAI-1 levels may be associated with a decreased incidence of reinfarction.8,10 As with the interaction between angiotensin-II and PAI-1, t-PA production may be augmented in the setting of increased bradykinin levels.7 ACE inhibition reduces angiotensin-II and increases bradykinin concentrations, thus allowing for potentially favorable alterations in the fibrinolytic balance following AMI, with a decrease in PAI-1 and an increase in t-PA production.
Although various investigators have demonstrated such changes in PAI-1 and t-PA with ACE inhibitor therapy,11-17 a head-to-head comparison of ACE inhibitors with different pharmacodynamic properties, exploring their relative fibrinolytic effects, has not been performed. Some of the nine U.S. FDA-approved agents within this class vary markedly in their ability to penetrate and inhibit vascular tissue ACE.18-21 It is documented that tissue-penetrating differences between the "high-tissue-penetrating" quinapril and "low-tissue-penetrating" enalapril, while equally reducing plasma-ACE, provide greater decreases in vascular-ACE with quinapril.19,22 This may be critical since PAI-1 and t-PA are at least in part synthesized locally in endothelial and smooth muscle tissue of the vascular wall.23-25 Also, the renin-angiotensin system and bradykinin are highly localized in vascular tissue.26 Because vascular tissue is a source of PAI-1 and t-PA, and a high concentration of target sites for ACE inhibitors are localized within the vascular tissue beds, ACE inhibitors with varied degrees of tissue penetration and blockade of vascular tissue ACE may differ in their propensity to inhibit production of PAI-1 and increase t-PA.
This investigation was used to determine how two ACE inhibitors with varied degrees of vascular tissue penetration influence fibrinolytic factors in the early time period following an AMI. On the basis of previous literature, we hypothesized that attenuation of PAI-1 production and augmentation of bradykinin-mediated t-PA production with ACE inhibitors in AMI patients are dependent on the increasing capacity of these agents to penetrate vascular tissue.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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18 years of age enrolled over an 8-month time period from the Texas Tech University Medical Center who were experiencing the following: chest pain onset < 24 hours associated with 1-mm ST-segment elevation in 2 contiguous electrocardiographic leads; new left bundle branch block; new, evolving pathologic Q-waves; or elevated plasma levels of cardiac-specific enzymes. The Human Subjects Institutional Review Board at our institution approved this study, and all subjects gave written informed consent. Patients were ineligible for enrollment if they had a medical history of heart failure, a contraindication for ACE inhibitor therapy, blood pressure < 100/60 mmHg at screening, serum creatinine > 2.0 mg/dL, or history of noncompliance with medications. Also, patients currently taking an ACE inhibitor, angiotensin receptor antagonist, or hormone replacement therapy were excluded.
Patients were randomly assigned to receive 14 days of treatment with either quinapril or enalapril. To ensure balanced treatment arms, stratification based on age (< or 60 years) and history of diabetes mellitus was performed. The equipotent minimally recommended starting dose of quinapril and enalapril was 5 mg and 2.5 mg, respectively, and was initiated within 6 hours of receiving informed consent. The second dose of quinapril and enalapril, given 12 hours later, was 10 mg and 5 mg, respectively, and administered every 12 hours times two doses. Subsequent doses were administered every 12 hours and titrated upward in 24-hour intervals. Equipotent dose titration for quinapril and enalapril proceeded in 10-mg and 5-mg dose increments, respectively. The equipotent target maximum doses were quinapril 40 mg and enalapril 20 mg every 12 hours. Patients who did not tolerate a specific dose due to excessive blood pressure reduction were returned to the prior dose level, and dose escalation was attempted again in 24 hours. Medication compliance was assessed in all patients using pill counts at each visit.
Comprehensive sample analysis (baseline, 12-h, days 1, 2, 3, 7, and 14) was available for 23 of the 30 patients. In the quinapril group, analysis was available for all 15 patients for the baseline and day 1 sample periods, with 13 of the 15 samples available for the 12-hour blood draw. One patient in the quinapril group underwent open-heart surgery after the day 1 blood draw, and therefore day 2, 3, 7, and 14 blood draws were not available for that patient. In the enalapril group, analysis was available for all 15 patients for the baseline, day 1, day 7, and day 14 samples. Twelve of the 15 samples were available for analysis in the 12-hour blood draw time period, and 14 of 15 samples were available for both the day 2 and day 3 blood draws.
Blood Sampling
PAI-1 antigen and t-PA antigen were measured in all patients. Blood samples for measuring these parameters were obtained at baseline and then 12 hours, 1 day, 2 days, 3 days, 7 days, and 14 days after ACE inhibitor initiation. Blood samples were collected between the hours of 7 and 9 in the morning to minimize confounding diurnal variations. Exceptions include the baseline and 12-hour samples, which may vary depending on the timing of patient presentation and ACE inhibitor initiation. After an overnight fast, all morning blood samples were collected from a venous cannula inserted into the forearm after resting for 15 minutes. The first 5 mL of blood was discarded, and the samples were collected in sodium citrate 5-mL glass Vacutainer tubes (Becton Dickinson Co.). Immediately after collection (within 5 min), the samples were centrifuged at 2500g for 15 minutes. The final plasma samples were then transferred to cryogenic vials, labeled accordingly, and immediately stored as a rapid-freeze at -80°C.
Sample Analysis
The quantitative determination of PAI-1 and t-PA antigens was analyzed by a blinded investigator using specific ELISA assays commercially available from Biopool, Inc. (TintElize® PAI-1 and TintElize® t-PA, respectively) and was based on well-established principles.27-29 Through a series of steps, a set of standard concentrations and sample plasmas was added to a microplate pretreated with monoclonal antibodies against the antigen of interest. A conjugate horseradish peroxidase solution was added to the microplate, which was then agitated to allow the antibody/antigen complexes to react with the horseradish peroxidase fragments. Next, the microplate was washed to remove unbound fragments, and a substrate was added to detect the sandwiched antibody/antigen/conjugate complex. The color change is proportional to the amount of antigen present. The microplate was read on a µQuant Universal microplate spectrophotometer (Bio Tek Instruments, Inc.) at 492 nm. The unknown sample plasma concentrations were then extrapolated from the standard curve concentrations, with resulting units of ng/mL. The accuracy of the aforementioned analysis in our laboratory, through the use of standard reference plasma as supplied by the assay manufacturer, is > 98%.
Statistical Analysis
An a priori power calculation was developed using data regarding ACE inhibitor influence on the PAI-1 antigen from a study with similar patient characteristics as that of our inclusion-exclusion criteria.17 Assuming an approximate 20% difference observed in the aforementioned trial, using alpha = 0.05 with two levels, a difference to detect of 8 ng/mL with an expected standard deviation of 1.5 ng/mL, and power = 0.8, we find a sample size of 12 (per group) needed for this study. Estimating a 10% attrition rate, we conservatively enrolled 15 patients in each treatment group to ensure power in measuring the proposed marker of our primary aims. A blinded statistician using SPSS (version 10) prepared the statistical analyses. Analyses consisted of (1) tabulation of means and standard deviations by treatment group and evaluation, (2) t-test comparisons of treatment groups by time point, and (3) a two-factor analysis of variance (ANOVA) for effects of each treatment over time. For analysis of differences in baseline characteristics between treatment groups, chi-square or Fisher's exact tests were used when appropriate. A p-value 
0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Fibrinolytic Parameters
Means, standard deviations, and p-values of PAI-1 antigen and t-PA antigen by treatment group, time, and evaluation are given in Tables II and III. The two treatment groups were roughly equivalent with respect to PAI-1 antigen at baseline (enalapril: 33.09 ± 14.47 ng/mL; quinapril: 32.07 ± 10.92 ng/mL) and t-PA antigen at baseline (enalapril: 15.21 ± 5.97 ng/mL; quinapril: 14.73 ± 4.64 ng/mL).
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On day 1 following study drug initiation, the PAI-1 antigen levels between treatment groups began to separate, with a favorable trend in lower levels with quinapril compared to enalapril (24.44 ± 14.96 ng/mL vs. 36.94 ± 19.49 ng/mL, respectively, p = 0.059). Three days after initial treatment, the quinapril group had a significantly lower mean PAI-1 antigen level compared to enalapril (17.32 ± 9.57 ng/mL vs. 27.49 ± 9.61 ng/mL, respectively, p = 0.009). While there were not statistically significant differences between the groups at other time points, treatment with quinapril resulted in lower PAI-1 antigen levels compared to enalapril at all time points after treatment initiation (Figure 1). In addition, evaluation of effects of treatments on PAI-1 antigen over time, by two-factor ANOVA with replication, showed significantly lower concentrations of PAI-1 antigen over the entire treatment period with quinapril versus enalapril (p < 0.003).
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When evaluating t-PA antigen over time, there were no differences between treatments except a trend at day 1 (Table III). The enalapril group had a mean t-PA antigen level of 17.39 ± 7.78 ng/mL compared to 12.29 ± 5.33 ng/mL for the quinapril group (p = 0.058). When evaluating the effects on t-PA antigen between quinapril and enalapril over the entire treatment period, no significant difference was found.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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The results of this investigation do suggest that quinapril, a commonly accepted high-tissue-penetrating agent, may provide a more beneficial PAI-1 reduction in the early days following an AMI compared to enalapril, a low-tissue-penetrating agent. After similar baseline values, the observed PAI-1 antigen levels were lower at all time points in the quinapril group, with a highly favorable trend toward significance on day 1 (p = 0.059) and with statistical significance on day 3 (p = 0.009). Possibly most important, analysis of the effects of quinapril versus enalapril on PAI-1 antigen over the entire treatment period found a significant difference (p < 0.003) suggesting a more profound PAI-1 reduction with quinapril compared to enalapril over the 2-week treatment period. There was no apparent difference between agents regarding effects on t-PA antigen. The discrepancy between apparent effects on PAI-1 and lack of effect on t-PA is not unexpected as the influence of the renin-angiotensin system on PAI-1 and t-PA is through independent mechanisms. Angiotensin II stimulates PAI-1 production while bradykinin influences t-PA, thus suggesting a lesser importance of the bradykinin-mediated mechanism at the vascular tissue level. Overall, in light of the fact that we used previously established real-world and FDA-approved equipotent doses of each agent,30,31 that were confirmed equivalent based on blood pressure effects in this study, the difference in PAI-1 effects between agents suggests that the beneficial shift in fibrinolytic balance (i.e., less PAI-1) may favor a more highly tissue-penetrating agent.
Numerous studies have explored the influence of ACE inhibitors on fibrinolytic balance in various patient populations.11-17 However, few controlled trials have evaluated early fibrinolytic effects when ACE inhibitors were initiated immediately following the onset of AMI. Vaughan and colleagues12 reported the largest (N = 120) investigation of its kind, with ramipril being initiated within 24 hours of AMI onset. Ramipril, also a commonly accepted high-tissue penetrator, significantly reduced PAI-1 antigen after 14 days compared to placebo. Full-dose ramipril reduced PAI-1 antigen from baseline by approximately 56%. In the current study, quinapril and enalapril decreased PAI-1 antigen by 31% and 19% at 14 days, respectively. The difference in the magnitude of PAI-1 antigen reduction between studies may be explained by a varied effect dependent on the patient population studied. The Vaughan study included only anterior AMI patients with a high incidence of diabetes mellitus (25% in the full-dose ramipril group), a disease that is known to significantly influence PAI-1.12 Our study included all AMI patients, including smaller non-Q-wave myocardial infarctions, and the incidence of diabetes mellitus was much lower in our study. Soejima and colleagues,17 in a patient population similar to ours (N = 30), found that the degree of PAI-1 antigen reduction with imidapril after 7 days of treatment was 19% from baseline, which was the same reduction observed in our enalapril group and much less than our quinapril group (32%) at 7 days. The Vaughan study also found a significant reduction in t-PA antigen with ramipril,12 whereas the effects on t-PA antigen were minimal relative to baseline and indistinguishable between the ACE inhibitors used in our study. Our t-PA antigen findings were not completely unexpected, as some investigations have observed t-PA antigen reduction with certain ACE inhibitors such as ramipril, enalapril, and trandolapril,12,13,16 while others, including that by Soejima et al, have found no significant t-PA effects.14,17 In two trials, quinapril and enalapril were both shown not to significantly alter t-PA antigen concentrations.32,33 Although differences in patient populations between studies may contribute to conflicting t-PA findings, it may also be explained by the relative degree of ACE inhibitor activity to inhibit bradykinin hydrolysis. Moreover, since to our knowledge, the current investigation marks the first to explore the influence of ACE inhibition on fibrinolytic balance over the first 3 days following an AMI and continuing through 2 weeks, comparison of our very early findings to others is limited.
Due to the large number of ACE inhibitors currently approved for use, with indications including hypertension, heart failure, postmyocardial infarction, and diabetic nephropathy, the findings of this study may have practical implications. Approved indications vary between agents, with some ACE inhibitors having all indications and others with one or a combination of indications. Although an approved indication is dependent on available clinical trial evidence, for cost or personal preference issues, certain ACE inhibitors are often used for conditions despite the lack of evidence or approved indication to support use of that agent in a particular setting. This inappropriate use of ACE inhibitors across FDA-approved indications is likely a result of a perceived and unsubstantiated belief in a "class effect" held by many clinicians. While the literature suggests benefit of all ACE inhibitors in lowering blood pressure, a true "class effect" has yet to be proven for many of the pharmacologic and pharmacodynamic properties of ACE inhibitors.
Theoretically, extrapolating proven effects of an ACE inhibitor from one clinical trial to that of all ACE inhibitors may lead to suboptimal ACE inhibitor treatment if an unproven agent is used in its stead. A number of large placebo-controlled studies have shown a survival benefit of various ACE inhibitors after myocardial infarction, but the magnitude of the mortality benefit observed in those trials differs from trial to trial and agent to agent. For example, studies of captopril, lisinopril, trandolapril, and ramipril have shown mortality reduction ranging from 7% to 27%.2-6 While this may be explained by differences in study design or patient populations, to truly evaluate the relative benefit between agents, head-to-head comparisons are needed, of which few exist. The Heart Outcomes Prevention Evaluation (HOPE) study found a significant reduction in myocardial infarction and overall cardiovascular death in high-risk atherosclerotic patients with the highly tissue-penetrating ACE inhibitor ramipril.34 Whether favorable fibrinolytic alterations contributed to the positive outcomes is unknown, but it may be that an ACE inhibitor with less vascular tissue penetration would not have demonstrated the same degree of benefit. Because differences in pharmacodynamic properties do exist between agents, particularly related to tissue penetration, those differences should be explored in the clinical setting. Prior literature has shown a reduction in mortality rates with ACE inhibitor use as early as 24 to 48 hours after myocardial infarction,35 and thus our findings imply that selection of an ACE inhibitor based on increasing degree of vascular tissue penetration may be beneficial in further reducing the risk of recurrent infarction in the early days following an index AMI. Also, our findings at least preliminarily dispute the contention that a comprehensive "class effect" exists with these agents.
Some limitations of the study should be mentioned. First, PAI-1 and t-PA antigens are surrogate endpoints, and the small sample size precludes one from making definitive conclusions regarding the relative effects on terminal endpoints, such as recurrent infarction and mortality. Rather, only clinical implications can be made based on the current findings. Although only day 1 and day 3 PAI-1 antigen levels approached or were statistically significant in favor of quinapril, the significant difference found when evaluating PAI-1 antigen effects over the entire treatment period after equivalent baseline levels supports the contention that the higher tissue-penetrating agent may provide a greater effect on the fibrinolytic balance. Also, while this study was designed to evaluate the relative effects of quinapril and enalapril in the early time period following AMI, the fibrinolytic effects with long-term treatment remain unknown. Although a placebo arm would have provided an ideal control for comparison of the active treatments, it would be unethical to deprive AMI patients of early ACE inhibitor therapy, given the benefit observed in clinical trials and the current recommendations regarding ACE inhibitor use after myocardial infarction.36
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication May 7, 2003; Revised version accepted November 22, 2003.
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REFERENCES |
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1. Fuster V, Badimon L, Badimon JJ, et al: The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326: 310-318.[Web of Science][Medline] [Order article via Infotrieve]
2. The Fourth International Study of Infarct Survival (ISIS-4) Collaborative Group: ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancet 1995;345: 669-685.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Gruppo Italiano per lo Studio della Sopravivenza nell'infacto Miocardio: GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343: 1115-1122.[Web of Science][Medline] [Order article via Infotrieve]
4. Pfeffer MA, Braunwald E, Moye LA, et al, for the SAVE Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327: 669-677.[Abstract]
5. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342: 821-828.[Web of Science][Medline] [Order article via Infotrieve]
6. Kober L, Torp-Pedersen C, Carlsen JE, et al, for the Trandolapril Cardiac Evaluation (TRACE) Study Group: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333: 1670-1676.
7. Brown NJ, Vaughn DE: Prothrombotic effects of angiotensin. Adv Intern Med 2000;45: 419-429.[Medline] [Order article via Infotrieve]
8. Hamsten A, de Faire U, Walldius G, et al: Plasminogen activator inhibitor in plasma: risk factor for recurrent MI. Lancet 1987;11: 3-9.
9. Hamsten A, Wiman B, de Faire U, et al: Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of MI. N Engl J Med 1985;313: 1557-1563.[Abstract]
10. Gram J, Jespersen J: A selection depression of tissue plasminogen activator (t-PA) activity in euglobulin characterizes a risk group among survivors of acute myocardial infarction. Thromb Haemost 1987;57: 137-139.[Web of Science][Medline] [Order article via Infotrieve]
11. Brown NJ, Agirbasli MA, Williams GH, et al: Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998;32: 965-971.
12. Vaughan DE, Rouleau J-L, Ridker PM, et al: Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997;96: 442-447.
13. Jansson JH, Boman K, Nilsson TK: Enalapril related changes in the fibrinolytic system in survivors of myocardial infarction. Eur J Clin Pharmacol 1993;44: 485-488.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Pederson OD, Gram J, Jeunemaitre X, et al: Does long-term angiotensin converting enzyme inhibition affect the concentration of tissue-type plasminogen activator-plasminogen activator inhibitor-1 in the blood of patients with a previous myocardial infarction? Coron Artery Dis 1997;8: 283-291.[Web of Science][Medline] [Order article via Infotrieve]
15. Moriyama Y, Ogawa H, Oshima S, et al: Relationship between serum angiotensin converting enzyme activity and plasma plasminogen activator inhibitor activity in patients with recent myocardial infarction. Coron Artery Dis 1998;9: 691-696.[Web of Science][Medline] [Order article via Infotrieve]
16. Wright RA, Flapan AD, Alberti GMM, et al: Effects of captopril therapy on endogenous fibrinolysis in men with recent myocardial infarction. J Am Coll Cardiol 1994;24: 67-73.[Abstract]
17. Soejima H, Ogawa H, Yasue H, et al: Effects of imidapril therapy on endogenous fibrinolysis in patients with recent myocardial infarction. Clin Cardiol 1997;20: 441-445.[Web of Science][Medline] [Order article via Infotrieve]
18. Unger T, Ganten D, Lang RE, et al: Persistent tissue converting enzyme inhibition following chronic treatment with Hoe 498 and MK421 in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1985;7: 36-41.[Web of Science][Medline] [Order article via Infotrieve]
19. Lyons D, Webster J, Benjamin N: Effect of enalapril and quinapril on forearm vascular ACE in man. Eur J Clinical Pharmacol 1997;51: 373-378.
20. Hornig B, Arakawa N, Haussmann D, et al: Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;98: 2842-2848.
21. Fabris B, Jackson B, Cubela R, et al: Angiotensin converting enzyme in the rat heart: studies of its inhibition in vitro and ex vivo. Clin Exp Pharmacol Physiol 1989;16: 309-313.[Web of Science][Medline] [Order article via Infotrieve]
22. Nakijima T, Yamada T, Setoguchi M: Prolonged inhibition of local angiotensin-converting enzyme after single or repeated treatment with quinapril in spontaneously hypertensive rats. J Cardiovasc Pharm 1992;19: 102-107.[Web of Science][Medline] [Order article via Infotrieve]
23. Van Hinsberg VWM, Kooistra T, Emeis JJ, et al: Regulation of plasminogen activator production by endothelial cells: role in fibrinolysis and local proteolysis. Int J Radiat Biol 1991;60: 261.[Web of Science][Medline] [Order article via Infotrieve]
24. Kruithof EKO, Nicolosa G, Bachmann F: Plasminogen activator inhibitor 1: development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 1987;70: 1645-1653.
25. Vaughan DE: The renin-angiotensin system and fibrinolysis. Am J Cardiol 1997;79: 12-16.
26. Weishaar RE, Panek RL, Major TC, et al: Evidence from a functional tissue renin-angiotensin system in the rat mesenteric vasculature and its involvement in regulating blood pressure. J Pharmacol Exp Ther 1991;256: 568-574.
27. Declerck PJ, Alessi MC, Verstreken M, et al: Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988;71: 220-225.
28. Rijken DC, Juhan-Vague I, de Cock F, Collen D: Measurement of human tissue-type plasminogen activator by a two-site immunoradiometric assay. J Lab Clin Med 1983;101: 274-284.[Web of Science][Medline] [Order article via Infotrieve]
29. Ranby M, Brandstrom A: Biological control of tissue plasminogen activator-mediated fibrinolysis. Enzyme 1988;40: 130-143.[Web of Science][Medline] [Order article via Infotrieve]
30. Bicket D: Using ACE inhibitors appropriately. Am Fam Physician 2002;66: 461-468.[Web of Science][Medline] [Order article via Infotrieve]
31. Drug Facts and Comparisons. 54th ed. St. Louis, MO: Wolters Kluwer, 2000.
32. Brown NJ, Gainer JV, Stein CM, et al: Bradykinin stimulates tissue plasminogen activator release in human vasculature. Hypertension 1999;33: 1431-1435.
33. Goodfield N, Newby DE, Ludlam CA, et al: Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation 1999;99: 2983-2995.
34. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342: 145-153.
35. Zuanetti G, Maggioni AP, Latini R, et al: The early beneficial effect of treatment with oral ACE-inhibitors in patients with acute MI [abstract]. Circulation 1995;92(Suppl. I): I-24.
36. Ryan TJ, Anderson JL, Antman TM, et al: 1999 update: ACC/AHA guidelines for the management of acute myocardial infarction: executive summary and recommendations. Circulation 1999;100: 1016-1030.
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