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1. Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial

Author

Cardinale, D, Ciceri, F, Latini, R, Franzosi, M, Sandri, M, Civelli, M, Cucchi, G, Menatti, E, Mangiavacchi, M, Cavina, R, Barbieri, E, Gori, S, Colombo, A, Curigliano, G, Salvatici, M, Rizzo, A, Ghisoni, F, Bianchi, A, Falci, C, Aquilina, M, Rocca, A, Monopoli, A, Milandri, C, Rossetti, G, Bregni, M, Malossi, A, Nassiacos, D, Verusio, C, Giordano, M, Staszewsky, L, Barlera, S, Nicolis, E, Magnoli, M, Masson, S, Cipolla, C, Curigliano, Sicuro, M, Rossetti, Maggioni, A, Labianca, R, Tettamanti, M, Senni, M, Finzi, A, Grosso, F, Vago, T, Gramenzi, S, Balconi, G, Bernasconi, R, Buratti, M, Ojeda-Fernandez, M, Vasami, A, Thiebat, B, Bare, C, Corzani, A, Coccolo, F, Colecchia, S, Pellegrini, C, Appio, L, Caico, I, Mesenzani, O, Campana, C, Gilardoni, M, Scognamiglio, G, Corrado, G, Battagin, D, De Rosa, F, Carpino, C, Palazzo, S, Giannessi, P, Zipoli, G, Pastori, P, Callegari, S, Sesenna, C, Fodor, C, Guiducci, D, Mazza, R, Turazza, F, Vallerio, P, Marbello, L, Sala, E, Fragasso, G, Trinca, S, Farolfi, A, Andreis, D, Lanzoni, L, Marchetti, F, Mioranza, E, Banzato, A, Re, F, Gaibazzi, N, Gullo, M, Turina, M, Gervasi, E, Giaroli, F, Barco, B, Bertolini, A, Sinagra, G, Aleksova, A, Guglielmi, A, Pinotti, G, Gueli, R, Mongiardi, C, Vallini, I, Cardinale D., Ciceri F., Latini R., Franzosi M. G., Sandri M. T., Civelli M., Cucchi G., Menatti E., Mangiavacchi M., Cavina R., Barbieri E., Gori S., Colombo A., Curigliano G., Salvatici M., Rizzo A., Ghisoni F., Bianchi A., Falci C., Aquilina M., Rocca A., Monopoli A., Milandri C., Rossetti G., Bregni M., Malossi A., Nassiacos D., Verusio C., Giordano M., Staszewsky L., Barlera S., Nicolis E. B., Magnoli M., Masson S., Cipolla C. M., Sicuro M., Maggioni A. P., Labianca R., Tettamanti M., Senni M., Finzi A., Grosso F., Vago T., Gramenzi S., Balconi G., Bernasconi R., Nicolis E., Buratti M. G., Ojeda-Fernandez M. L., Vasami A., Thiebat B., Bare C., Corzani A., Coccolo F., Colecchia S., Pellegrini C., Appio L., Caico I., Mesenzani O., Campana C., Gilardoni M., Scognamiglio G., Corrado G., Battagin D., De Rosa F., Carpino C., Palazzo S., Giannessi P. G., Zipoli G., Pastori P., Callegari S., Sesenna C., Fodor C., Guiducci D., Mazza R., Turazza F. M., Vallerio P., Marbello L., Sala E., Fragasso G., Trinca S., Farolfi A., Andreis D., Lanzoni L., Marchetti F., Mioranza E., Banzato A., Re F., Gaibazzi N., Gullo M., Turina M. C., Gervasi E., Giaroli F., Barco B., Bertolini A., Sinagra G., Aleksova A., Guglielmi A., Pinotti G., Gueli R., Mongiardi C., Vallini I., Cardinale, D, Ciceri, F, Latini, R, Franzosi, M, Sandri, M, Civelli, M, Cucchi, G, Menatti, E, Mangiavacchi, M, Cavina, R, Barbieri, E, Gori, S, Colombo, A, Curigliano, G, Salvatici, M, Rizzo, A, Ghisoni, F, Bianchi, A, Falci, C, Aquilina, M, Rocca, A, Monopoli, A, Milandri, C, Rossetti, G, Bregni, M, Malossi, A, Nassiacos, D, Verusio, C, Giordano, M, Staszewsky, L, Barlera, S, Nicolis, E, Magnoli, M, Masson, S, Cipolla, C, Curigliano, Sicuro, M, Rossetti, Maggioni, A, Labianca, R, Tettamanti, M, Senni, M, Finzi, A, Grosso, F, Vago, T, Gramenzi, S, Balconi, G, Bernasconi, R, Buratti, M, Ojeda-Fernandez, M, Vasami, A, Thiebat, B, Bare, C, Corzani, A, Coccolo, F, Colecchia, S, Pellegrini, C, Appio, L, Caico, I, Mesenzani, O, Campana, C, Gilardoni, M, Scognamiglio, G, Corrado, G, Battagin, D, De Rosa, F, Carpino, C, Palazzo, S, Giannessi, P, Zipoli, G, Pastori, P, Callegari, S, Sesenna, C, Fodor, C, Guiducci, D, Mazza, R, Turazza, F, Vallerio, P, Marbello, L, Sala, E, Fragasso, G, Trinca, S, Farolfi, A, Andreis, D, Lanzoni, L, Marchetti, F, Mioranza, E, Banzato, A, Re, F, Gaibazzi, N, Gullo, M, Turina, M, Gervasi, E, Giaroli, F, Barco, B, Bertolini, A, Sinagra, G, Aleksova, A, Guglielmi, A, Pinotti, G, Gueli, R, Mongiardi, C, Vallini, I, Cardinale D., Ciceri F., Latini R., Franzosi M. G., Sandri M. T., Civelli M., Cucchi G., Menatti E., Mangiavacchi M., Cavina R., Barbieri E., Gori S., Colombo A., Curigliano G., Salvatici M., Rizzo A., Ghisoni F., Bianchi A., Falci C., Aquilina M., Rocca A., Monopoli A., Milandri C., Rossetti G., Bregni M., Malossi A., Nassiacos D., Verusio C., Giordano M., Staszewsky L., Barlera S., Nicolis E. B., Magnoli M., Masson S., Cipolla C. M., Sicuro M., Maggioni A. P., Labianca R., Tettamanti M., Senni M., Finzi A., Grosso F., Vago T., Gramenzi S., Balconi G., Bernasconi R., Nicolis E., Buratti M. G., Ojeda-Fernandez M. L., Vasami A., Thiebat B., Bare C., Corzani A., Coccolo F., Colecchia S., Pellegrini C., Appio L., Caico I., Mesenzani O., Campana C., Gilardoni M., Scognamiglio G., Corrado G., Battagin D., De Rosa F., Carpino C., Palazzo S., Giannessi P. G., Zipoli G., Pastori P., Callegari S., Sesenna C., Fodor C., Guiducci D., Mazza R., Turazza F. M., Vallerio P., Marbello L., Sala E., Fragasso G., Trinca S., Farolfi A., Andreis D., Lanzoni L., Marchetti F., Mioranza E., Banzato A., Re F., Gaibazzi N., Gullo M., Turina M. C., Gervasi E., Giaroli F., Barco B., Bertolini A., Sinagra G., Aleksova A., Guglielmi A., Pinotti G., Gueli R., Mongiardi C., and Vallini I.

Abstract

Background: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. Methods: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; ‘prevention’ arm), and enalapril started only in patients with an increase in troponin during or after CT (‘troponin-triggered’ arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. Findings: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270–360] and 240 [240–240] mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. Interpretation: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.

Published
2018

2. Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., Jankowski, Janusz, Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., and Jankowski, Janusz

Abstract

Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results—We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions—We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

3. Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., Jankowski, Janusz, Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., and Jankowski, Janusz

Abstract

Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results—We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions—We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

4. Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., Jankowski, Janusz, Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., and Jankowski, Janusz

Abstract

Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results—We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions—We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

5. Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

Author

Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., Jankowski, Janusz, Sabater-Lleal, M., Huang, J., Chasman, D., Naitza, S., Dehghan, A., Johnson, A. D., Teumer, A., Reiner, A. P., Folkersen, L., Basu, S., Rudnicka, A. R., Trompet, S., Malarstig, A., Baumert, J., Bis, J. C., Guo, X., Hottenga, J. J., Shin, S.-Y., Lopez, L. M., Lahti, J., Tanaka, T., Yanek, L. R., Oudot-Mellakh, T., Wilson, J. F., Navarro, P., Huffman, J. E., Zemunik, T., Redline, S., Mehra, R., Pulanic, D., Rudan, I., Wright, A. F., Kolcic, I., Polasek, O., Wild, S. H., Campbell, H., Curb, J. D., Wallace, R., Liu, S., Eaton, C. B., Becker, D. M., Becker, L. C., Bandinelli, S., Raikkonen, K., Widen, E., Palotie, A., Fornage, M., Green, D., Gross, M., Davies, G., Harris, S. E., Liewald, D. C., Starr, J. M., Williams, F. M. K., Grant, P. J., Spector, T. D., Strawbridge, R. J., Silveira, A., Sennblad, B., Rivadeneira, F., Uitterlinden, A. G., Franco, O. H., Hofman, A., van Dongen, J., Willemsen, G., Boomsma, D. I., Yao, J., Swords Jenny, N., Haritunians, T., McKnight, B., Lumley, T., Taylor, K. D., Rotter, J. I., Psaty, B. M., Peters, A., Gieger, C., Illig, T., Grotevendt, A., Homuth, G., Volzke, H., Kocher, T., Goel, A., Franzosi, M. G., Seedorf, U., Clarke, R., Steri, M., Tarasov, K. V., Sanna, S., Schlessinger, D., Stott, D. J., Sattar, N., Buckley, B. M., Rumley, A., Lowe, G. D., McArdle, W. L., Chen, M.-H., Tofler, G. H., Song, J., Boerwinkle, E., Folsom, A. R., Rose, L. M., Franco-Cereceda, A., Teichert, M., Ikram, M. A., Mosley, T. H., Bevan, S., Dichgans, M., Rothwell, P. M., Sudlow, C. L. M., Hopewell, J. C., Chambers, J. C., Saleheen, D., Kooner, J. S., Danesh, J., Nelson, C. P., Erdmann, J., Reilly, M. P., Kathiresan, S., Schunkert, H., Morange, P.-E., Ferrucci, L., Eriksson, J. G., Jacobs, D., Deary, I. J., Soranzo, N., Witteman, J. C. M., de Geus, E. J. C., Tracy, R. P., Hayward, C., Koenig, W., Cucca, F., Jukema, J. W., Eriksson, P., Seshadri, S., Markus, H. S., Watkins, H., Samani, N. J., Wallaschofski, H., Smith, N. L., Tregouet, D., Ridker, P. M., Tang, W., Strachan, D. P., Hamsten, A., O'Donnell, C. J., and Jankowski, Janusz

Abstract

Background—Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. Methods and Results—We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. Conclusions—We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Published
2013

6. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Author

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Norrving, B, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, Y-C, Woo, D, Nalls, MA, Mueller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, M-G, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, Macleod, MJ, Slowik, A, Walters, M, Rosand, J, Sharma, P, Farrall, M, Sudlow, CLM, Rothwell, PM, Dichgans, M, Donnelly, P, Markus, HS, Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Norrving, B, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, Y-C, Woo, D, Nalls, MA, Mueller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, M-G, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, Macleod, MJ, Slowik, A, Walters, M, Rosand, J, Sharma, P, Farrall, M, Sudlow, CLM, Rothwell, PM, Dichgans, M, Donnelly, P, and Markus, HS

Abstract

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Published
2012

7. Association between C reactive protein and coronary heart disease : mendelian randomisation analysis based on individual participant data

Author

Wensley, Frances, Gao, Pei, Burgess, Stephen, Kaptoge, Stephen, Di Angelantonio, Emanuele, Shah, Tina, Engert, James C., Clarke, Robert, Davey-Smith, George, Nordestgaard, Borge G., Saleheen, Danish, Samani, Nilesh J., Sandhu, Manjinder, Anand, Sonia, Pepys, Mark B., Smeeth, Liam, Whittaker, John, Casas, Juan Pablo, Thompson, Simon G., Hingorani, Aroon D., Danesh, John, Eiriksdottir, G., Harris, T. B., Launer, L. J., Gudnason, V., Folsom, A. R., Andrews, G., Ballantyne, C. M., Samani, N. J., Hall, A. S., Braund, P. S., Balmforth, A. J., Whincup, P. H., Morris, R., Lawlor, D. A., Lowe, G. D. O., Timpson, N., Ebrahim, S., Ben-Shlomo, Y., Davey-Smith, G., Nordestgaard, B. G., Tybjaerg-Hansen, A., Zacho, J., Brown, M., Sandhu, M., Ricketts, S. L., Ashford, S., Lange, L., Reiner, A., Cushman, M., Tracy, R., Wu, C., Ge, J., Zou, Y., Sun, A., Hung, J., McQuillan, B., Thompson, P., Beilby, J., Warrington, N., Palmer, L. J., Wanner, C., Drechsler, C., Hoffmann, M. M., Fowkes, F. G. R., Tzoulaki, I., Kumari, M., Miller, M., Marmot, M., Onland-Moret, C., van der Schouw, Y. T., Boer, J. M., Wijmenga, C., Khaw, K-T, Vasan, R. S., Schnabel, R. B., Yamamoto, J. F., Benjamin, E. J., Schunkert, H., Erdmann, J., Koenig, I. R., Hengstenberg, C., Chiodini, B., Franzosi, M. G., Pietri, S., Gori, F., Rudock, M., Liu, Y., Lohman, K., Humphries, S. E., Hamsten, A., Norman, P. E., Hankey, G. J., Jamrozik, K., Rimm, E. B., Pai, J. K., Psaty, B. M., Heckbert, S. R., Bis, J. C., Yusuf, S., Anand, S., Engert, J. C., Xie, C., Collins, R., Clarke, R., Bennett, D., Kooner, J., Chambers, J., Elliott, P., Maerz, W., Kleber, M. E., Boehm, B. O., Winkelmann, B. R., Melander, O., Berglund, G., Koenig, W., Thorand, B., Baumert, J., Peters, A., Manson, J., Cooper, J. A., Talmud, P. J., Ladenvall, P., Johansson, L., Jansson, Jan-Håkan, Hallmans, Göran, Reilly, M. P., Qu, L., Li, M., Rader, D. J., Watkins, H., Hopewell, J., Saleheen, D., Danesh, J., Frossard, P., Sattar, N., Robertson, M., Shepherd, J., Schaefer, E., Hofman, A., Witteman, J. C. M., Kardys, I., Dehghan, A., de Faire, U., Bennet, A., Gigante, B., Leander, K., Peters, B., Maitland-van der Zee, A. H., de Boer, A., Klungel, O., Greenland, P., Dai, J., Liu, S., Brunner, E., Kivimaki, M., O'Reilly, D., Ford, I., Packard, C. J., Wensley, Frances, Gao, Pei, Burgess, Stephen, Kaptoge, Stephen, Di Angelantonio, Emanuele, Shah, Tina, Engert, James C., Clarke, Robert, Davey-Smith, George, Nordestgaard, Borge G., Saleheen, Danish, Samani, Nilesh J., Sandhu, Manjinder, Anand, Sonia, Pepys, Mark B., Smeeth, Liam, Whittaker, John, Casas, Juan Pablo, Thompson, Simon G., Hingorani, Aroon D., Danesh, John, Eiriksdottir, G., Harris, T. B., Launer, L. J., Gudnason, V., Folsom, A. R., Andrews, G., Ballantyne, C. M., Samani, N. J., Hall, A. S., Braund, P. S., Balmforth, A. J., Whincup, P. H., Morris, R., Lawlor, D. A., Lowe, G. D. O., Timpson, N., Ebrahim, S., Ben-Shlomo, Y., Davey-Smith, G., Nordestgaard, B. G., Tybjaerg-Hansen, A., Zacho, J., Brown, M., Sandhu, M., Ricketts, S. L., Ashford, S., Lange, L., Reiner, A., Cushman, M., Tracy, R., Wu, C., Ge, J., Zou, Y., Sun, A., Hung, J., McQuillan, B., Thompson, P., Beilby, J., Warrington, N., Palmer, L. J., Wanner, C., Drechsler, C., Hoffmann, M. M., Fowkes, F. G. R., Tzoulaki, I., Kumari, M., Miller, M., Marmot, M., Onland-Moret, C., van der Schouw, Y. T., Boer, J. M., Wijmenga, C., Khaw, K-T, Vasan, R. S., Schnabel, R. B., Yamamoto, J. F., Benjamin, E. J., Schunkert, H., Erdmann, J., Koenig, I. R., Hengstenberg, C., Chiodini, B., Franzosi, M. G., Pietri, S., Gori, F., Rudock, M., Liu, Y., Lohman, K., Humphries, S. E., Hamsten, A., Norman, P. E., Hankey, G. J., Jamrozik, K., Rimm, E. B., Pai, J. K., Psaty, B. M., Heckbert, S. R., Bis, J. C., Yusuf, S., Anand, S., Engert, J. C., Xie, C., Collins, R., Clarke, R., Bennett, D., Kooner, J., Chambers, J., Elliott, P., Maerz, W., Kleber, M. E., Boehm, B. O., Winkelmann, B. R., Melander, O., Berglund, G., Koenig, W., Thorand, B., Baumert, J., Peters, A., Manson, J., Cooper, J. A., Talmud, P. J., Ladenvall, P., Johansson, L., Jansson, Jan-Håkan, Hallmans, Göran, Reilly, M. P., Qu, L., Li, M., Rader, D. J., Watkins, H., Hopewell, J., Saleheen, D., Danesh, J., Frossard, P., Sattar, N., Robertson, M., Shepherd, J., Schaefer, E., Hofman, A., Witteman, J. C. M., Kardys, I., Dehghan, A., de Faire, U., Bennet, A., Gigante, B., Leander, K., Peters, B., Maitland-van der Zee, A. H., de Boer, A., Klungel, O., Greenland, P., Dai, J., Liu, S., Brunner, E., Kivimaki, M., O'Reilly, D., Ford, I., and Packard, C. J.

Abstract

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference). Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

Published
2011
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8. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group

Author

Latini, R, Tognoni, G, Maggioni, A P, Baigent, C, Braunwald, E, Chen, Z M, Collins, R, Flather, M, Franzosi, M G, Kjekshus, J, Køber, L, Liu, L S, Peto, R, Pfeffer, M, Pizzetti, F, Santoro, E, Sleight, P, Swedberg, K, Tavazzi, L, Wang, W, Yusuf, S, Latini, R, Tognoni, G, Maggioni, A P, Baigent, C, Braunwald, E, Chen, Z M, Collins, R, Flather, M, Franzosi, M G, Kjekshus, J, Køber, L, Liu, L S, Peto, R, Pfeffer, M, Pizzetti, F, Santoro, E, Sleight, P, Swedberg, K, Tavazzi, L, Wang, W, and Yusuf, S

Abstract

Udgivelsesdato: 2000-Jun, OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outco

Published
2000

9. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group

Author

Latini, R, Tognoni, G, Maggioni, A P, Baigent, C, Braunwald, E, Chen, Z M, Collins, R, Flather, M, Franzosi, M G, Kjekshus, J, Køber, L, Liu, L S, Peto, R, Pfeffer, M, Pizzetti, F, Santoro, E, Sleight, P, Swedberg, K, Tavazzi, L, Wang, W, Yusuf, S, Latini, R, Tognoni, G, Maggioni, A P, Baigent, C, Braunwald, E, Chen, Z M, Collins, R, Flather, M, Franzosi, M G, Kjekshus, J, Køber, L, Liu, L S, Peto, R, Pfeffer, M, Pizzetti, F, Santoro, E, Sleight, P, Swedberg, K, Tavazzi, L, Wang, W, and Yusuf, S

Abstract

Udgivelsesdato: 2000-Jun, OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outco

Published
2000

10. MEDICAL SCIENCE. GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction

Author

Feruglio, G. A., Lotto, A., Rovelli, F., Solinas, P., Tavazzi, L., Tognoni, G., De Vita, C., Franzosi, M. G., Maggiom, A. P., Mauri, F., Volpi, A., Selvini, A., Donato, L., Garattmi, S., Loi, U., Sirchia, G., Ambrosioni, E., Camerini, F., Campolo, L., Donati, M. B., Ferrari, M., Farchi, G., Geraci, E., Mannucci, P. M., Marubini, E., Neri Semeri, G. G., Peto, R., Prati, P. L., Specchia, G., Vecchio, C., Visani, L., Yusuf, S., Mezzanotte, G., Santoro, E., Bruno, M., Cappello, T., Coppini, A., Fincati, F., Mantovani, G., Pangrazzi, J., Pogna, M., Turazza, F. M., Ansehni, M., Barbonaglia, L., Bigi, R., Cavalli, A., Frigerio, M., Giordano, A., Gualtierotti, C., Torta, D., Vinci, P., Bossi, M., Furlanello, F., Braito, E., Giulia, V., Palmieri, M., Majoimo, P., Pinelli, G., Papi, L., Nardelli, A., Capestro, F., Rossi, A., Ricci, D., Mininni, N., Bianco, G., Barbuzzi, S., Plastina, F., Di Giovanna, F., Mereu, D., Giordano, F., Barlotti, R., Loparco, G., Boscarino, S., Ruggeri, G., Anastasi, R., Paciaroni, E., Tomassini, P. F., Purcaro, A., Francesconi, M., Figliolia, S., Tesse, S., Devoti, G., Giometti, R., Teoni, P., Burali, A., Zucconelli, V., Iervoglini, A., Amabili, S., Caratti, C. A., Zola, G., Ferraguto, P., Sagci, G., Rotiroti, D., Genovese, M., Da€TMamato, N., Taurino, L., Colonna, L., Bovenzi, F., Messina, D., Sarcina, G., Compostella, L., Cucchini, F., Malacrida, R., Gradel, C., Bridda, A., Pellegrini, P., Acone, L., Bruno, A., Tespili, M., Guaghurrii, G., Casari, A., Bobba, F., Scaramuzzino, G., Berardi, C., De Castro, U., Fulvi, M., Lintner, W., Erlicher, A., Pitscheider, W., Scola Gagliardi, R., Bonizzato, G., Roggero, C., Perrini, A., Tsialtas, D., Straneo, U., Storelli, A., Verrienti, A., Albonico, B., Corradi, L., De Petra, V., Villani, C., Maxia, P., Bianco, A., Crabu, E., Centamore, G., Di Stefano, G., Vancheri, F., Amico, C., Baldini, F., Santopuoli, G., Pantaleoni, A., Contessotto, F., Terlizzi, R., Turchi, E., Teglio, V., Pignatti, F., Aletto, C., Gozzelino, G., Pettinati, G., De Santis, F., Correale, E., Romano, S., Perrotta, R., Tritto, C., May, L., Achilli, G., Suzzi, G., Cemetti, C., Longobardi, R., Somma, G., Palumbo, C., Gallone, P., Sorrentino, F., Dato, A., Della Monica, R., Pagano, L., Alberti, A., Orselli, L., Negrini, M., De Ponti, C., Acito, P., Capelletti, D., Bortolini, F., Coppola, V., Ciglia, C., De Cesare, M., De Lio, U., Maiolino, P., Giannini, R., Niccolini, A., Marinoni, C., Guasconi, C., Sonnino, S., Pagliei, M., Ferrari, G., Politi, A., Galli, M., De Rinaldis, G., Calcagnile, A., Bendinelli, S., Lusetti, L., Mollaioli, M., Cosmi, F., Venneri, N., Feraco, E., Lauro, A., Catelli, P., Poluzzi, C., Distante, S., Pedroni, P., Zampaglione, G., Lumare, R., Bruna, C., De Benedictis, N., Ziacchi, V., Lomanto, B., Riva, D., Bertocchi, P., Tirella, G., Tessitori, M., Bini, A., Peruzzi, F., Maresta, A., Pirazzini, L., Gaggi, S., Frausini, G., Malacame, C., Codeca, L., Cappato, R., Andreoli, L., Bastoni, L. A., Pucci, P., Sarro, F., Vergassola, R., Barchielli, M., De Matteis, D., Carrone, M., Liberati, R., Meniconi, L., Radogna, M., Tallone, M., Ieri, A., Ferreri, A., Guidali, P., Canziani, R., Mariello, F., Minelli, C., Muzio, L., Rota Baldini, M., Lupi, G., Cecchi, A., Giuliano, G., Bellotti, S., Livi, S., Corti, E., Rossi, P., Delfino, R., Iannetti, M., Pastorini, C., Pennesi, A., Di Giacinto, N., Bertolo, L., Slomp, L., Cresti, A., Svetoni, N., Distefano, S., Veneri, L., Moretti, S., Palermo, R., Giovanelli, N., Parchi, C., Dethomads, M., Paparella, N., Carrino, C., Aquaro, G., Idone, P., Marsili, P., Sideri, F., Valerio, A., Tullio, D., Ragazzini, G., Gramenzi, S., De Pasquale, B., Gelfo, P. G., Rosselli, P., De Marchi, E., Greco, M. R., Fazio, A. M., Savoia, M. T., Gerosa, C., Barbiero, M., Barbaresi, F., Volta, G., Da€TMurbano, M., Passoni, F., Parola, G., Lanzini, A., Baldini, U., Del Bene, P., Orlandi, M., Oddone, A., Lazzari, M., Ballerini, B., Bozzi, L., Moccetti, T., Bemasconi, E., Sanguinetti, M., Tognoli, T., Bardelli, G., Maggi, A., Turato, R., Piva, M., Izzo, A., Tantalo, L., Rizzi, A., Scilabra, G., Varvaro, F., Colombo, G., Grieco, A., Dovico, E., Belluzzi, F., Casellato, F., Lecchi, G., Maugeri Sacci, C., Consolo, A., Piccolo, E., Zuin, G., Zappa, C., Sanna, G. P., Dossena, M. G., Corsini, C., Lettino, M., Marconi, M., Mafrici, A., Leonardi, G., Moreo, A., Seregni, R., Pastine, I., Casazza, F., Regalia, F., Maggiolini, S., Benenati, P. M., Rigo, R., Pascotto, P., Zanocco, A., Artusi, L., Cappelli, C., Bernardi, C., Pahnieri, M., Zilio, G., Sandri, R., Neri, G., Valagussa, F., Osculati, G., Cira, A., Da€TManiello, L., Piantadosi, F. R., Improta, M., Severino, S., Bisconti, C., Mostacci, M., Randon, L., Boschello, M., Allegri, M., Freggiaro, V., Mureddu, V., Soro, F., Marras, E., Marchi, S. M., De Luca, C., Manetta, M., Dalla Volta, S., Maddalena, F., Donzelli, M., Vitrano, M. G., Canonico, A., Ledda, A., Bellomare, D., Carrubba, A., Da€TMantonio, E., Scardulla, C., Raineri, A., Traina, M., La Calce, C., Cirincione, V., Montanar, F., Strizzolo, L., Di Gregorio, D., Mantini, L., Chiriatti, G., Gazzola, U., Rosi, A., Mellini, M., Piazza, R., Micheli, G., Bechi, S., Martines, C., Marchese, D., Bigalli, A., Davini, P., Boem, A., Del Citerna, F., Giomi, A., Codeluppi, P., Negrelli, M., Brieda, M., Charmet, P. A., Petrella, A., Bardazzi, L., Bianco, G. A., Marco, A., Licitra, R., Lettica, G. V., Tumiotto, G., Bosi, S., Spitali, G., Casali, G., Bottoni, N., Parenti, G. F., Triulzi, E., Brighi, F., Benati, A., De Sanctis, A., Mene, A., Pesaresi, A., Bologna, F., Lumia, F., Barbato, G., Milazzotto, F., Proietti, F., Angrisani, G., Azzolini, P., Coppola, E., Trani, Carlo, Masini, V., Rocchi, M., Borgia, M. C., Luciani, C., Vitucci, N. C., Giuliani, P., Tugnoli, F., Vetta, C., Altieri, T., Gimigliano, F., Striano, U., Salituri, S., Zanazzi, G., Zonzin, P., Bugatti, U., Ravera, B., Allemano, P., Reynaud, S., Sanson, A., Milani, L., De Simone, M. V., Villella, A., Grazzini, M., Amidei, S., Ansehni, L., Benza, G., Tagliamonte, A., Messina, V., Etro, M. D., Vivaldi, F., Cortese, R., Ibba, G. V., Sannia, L., Pedrazzini, F., Gazzotti, G. L., Pizzuti, A., Antonielli, E., Becchi, G., Filice, A., Salmoiraghi, A., Caramanno, G., Caporicci, D., Brun, M., Ferrario, G., Giani, P., Ronconi, G., Douglas, S., Bianchi, C., Cucchi, G., Marieni, M., Marcellini, G., Speca, G., Beato, E., Serabni, N., Bazzucchi, M., Coronelli, R., Rossi, L., Basso, G., Presbitero, P., Bevilacqua, R., Pallisco, O., Di Leo, M., Golzio, P. G., Parigi, A., Belli, R., Trinchero, R., Gaschino, G., Barenghi, M., Poggio, G. L., Braschi, G. B., Sciacca, R., Sammartano, A., Braito, G., Cuzzato, V., Frigo, G., Perissinono, F., Galati, A., Accogli, M., Morgera, T., Barbieri, L., Slavich, G. A., Fresco, C., Cuda, A., Liguori, A., Cozzi, A., Caico, S., Alberio, M., Di Marco, G., De Vito, G., Valente, S., Zagatti, G., Zardini, P., Nidasio, G. P., Girardi, P., Mazzini, C., Nava, S., Achilli, A., Bisogno, A., Pasotti, C., Ballestra, A. M., Giustarini, C., Trani C. (ORCID:0000-0001-9777-013X), Feruglio, G. A., Lotto, A., Rovelli, F., Solinas, P., Tavazzi, L., Tognoni, G., De Vita, C., Franzosi, M. G., Maggiom, A. P., Mauri, F., Volpi, A., Selvini, A., Donato, L., Garattmi, S., Loi, U., Sirchia, G., Ambrosioni, E., Camerini, F., Campolo, L., Donati, M. B., Ferrari, M., Farchi, G., Geraci, E., Mannucci, P. M., Marubini, E., Neri Semeri, G. G., Peto, R., Prati, P. L., Specchia, G., Vecchio, C., Visani, L., Yusuf, S., Mezzanotte, G., Santoro, E., Bruno, M., Cappello, T., Coppini, A., Fincati, F., Mantovani, G., Pangrazzi, J., Pogna, M., Turazza, F. M., Ansehni, M., Barbonaglia, L., Bigi, R., Cavalli, A., Frigerio, M., Giordano, A., Gualtierotti, C., Torta, D., Vinci, P., Bossi, M., Furlanello, F., Braito, E., Giulia, V., Palmieri, M., Majoimo, P., Pinelli, G., Papi, L., Nardelli, A., Capestro, F., Rossi, A., Ricci, D., Mininni, N., Bianco, G., Barbuzzi, S., Plastina, F., Di Giovanna, F., Mereu, D., Giordano, F., Barlotti, R., Loparco, G., Boscarino, S., Ruggeri, G., Anastasi, R., Paciaroni, E., Tomassini, P. F., Purcaro, A., Francesconi, M., Figliolia, S., Tesse, S., Devoti, G., Giometti, R., Teoni, P., Burali, A., Zucconelli, V., Iervoglini, A., Amabili, S., Caratti, C. A., Zola, G., Ferraguto, P., Sagci, G., Rotiroti, D., Genovese, M., Da€TMamato, N., Taurino, L., Colonna, L., Bovenzi, F., Messina, D., Sarcina, G., Compostella, L., Cucchini, F., Malacrida, R., Gradel, C., Bridda, A., Pellegrini, P., Acone, L., Bruno, A., Tespili, M., Guaghurrii, G., Casari, A., Bobba, F., Scaramuzzino, G., Berardi, C., De Castro, U., Fulvi, M., Lintner, W., Erlicher, A., Pitscheider, W., Scola Gagliardi, R., Bonizzato, G., Roggero, C., Perrini, A., Tsialtas, D., Straneo, U., Storelli, A., Verrienti, A., Albonico, B., Corradi, L., De Petra, V., Villani, C., Maxia, P., Bianco, A., Crabu, E., Centamore, G., Di Stefano, G., Vancheri, F., Amico, C., Baldini, F., Santopuoli, G., Pantaleoni, A., Contessotto, F., Terlizzi, R., Turchi, E., Teglio, V., Pignatti, F., Aletto, C., Gozzelino, G., Pettinati, G., De Santis, F., Correale, E., Romano, S., Perrotta, R., Tritto, C., May, L., Achilli, G., Suzzi, G., Cemetti, C., Longobardi, R., Somma, G., Palumbo, C., Gallone, P., Sorrentino, F., Dato, A., Della Monica, R., Pagano, L., Alberti, A., Orselli, L., Negrini, M., De Ponti, C., Acito, P., Capelletti, D., Bortolini, F., Coppola, V., Ciglia, C., De Cesare, M., De Lio, U., Maiolino, P., Giannini, R., Niccolini, A., Marinoni, C., Guasconi, C., Sonnino, S., Pagliei, M., Ferrari, G., Politi, A., Galli, M., De Rinaldis, G., Calcagnile, A., Bendinelli, S., Lusetti, L., Mollaioli, M., Cosmi, F., Venneri, N., Feraco, E., Lauro, A., Catelli, P., Poluzzi, C., Distante, S., Pedroni, P., Zampaglione, G., Lumare, R., Bruna, C., De Benedictis, N., Ziacchi, V., Lomanto, B., Riva, D., Bertocchi, P., Tirella, G., Tessitori, M., Bini, A., Peruzzi, F., Maresta, A., Pirazzini, L., Gaggi, S., Frausini, G., Malacame, C., Codeca, L., Cappato, R., Andreoli, L., Bastoni, L. A., Pucci, P., Sarro, F., Vergassola, R., Barchielli, M., De Matteis, D., Carrone, M., Liberati, R., Meniconi, L., Radogna, M., Tallone, M., Ieri, A., Ferreri, A., Guidali, P., Canziani, R., Mariello, F., Minelli, C., Muzio, L., Rota Baldini, M., Lupi, G., Cecchi, A., Giuliano, G., Bellotti, S., Livi, S., Corti, E., Rossi, P., Delfino, R., Iannetti, M., Pastorini, C., Pennesi, A., Di Giacinto, N., Bertolo, L., Slomp, L., Cresti, A., Svetoni, N., Distefano, S., Veneri, L., Moretti, S., Palermo, R., Giovanelli, N., Parchi, C., Dethomads, M., Paparella, N., Carrino, C., Aquaro, G., Idone, P., Marsili, P., Sideri, F., Valerio, A., Tullio, D., Ragazzini, G., Gramenzi, S., De Pasquale, B., Gelfo, P. G., Rosselli, P., De Marchi, E., Greco, M. R., Fazio, A. M., Savoia, M. T., Gerosa, C., Barbiero, M., Barbaresi, F., Volta, G., Da€TMurbano, M., Passoni, F., Parola, G., Lanzini, A., Baldini, U., Del Bene, P., Orlandi, M., Oddone, A., Lazzari, M., Ballerini, B., Bozzi, L., Moccetti, T., Bemasconi, E., Sanguinetti, M., Tognoli, T., Bardelli, G., Maggi, A., Turato, R., Piva, M., Izzo, A., Tantalo, L., Rizzi, A., Scilabra, G., Varvaro, F., Colombo, G., Grieco, A., Dovico, E., Belluzzi, F., Casellato, F., Lecchi, G., Maugeri Sacci, C., Consolo, A., Piccolo, E., Zuin, G., Zappa, C., Sanna, G. P., Dossena, M. G., Corsini, C., Lettino, M., Marconi, M., Mafrici, A., Leonardi, G., Moreo, A., Seregni, R., Pastine, I., Casazza, F., Regalia, F., Maggiolini, S., Benenati, P. M., Rigo, R., Pascotto, P., Zanocco, A., Artusi, L., Cappelli, C., Bernardi, C., Pahnieri, M., Zilio, G., Sandri, R., Neri, G., Valagussa, F., Osculati, G., Cira, A., Da€TManiello, L., Piantadosi, F. R., Improta, M., Severino, S., Bisconti, C., Mostacci, M., Randon, L., Boschello, M., Allegri, M., Freggiaro, V., Mureddu, V., Soro, F., Marras, E., Marchi, S. M., De Luca, C., Manetta, M., Dalla Volta, S., Maddalena, F., Donzelli, M., Vitrano, M. G., Canonico, A., Ledda, A., Bellomare, D., Carrubba, A., Da€TMantonio, E., Scardulla, C., Raineri, A., Traina, M., La Calce, C., Cirincione, V., Montanar, F., Strizzolo, L., Di Gregorio, D., Mantini, L., Chiriatti, G., Gazzola, U., Rosi, A., Mellini, M., Piazza, R., Micheli, G., Bechi, S., Martines, C., Marchese, D., Bigalli, A., Davini, P., Boem, A., Del Citerna, F., Giomi, A., Codeluppi, P., Negrelli, M., Brieda, M., Charmet, P. A., Petrella, A., Bardazzi, L., Bianco, G. A., Marco, A., Licitra, R., Lettica, G. V., Tumiotto, G., Bosi, S., Spitali, G., Casali, G., Bottoni, N., Parenti, G. F., Triulzi, E., Brighi, F., Benati, A., De Sanctis, A., Mene, A., Pesaresi, A., Bologna, F., Lumia, F., Barbato, G., Milazzotto, F., Proietti, F., Angrisani, G., Azzolini, P., Coppola, E., Trani, Carlo, Masini, V., Rocchi, M., Borgia, M. C., Luciani, C., Vitucci, N. C., Giuliani, P., Tugnoli, F., Vetta, C., Altieri, T., Gimigliano, F., Striano, U., Salituri, S., Zanazzi, G., Zonzin, P., Bugatti, U., Ravera, B., Allemano, P., Reynaud, S., Sanson, A., Milani, L., De Simone, M. V., Villella, A., Grazzini, M., Amidei, S., Ansehni, L., Benza, G., Tagliamonte, A., Messina, V., Etro, M. D., Vivaldi, F., Cortese, R., Ibba, G. V., Sannia, L., Pedrazzini, F., Gazzotti, G. L., Pizzuti, A., Antonielli, E., Becchi, G., Filice, A., Salmoiraghi, A., Caramanno, G., Caporicci, D., Brun, M., Ferrario, G., Giani, P., Ronconi, G., Douglas, S., Bianchi, C., Cucchi, G., Marieni, M., Marcellini, G., Speca, G., Beato, E., Serabni, N., Bazzucchi, M., Coronelli, R., Rossi, L., Basso, G., Presbitero, P., Bevilacqua, R., Pallisco, O., Di Leo, M., Golzio, P. G., Parigi, A., Belli, R., Trinchero, R., Gaschino, G., Barenghi, M., Poggio, G. L., Braschi, G. B., Sciacca, R., Sammartano, A., Braito, G., Cuzzato, V., Frigo, G., Perissinono, F., Galati, A., Accogli, M., Morgera, T., Barbieri, L., Slavich, G. A., Fresco, C., Cuda, A., Liguori, A., Cozzi, A., Caico, S., Alberio, M., Di Marco, G., De Vito, G., Valente, S., Zagatti, G., Zardini, P., Nidasio, G. P., Girardi, P., Mazzini, C., Nava, S., Achilli, A., Bisogno, A., Pasotti, C., Ballestra, A. M., Giustarini, C., and Trani C. (ORCID:0000-0001-9777-013X)

Abstract

A multicentre, randomised, open trial with a 2 x 2 factorial design was conducted to compare the benefits and risks of two thrombolytic agents, streptokinase (SK, 1·5 MU infused intravenously over 30-60 min) and alteplase (tPA, 100 mg infused intravenously over 3 h) in patients with acute myocardial infarction admitted to coronary care units within 6 h from onset of symptoms. The patients were also randomised to receive heparin (12 500 U subcutaneously twice daily until discharge from hospital, starting 12 h after beginning the tPA or SK infusion) or usual therapy. All patients without specific contraindications were given atenolol (5-10 mg iv) and aspirin (300-325 mg a day). The end-point of the study was the combined estimate of death plus severe left ventricular damage. 12 490 patients were randomised to four treatment groups (SK alone, SK plus heparin, tPA alone, tPA plus heparin). No specific differences between the two thrombolytic agents were detected as regards the combined end-point (tPA 23·1%; SK 22·5%; relative risk 1·04, 95% Cl 0·95-1·13), nor after the addition of heparin to the aspirin treatment (hep 22·7%, no hep 22·9%; RR 0·99, 95% Cl 0·91-1·08). The outcome of patients allocated to the four treatment groups was similar with respect to baseline risk factors such as age, Killip class, hours from onset of symptoms, and site and type of infarct. The rates of major in-hospital cardiac complications (reinfarction, post-infarction angina) were also similar. The incidence of major bleeds was significantly higher in SK and heparin treated patients (respectively, tPA 0·5%, SK 1·0%, RR 0·57, 95% Cl 0·38-0·85; hep 1·0%, no hep 0·6%, RR 1·64, 95% Cl 1·09-2·45), whereas the overall incidence of stroke was similar in all groups. SK and tPA appear equally effective and safe for use in routine conditions of care, in all infarct patients who have no contraindications, with or without post-thrombolytic heparin treatment. The 8·8% hospital mortality of the study popula

Published
1990

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