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1. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

Author

Agodoa, L, Algra, A, Asselbergs, F W, Beckett, N, Berge, E, Black, H, Brouwers, F P J, Brown, M, Bulpitt, C J, Byington, B, Cutler, J, Devereaux, R B, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S E, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L H, Lueders, S, MacMahon, S, Mancia, G, Matsuzaki, M, Mehlum, M H, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Poulter, N R, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J A, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W H, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z Y, Anderson, C, Baigent, C, Brenner, BM, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundström, J, Turnbull, F, Viberti, G, Wang, J, Nazarzadeh, Milad, Bidel, Zeinab, Canoy, Dexter, Copland, Emma, Bennett, Derrick A, Dehghan, Abbas, Davey Smith, George, Holman, Rury R, Woodward, Mark, Gupta, Ajay, Adler, Amanda I, Wamil, Malgorzata, Sattar, Naveed, Cushman, William C, McManus, Richard J, Teo, Koon, Davis, Barry R, Chalmers, John, Pepine, Carl J, and Rahimi, Kazem

Published
2022
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2. Long-term exposure to antihypertensive drugs and the risk of cancer occurrence: evidence from a large population-based study

Author

Franchi, M, Torrigiani, G, Kjeldsen, S, Mancia, G, Corrao, G, Franchi M., Torrigiani G., Kjeldsen S. E., Mancia G., Corrao G., Franchi, M, Torrigiani, G, Kjeldsen, S, Mancia, G, Corrao, G, Franchi M., Torrigiani G., Kjeldsen S. E., Mancia G., and Corrao G.

Abstract

Objective: Available data on the association between antihypertensive drugs and cancer are characterized by a few years follow-up. Our aim has been to evaluate the association between long-term exposure to antihypertensive drugs and the risk of cancer occurrence. Methods: Using the healthcare utilization databases of the Lombardy region (Italy), individuals aged 40–85years who had no previous history of cancer and were newly dispensed with at least one antihypertensive drug from the major drug classes between 2009 and 2011 were followed from the first drug dispensation to December 31, 2020. Data were analyzed according to the first drug used and the intention to treat principle, but also via an ‘‘as treated’’ approach, that is, by considering changes of and exposure to drugs during follow-up. The association between the duration of exposure to each drug class and the risk of cancer occurrence was evaluated using the adjusted Cox regression models. Results: The study cohort included 338 910 new drug users (median age, 59years; 49.5% males). During a median follow-up of 10.2years, 36 556 cancers occurred. There was no consistent significant association between the risk of cancer occurrence and angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, or thiazides. A progressive, weak increase in cancer occurrence was associated with progressive exposure to calcium channel blockers and, limited to long-term exposure, to beta-blockers. A modest progressive increase in risk was observed also for thiazide-like and loop diuretics in the as treated, although not in the intention to treat approach. Conclusions: Long-term evaluation of exposure to antihypertensive drugs did not show consistent associations between thiazides, angiotensin-receptor blockers, or angiotensin-converting-enzyme inhibitors and the risk of cancer occurrence. A weak association was observed between cancer and the duration of exposure to calcium channel blockers and beta-blockers.

Published
2024

4. The current best drug treatment for hypertensive heart failure with preserved ejection fraction

Author

Rist, A, Sevre, K, Wachtell, K, Devereux, R, Aurigemma, G, Smiseth, O, Kjeldsen, S, Julius, S, Pitt, B, Burnier, M, Kreutz, R, Oparil, S, Mancia, G, Zannad, F, Rist A., Sevre K., Wachtell K., Devereux R. B., Aurigemma G. P., Smiseth O. A., Kjeldsen S. E., Julius S., Pitt B., Burnier M., Kreutz R., Oparil S., Mancia G., Zannad F., Rist, A, Sevre, K, Wachtell, K, Devereux, R, Aurigemma, G, Smiseth, O, Kjeldsen, S, Julius, S, Pitt, B, Burnier, M, Kreutz, R, Oparil, S, Mancia, G, Zannad, F, Rist A., Sevre K., Wachtell K., Devereux R. B., Aurigemma G. P., Smiseth O. A., Kjeldsen S. E., Julius S., Pitt B., Burnier M., Kreutz R., Oparil S., Mancia G., and Zannad F.

Abstract

More than 90 % of patients developing heart failure (HF) have hypertension. The most frequent concomitant conditions are type-2 diabetes mellitus, obesity, atrial fibrillation, and coronary disease. HF outcome research focuses on decreasing mortality and preventing hospitalization for worsening HF syndrome. All drugs that decrease these HF endpoints lower blood pressure. Current drug treatments for HF are (i) angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors, (ii) selected beta-blockers, (iii) steroidal and non-steroidal mineralocorticoid receptor antagonists, and (iv) sodium-glucose cotransporter 2 inhibitors. For various reasons, these drug treatments were first studied in HF patients with a reduced ejection fraction (HFrEF). Subsequently, they have been investigated in HF patients with a preserved left ventricular ejection fraction (LVEF, HFpEF) of mostly hypertensive etiology, and with modest benefits largely assessed on top of background treatment with the drugs already proven effective in HFrEF. Additionally, diuretics are given on symptomatic indications. Patients with HFpEF may have diastolic dysfunction but also systolic dysfunction visualized by lack of longitudinal shortening. Considering the totality of evidence and the overall need for antihypertensive treatment and/or treatment of hypertensive complications in almost all HF patients, the principal drug treatment of HF appears to be the same regardless of LVEF. Rather than LVEF-guided treatment of HF, treatment of HF should be directed by symptoms (related to the level of fluid retention), signs (tachycardia), severity (NYHA functional class), and concomitant diseases and conditions. All HF patients should be given all the drug classes mentioned above if well tolerated.

Published
2024

5. Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Author

Adler, A, Agodoa, L, Algra, A, Asselbergs, F W, Beckett, N, Berge, E, Black, H, Brouwers, F P J, Brown, M, Bulpitt, C J, Byington, B, Chalmers, J, Cushman, W C, Cutler, J, Davis, B R, Devereaux, R B, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A K, Holman, R R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S E, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L H, Lueders, S, MacMahon, S, Mancia, G, Matsuzaki, M, Mehlum, M H, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C J, Pfeffer, M, Poulter, N R, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J A, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W H, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z Y, Anderson, C, Baigent, C, Brenner, BM, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundström, J, Turnbull, F, Viberti, G, Wang, J, Copland, Emma, Canoy, Dexter, Nazarzadeh, Milad, Bidel, Zeinab, Ramakrishnan, Rema, Woodward, Mark, Chalmers, John, Teo, Koon K, Pepine, Carl J, Davis, Barry R, Kjeldsen, Sverre, Sundström, Johan, and Rahimi, Kazem

Published
2021
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6. 2024 European Society of Hypertension clinical practice guidelines for the management of arterial hypertension

Author

Kreutz, R, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, de Pinho, R, Albini, F, Boivin, J, Doumas, M, Nemcsik, J, Rodilla, E, Agabiti-Rosei, E, Algharably, E, Agnelli, G, Benetos, A, Hitij, J, Cífková, R, Cornelissen, V, Danser, A, Delles, C, Huelgas, R, Járai, Z, Palatini, P, Pathak, A, Persu, A, Polonia, J, Sarafidis, P, Stergiou, G, Thomopoulos, C, Wanner, C, Weber, T, Williams, B, Kjeldsen, S, Mancia, G, Kreutz, Reinhold, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, de Pinho, Rosa Maria, Albini, Fabio Lucio, Boivin, Jean-Marc, Doumas, Michalis, Nemcsik, János, Rodilla, Enrique, Agabiti-Rosei, Enrico, Algharably, Engi Abd Elhady, Agnelli, Giancarlo, Benetos, Athanase, Hitij, Jana Brguljan, Cífková, Renata, Cornelissen, Véronique, Danser, A H Jan, Delles, Christian, Huelgas, Ricardo Gómez, Járai, Zoltán, Palatini, Paolo, Pathak, Atul, Persu, Alexandre, Polonia, Jorge, Sarafidis, Pantelis, Stergiou, George, Thomopoulos, Costas, Wanner, Christoph, Weber, Thomas, Williams, Bryan, Kjeldsen, Sverre E, Mancia, Giuseppe, Kreutz, R, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, de Pinho, R, Albini, F, Boivin, J, Doumas, M, Nemcsik, J, Rodilla, E, Agabiti-Rosei, E, Algharably, E, Agnelli, G, Benetos, A, Hitij, J, Cífková, R, Cornelissen, V, Danser, A, Delles, C, Huelgas, R, Járai, Z, Palatini, P, Pathak, A, Persu, A, Polonia, J, Sarafidis, P, Stergiou, G, Thomopoulos, C, Wanner, C, Weber, T, Williams, B, Kjeldsen, S, Mancia, G, Kreutz, Reinhold, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, de Pinho, Rosa Maria, Albini, Fabio Lucio, Boivin, Jean-Marc, Doumas, Michalis, Nemcsik, János, Rodilla, Enrique, Agabiti-Rosei, Enrico, Algharably, Engi Abd Elhady, Agnelli, Giancarlo, Benetos, Athanase, Hitij, Jana Brguljan, Cífková, Renata, Cornelissen, Véronique, Danser, A H Jan, Delles, Christian, Huelgas, Ricardo Gómez, Járai, Zoltán, Palatini, Paolo, Pathak, Atul, Persu, Alexandre, Polonia, Jorge, Sarafidis, Pantelis, Stergiou, George, Thomopoulos, Costas, Wanner, Christoph, Weber, Thomas, Williams, Bryan, Kjeldsen, Sverre E, and Mancia, Giuseppe

Published
2024

7. Rationale of treatment recommendations in the 2023 ESH hypertension guidelines

Author

Mancia, G, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, Kjeldsen, S, Kreutz, R, Mancia, Giuseppe, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, Kjeldsen, Sverre E, Kreutz, Reinhold, Mancia, G, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, Kjeldsen, S, Kreutz, R, Mancia, Giuseppe, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, Kjeldsen, Sverre E, and Kreutz, Reinhold

Published
2024

10. Structural and electro-anatomical characterization of the equine pulmonary veins:implications for atrial fibrillation

Author

Kjeldsen, S. T., Nissen, S. D., Saljic, A., Hesselkilde, E. M., Carstensen, H., Sattler, S. M., Jespersen, T., Linz, D., Hopster-Iversen, C., Kutieleh, R., Sanders, P., Buhl, R., Kjeldsen, S. T., Nissen, S. D., Saljic, A., Hesselkilde, E. M., Carstensen, H., Sattler, S. M., Jespersen, T., Linz, D., Hopster-Iversen, C., Kutieleh, R., Sanders, P., and Buhl, R.

Abstract

Introduction/objectives: Spontaneous pulmonary vein (PV) activity triggers atrial fibrillation (AF) in humans. Although AF frequently occurs in horses, the origin remains unknown. This study investigated the structural and electro-anatomical properties of equine PVs to determine the potential presence of an arrhythmogenic substrate. Animals, materials and methods: Endocardial three-dimensional electro-anatomical mapping (EnSite Precision) using high-density (HD) catheters was performed in 13 sedated horses in sinus rhythm. Left atrium (LA) access was obtained retrogradely through the carotid artery. Post-mortem, tissue was harvested from the LA, right atrium (RA), and PVs for histological characterization and quantification of ion channel expression using immunohistochemical analysis. Results: Geometry, activation maps, and voltage maps of the PVs were created and a median of four ostia were identified. Areas of reduced conduction were found at the veno-atrial junction. The mean myocardial sleeve length varied from 28 ± 13 to 49 ± 22 mm. The PV voltage was 1.2 ± 1.4 mV and lower than the LA (3.4 ± 0.9 mV, P < 0.001). The fibrosis percentage was higher in PV myocardium (26.1 ± 6.6 %) than LA (14.5 ± 5.0 %, P = 0.003). L-type calcium channel (CaV1.2) expression was higher in PVs than LA (P = 0.001). T-type calcium channels (CaV3.3), connexin-43, ryanodine receptor-2, and small conductance calcium-activated potassium channel-3 was expressed in PVs. Conclusions: The veno-atrial junction had lower voltages, increased structural heterogeneity and areas of slower conduction. Myocardial sleeves had variable lengths, and a different ion channel expression compared to the atria. Heterogeneous properties of the PVs interacting with the adjacent LA likely provide the milieu for re-entry and AF initiation.

Published
2024

11. TIME to face the reality about evening dosing of antihypertensive drugs in hypertension

Author

Kjeldsen, S, Egan, B, Narkiewicz, K, Kreutz, R, Burnier, M, Oparil, S, Mancia, G, Kjeldsen S. E., Egan B. M., Narkiewicz K., Kreutz R., Burnier M., Oparil S., Mancia G., Kjeldsen, S, Egan, B, Narkiewicz, K, Kreutz, R, Burnier, M, Oparil, S, Mancia, G, Kjeldsen S. E., Egan B. M., Narkiewicz K., Kreutz R., Burnier M., Oparil S., and Mancia G.

Published
2023

12. Key questions regarding the SYMPLICITY HTN-3 trial

Author

Kjeldsen, S, Burnier, M, Narkiewicz, K, Kreutz, R, Mancia, G, Kjeldsen S. E., Burnier M., Narkiewicz K., Kreutz R., Mancia G., Kjeldsen, S, Burnier, M, Narkiewicz, K, Kreutz, R, Mancia, G, Kjeldsen S. E., Burnier M., Narkiewicz K., Kreutz R., and Mancia G.

Published
2023

13. Middle-Aged and Older Patients With Left Ventricular Hypertrophy: Higher Mortality With Drug Treated Systolic Blood Pressure Below 130 mm Hg

Author

Heimark, S, Mehlum, M, Mancia, G, Soraas, C, Liestol, K, Wachtell, K, Larstorp, A, Rostrup, M, Mariampillai, J, Kjeldsen, S, Julius, S, Weber, M, Heimark S., Mehlum M. H., Mancia G., Soraas C. L., Liestol K., Wachtell K., Larstorp A. C., Rostrup M., Mariampillai J. E., Kjeldsen S. E., Julius S., Weber M. A., Heimark, S, Mehlum, M, Mancia, G, Soraas, C, Liestol, K, Wachtell, K, Larstorp, A, Rostrup, M, Mariampillai, J, Kjeldsen, S, Julius, S, Weber, M, Heimark S., Mehlum M. H., Mancia G., Soraas C. L., Liestol K., Wachtell K., Larstorp A. C., Rostrup M., Mariampillai J. E., Kjeldsen S. E., Julius S., and Weber M. A.

Abstract

BACKGROUND: Approximately 40% of people with hypertension have left ventricular hypertrophy (LVH) detected by ECG or echocardiography. Because patients with LVH have poor myocardial microcirculation, they may be too sensitive to lowering systolic blood pressure (SBP) too much due to a lack of myocardial perfusion pressure. We aimed to investigate whether the average achieved SBP <130 mm Hg may cause harm in patients with LVH in the Valsartan Antihypertensive Long-Term Use Evaluation trial (VALUE). METHODS: Of the 15 245 VALUE participants, we identified 13 803 patients without cardiovascular events during the first 6 months after randomization. Of these, 2458 patients had electrocardiographic LVH (ECG-LVH). Cox analyses adjusted for age, gender, and baseline variables compared cardiac and all-cause mortality and other prespecified end points for patients who achieved average SBP 130 to 139 mm Hg (No-LVH group n=4863; ECG-LVH group n=929) and <130 mm Hg (No-LVH group n=2107; ECG-LVH group n=305). Reference groups were patients who achieved average SBP ≥140 mm Hg following the first excluded 6 months (No-LVH group n=4375; ECG-LVH group n=1224). RESULTS: The No-LVH group achieving average SBP <130 mm Hg had a significantly lower incidence of several cardiovascular end points. The ECG-LVH group achieving average SBP <130 mm Hg had higher cardiac mortality (hazard ratio, 1.98 [95% CIs, 1.06-3.70]; P=0.032) and all-cause mortality (hazard ratio, 1.74 [95% CIs, 1.17-2.60]; P=0.007), and SBP <130 mm Hg was not associated with a reduction in any end point. CONCLUSIONS: Our findings may be seen as a signal that caution is warranted when treating middle-aged and older patients with electrocardiographic or echocardiographic LVH to SBP <130 mm Hg.

Published
2023

15. AVERAGE ACHIEVED BP <130/80 MMHG IN HIGH-RISK MIDDLE-AGED AND OLDER HYPERTENSIVE PATIENTS PROVIDES STRONG CARDIOVASCULAR PROTECTION EXCEPT IN LEFT VENTRICULAR HYPERTROPHY

Author

Heimark, S, Mehlum, M, Mancia, G, Soraas, C, Liestöl, K, Kjeldsen, S, Larstorp, A, Rostrup, M, Mariampillai, J, Wachtell, K, Julius, S, Weber, M, Mehlum, MH, Soraas, CL, Kjeldsen, SE, Larstorp, ACK, Mariampillai, JE, Weber, MA, Heimark, S, Mehlum, M, Mancia, G, Soraas, C, Liestöl, K, Kjeldsen, S, Larstorp, A, Rostrup, M, Mariampillai, J, Wachtell, K, Julius, S, Weber, M, Mehlum, MH, Soraas, CL, Kjeldsen, SE, Larstorp, ACK, Mariampillai, JE, and Weber, MA

Published
2023

19. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA)

Author

Mancia, G, Kreutz, R, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, Agabiti-Rosei, E, Algharably, E, Azizi, M, Benetos, A, Borghi, C, Hitij, J, Cifkova, R, Coca, A, Cornelissen, V, Cruickshank, J, Cunha, P, Danser, A, Pinho, R, Delles, C, Dominiczak, A, Dorobantu, M, Doumas, M, Fernández-Alfonso, M, Halimi, J, Járai, Z, Jelaković, B, Jordan, J, Kuznetsova, T, Laurent, S, Lovic, D, Lurbe, E, Mahfoud, F, Manolis, A, Miglinas, M, Narkiewicz, K, Niiranen, T, Palatini, P, Parati, G, Pathak, A, Persu, A, Polonia, J, Redon, J, Sarafidis, P, Schmieder, R, Spronck, B, Stabouli, S, Stergiou, G, Taddei, S, Thomopoulos, C, Tomaszewski, M, Van de Borne, P, Wanner, C, Weber, T, Williams, B, Zhang, Z, Kjeldsen, S, Mancia, Giuseppe, Kreutz, Reinhold, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, Agabiti-Rosei, Enrico, Algharably, Engi Abd Elhady, Azizi, Michel, Benetos, Athanase, Borghi, Claudio, Hitij, Jana Brguljan, Cifkova, Renata, Coca, Antonio, Cornelissen, Veronique, Cruickshank, J Kennedy, Cunha, Pedro G, Danser, A H Jan, Pinho, Rosa Maria de, Delles, Christian, Dominiczak, Anna F, Dorobantu, Maria, Doumas, Michalis, Fernández-Alfonso, María S, Halimi, Jean-Michel, Járai, Zoltán, Jelaković, Bojan, Jordan, Jens, Kuznetsova, Tatiana, Laurent, Stephane, Lovic, Dragan, Lurbe, Empar, Mahfoud, Felix, Manolis, Athanasios, Miglinas, Marius, Narkiewicz, Krzystof, Niiranen, Teemu, Palatini, Paolo, Parati, Gianfranco, Pathak, Atul, Persu, Alexandre, Polonia, Jorge, Redon, Josep, Sarafidis, Pantelis, Schmieder, Roland, Spronck, Bart, Stabouli, Stella, Stergiou, George, Taddei, Stefano, Thomopoulos, Costas, Tomaszewski, Maciej, Van de Borne, Philippe, Wanner, Christoph, Weber, Thomas, Williams, Bryan, Zhang, Zhen-Yu, Kjeldsen, Sverre E, Mancia, G, Kreutz, R, Brunström, M, Burnier, M, Grassi, G, Januszewicz, A, Muiesan, M, Tsioufis, K, Agabiti-Rosei, E, Algharably, E, Azizi, M, Benetos, A, Borghi, C, Hitij, J, Cifkova, R, Coca, A, Cornelissen, V, Cruickshank, J, Cunha, P, Danser, A, Pinho, R, Delles, C, Dominiczak, A, Dorobantu, M, Doumas, M, Fernández-Alfonso, M, Halimi, J, Járai, Z, Jelaković, B, Jordan, J, Kuznetsova, T, Laurent, S, Lovic, D, Lurbe, E, Mahfoud, F, Manolis, A, Miglinas, M, Narkiewicz, K, Niiranen, T, Palatini, P, Parati, G, Pathak, A, Persu, A, Polonia, J, Redon, J, Sarafidis, P, Schmieder, R, Spronck, B, Stabouli, S, Stergiou, G, Taddei, S, Thomopoulos, C, Tomaszewski, M, Van de Borne, P, Wanner, C, Weber, T, Williams, B, Zhang, Z, Kjeldsen, S, Mancia, Giuseppe, Kreutz, Reinhold, Brunström, Mattias, Burnier, Michel, Grassi, Guido, Januszewicz, Andrzej, Muiesan, Maria Lorenza, Tsioufis, Konstantinos, Agabiti-Rosei, Enrico, Algharably, Engi Abd Elhady, Azizi, Michel, Benetos, Athanase, Borghi, Claudio, Hitij, Jana Brguljan, Cifkova, Renata, Coca, Antonio, Cornelissen, Veronique, Cruickshank, J Kennedy, Cunha, Pedro G, Danser, A H Jan, Pinho, Rosa Maria de, Delles, Christian, Dominiczak, Anna F, Dorobantu, Maria, Doumas, Michalis, Fernández-Alfonso, María S, Halimi, Jean-Michel, Járai, Zoltán, Jelaković, Bojan, Jordan, Jens, Kuznetsova, Tatiana, Laurent, Stephane, Lovic, Dragan, Lurbe, Empar, Mahfoud, Felix, Manolis, Athanasios, Miglinas, Marius, Narkiewicz, Krzystof, Niiranen, Teemu, Palatini, Paolo, Parati, Gianfranco, Pathak, Atul, Persu, Alexandre, Polonia, Jorge, Redon, Josep, Sarafidis, Pantelis, Schmieder, Roland, Spronck, Bart, Stabouli, Stella, Stergiou, George, Taddei, Stefano, Thomopoulos, Costas, Tomaszewski, Maciej, Van de Borne, Philippe, Wanner, Christoph, Weber, Thomas, Williams, Bryan, Zhang, Zhen-Yu, and Kjeldsen, Sverre E

Abstract

Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

Published
2023

20. Late outcomes of renal denervation are more favourable than early ones: facts or fancies?

Author

Persu, A, Stoenoiu, M, Maes, F, Kreutz, R, Mancia, G, Kjeldsen, S, Stoenoiu, MS, Kjeldsen, SE, Persu, A, Stoenoiu, M, Maes, F, Kreutz, R, Mancia, G, Kjeldsen, S, Stoenoiu, MS, and Kjeldsen, SE

Abstract

Following second-generation randomized trials, there is evidence that renal denervation (RDN) decreases blood pressure (BP), although to a lesser extent than suggested in the initial controlled and observational studies. The recent publication of the 36-month follow-up of the Symplicity HTN-3 trial has raised expectations, suggesting increasing, late benefits of the procedure, despite initially negative results. These findings come after those obtained at 36 months in the sham-controlled trial SPYRAL HTN-ON MED and in the Global Symplicity Registry. However, they are susceptible to biases inherent in observational studies (after unblinding for sham-control) and non-random, substantial attrition of treatment groups at 36 months, and used interpolation of missing BPs. More importantly, in SPYRAL HTN-ON MED and Symplicity HTN-3, long-term BP changes in patients from the initial RDN group were compared with those in a heterogeneous control group, including both control patients who did not benefit from RDN and patients who eventually crossed over to RDN. In crossover patients, the last BP before RDN was imputed to subsequent follow-up. In Symplicity HTN-3, this particular approach led to the claim of increasing long-term benefits of RDN. However, comparison of BP changes in patients from the RDN group and control patients who did not undergo RDN, without imputation of BPs from crossover patients, does not support this view. The good news is that despite the suggestion of sympathetic nerve regrowth after RDN in some animal models, there is no strong signal in favour of a decreasing effect of RDN over time, up to 24 or even 36 months. Still, current data do not support a long-term increase in the effect of RDN and the durability of RDN-related BP reduction remains to be formally demonstrated.

Published
2023

21. Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Author

Copland, E, Canoy, D, Nazarzadeh, M, Bidel, Z, Ramakrishnan, R, Woodward, M, Chalmers, J, Teo, K, Pepine, C, Davis, B, Kjeldsen, S, Sundstrom, J, Rahimi, K, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, B, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Turnbull, F, Viberti, G, Wang, J, Copland E., Canoy D., Nazarzadeh M., Bidel Z., Ramakrishnan R., Woodward M., Chalmers J., Teo K. K., Pepine C. J., Davis B. R., Kjeldsen S., Sundstrom J., Rahimi K., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington B., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C., Patel A., Pfeffer M., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Yui Y., Yusuf S., Zanchetti A., Zhang Z. Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Pitt B., Rodgers A., Rothwell P., Salimi-Khorshidi G., Turnbull F., Viberti G., Wang J., Copland, E, Canoy, D, Nazarzadeh, M, Bidel, Z, Ramakrishnan, R, Woodward, M, Chalmers, J, Teo, K, Pepine, C, Davis, B, Kjeldsen, S, Sundstrom, J, Rahimi, K, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, B, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Turnbull, F, Viberti, G, Wang, J, Copland E., Canoy D., Nazarzadeh M., Bidel Z., Ramakrishnan R., Woodward M., Chalmers J., Teo K. K., Pepine C. J., Davis B. R., Kjeldsen S., Sundstrom J., Rahimi K., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington B., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C., Patel A., Pfeffer M., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Yui Y., Yusuf S., Zanchetti A., Zhang Z. Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Pitt B., Rodgers A., Rothwell P., Salimi-Khorshidi G., Turnbull F., Viberti G., and Wang J.

Published
2021

22. Hypertension and heart failure with preserved ejection fraction: Position paper by the European Society ofHypertension

Author

Kasiakogias, A, Rosei, E, Camafort, M, Ehret, G, Faconti, L, Ferreira, J, Brguljan, J, Januszewicz, A, Kahan, T, Manolis, A, Tsioufis, K, Weber, T, Lueder, T, Smiseth, O, Wachtell, K, Kjeldsen, S, Zannad, F, Mancia, G, Kreutz, R, Kasiakogias A., Rosei E. A., Camafort M., Ehret G., Faconti L., Ferreira J. P., Brguljan J., Januszewicz A., Kahan T., Manolis A., Tsioufis K., Weber T., Lueder T. G. v., Smiseth O. A., Wachtell K., Kjeldsen S. E., Zannad F., Mancia G., Kreutz R., Kasiakogias, A, Rosei, E, Camafort, M, Ehret, G, Faconti, L, Ferreira, J, Brguljan, J, Januszewicz, A, Kahan, T, Manolis, A, Tsioufis, K, Weber, T, Lueder, T, Smiseth, O, Wachtell, K, Kjeldsen, S, Zannad, F, Mancia, G, Kreutz, R, Kasiakogias A., Rosei E. A., Camafort M., Ehret G., Faconti L., Ferreira J. P., Brguljan J., Januszewicz A., Kahan T., Manolis A., Tsioufis K., Weber T., Lueder T. G. v., Smiseth O. A., Wachtell K., Kjeldsen S. E., Zannad F., Mancia G., and Kreutz R.

Abstract

Hypertension constitutes a major risk factor for heart failure with preserved ejection fraction (HFpEF). HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality. Specific guideline-directed medical therapy (GDMT) for HFpEF is not established due to lack of positive outcome data from randomized controlled trials (RCTs) and limitations of available studies. Although available evidence is limited, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensinconverting enzyme inhibitors or angiotensin receptor blockers provides the backbone of BP-lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, we propose that this core drug treatment strategy is also applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor. In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors, currently already indicated for high-risk patients with diabetes to reduce heart failure hospitalizations, and finerenone represent promising therapies and results from ongoing RCTs are eagerly awaited. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high-quality RCTs are major unmet needs in hypertension research and calls for action.

Published
2021

23. Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis

Author

Rahimi, K, Bidel, Z, Nazarzadeh, M, Copland, E, Canoy, D, Wamil, M, Majert, J, Mcmanus, R, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Boersma, E, Brouwers, F, Brown, M, Brugts, J, Bulpitt, C, Byington, R, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Chalmers, J, Davis, B, Pepine, C, Teo, K, Rahimi K., Bidel Z., Nazarzadeh M., Copland E., Canoy D., Wamil M., Majert J., McManus R., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Boersma E., Brouwers F. P. J., Brown M., Brugts J. J., Bulpitt C. J., Byington R. P., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J. P., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Chalmers J., Davis B. R., Pepine C. J., Teo K. K., Rahimi, K, Bidel, Z, Nazarzadeh, M, Copland, E, Canoy, D, Wamil, M, Majert, J, Mcmanus, R, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Boersma, E, Brouwers, F, Brown, M, Brugts, J, Bulpitt, C, Byington, R, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Chalmers, J, Davis, B, Pepine, C, Teo, K, Rahimi K., Bidel Z., Nazarzadeh M., Copland E., Canoy D., Wamil M., Majert J., McManus R., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Boersma E., Brouwers F. P. J., Brown M., Brugts J. J., Bulpitt C. J., Byington R. P., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J. P., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Chalmers J., Davis B. R., Pepine C. J., and Teo K. K.

Abstract

Background: The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods: We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (<55 years, 55–64 years, 65–74 years, 75–84 years, and ≥85 years) and blood pressure categories (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg systolic blood pressure and from <70 mm Hg to ≥110 mm Hg diastolic). We used a fixed effects one-stage approach and applied Cox proportional hazard models, stratified by trial, to analyse the data. The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission. Findings: We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg

Published
2021

24. Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus compared to all middle-aged and elderly hypertensive study patients with high cardiovascular risk

Author

Olsen, E, Holzhauer, B, Julius, S, Kjeldsen, S, Larstorp, A, Mancia, G, Mehlum, M, Mo, R, Rostrup, M, Soraas, C, Zappe, D, Weber, M, Olsen E., Holzhauer B., Julius S., Kjeldsen S. E., Larstorp A. C. K., Mancia G., Mehlum M. H., Mo R., Rostrup M., Soraas C. L., Zappe D., Weber M. A., Olsen, E, Holzhauer, B, Julius, S, Kjeldsen, S, Larstorp, A, Mancia, G, Mehlum, M, Mo, R, Rostrup, M, Soraas, C, Zappe, D, Weber, M, Olsen E., Holzhauer B., Julius S., Kjeldsen S. E., Larstorp A. C. K., Mancia G., Mehlum M. H., Mo R., Rostrup M., Soraas C. L., Zappe D., and Weber M. A.

Abstract

Purpose: Event-based clinical outcome trials have shown limited evidence to support guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly hypertensive patients with diabetes mellitus or with general high cardiovascular (CV) risk. We addressed this issue by post-hoc analysing the risk of CV events in patients who participated in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and compared the hypertensive patients with type 2 diabetes mellitus with all high-risk hypertensive patients. Materials and methods: Patients were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥75%) in which BP was reduced to <140/90 or <130/80 mmHg. Patients with diabetes mellitus (n = 5250) were compared with the entire VALUE population with high CV risk (n = 15,245). Results: After adjustments for baseline differences between groups, a reduction in the proportion of visits in which BP was reduced to <140/90 mmHg, but not to <130/80 mmHg, was accompanied by a progressive increase in the risk of CV morbidity and mortality as well as stroke, myocardial infarction and heart failure in both diabetes mellitus and in all high-risk patients. Target BP <130/80 mmHg reduced stroke risk in the main population but not in the diabetes mellitus patients. Patients with diabetes mellitus had higher event rates for the primary cardiac endpoint and all-cause mortality driven by a higher rate of heart failure. Conclusion: In the high-risk hypertensive patients of the VALUE trial achieving more frequently BP <140/90 mmHg, but not <130/80 mmHg, showed principally the same protective effect on overall and cause-specific cardiovascular outcomes in patients with diabetes mellitus and in the general high-risk hypertensive population.

Published
2021

25. Cardiovascular outcomes at recommended blood pressure targets in middle-aged and elderly patients with type 2 diabetes mellitus and hypertension

Author

Olsen, E, Holzhauer, B, Julius, S, Kjeldsen, S, Larstorp, A, Mancia, G, Mehlum, M, Mo, R, Rostrup, M, Soraas, C, Zappe, D, Weber, M, Olsen E., Holzhauer B., Julius S., Kjeldsen S. E., Larstorp A. C. K., Mancia G., Mehlum M. H., Mo R., Rostrup M., Soraas C. L., Zappe D., Weber M. A., Olsen, E, Holzhauer, B, Julius, S, Kjeldsen, S, Larstorp, A, Mancia, G, Mehlum, M, Mo, R, Rostrup, M, Soraas, C, Zappe, D, Weber, M, Olsen E., Holzhauer B., Julius S., Kjeldsen S. E., Larstorp A. C. K., Mancia G., Mehlum M. H., Mo R., Rostrup M., Soraas C. L., Zappe D., and Weber M. A.

Abstract

Purpose: Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly people with type 2 diabetes mellitus and hypertension. We addressed this issue by post-hoc analysing the risk of cardiovascular (CV) events in mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. Material and methods: Patients (n = 5250) were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥ 75%) in which BP was reduced to <140/90 or <130/80 mmHg. Results: After adjustment for baseline demographic differences between groups, a reduction in the proportion of visits in which BP achieved <140/90 mmHg accompanied a progressive increase in the risk of CV mortality and morbidity as well as of cause-specific events such as stroke, myocardial infarction and heart failure. A progressive reduction in the proportion of visits in which BP was reduced <130/80 mmHg did not have any effect on CV risks. Conclusion: In mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the VALUE trial, achieving more frequently BP <140/90 mmHg showed a marked protective effect on overall and all cause-specific cardiovascular outcomes. This was not the case for a more frequent achievement of the more intensive BP target, i.e. <130/80 mmHg.

Published
2021

26. Missing Verification of Source Data in Hypertension Research: The HYGIA PROJECT in Perspective

Author

Brunstrom, M, Kjeldsen, S, Kreutz, R, Gjesdal, K, Narkiewicz, K, Burnier, M, Oparil, S, Mancia, G, Brunstrom M., Kjeldsen S. E., Kreutz R., Gjesdal K., Narkiewicz K., Burnier M., Oparil S., Mancia G., Brunstrom, M, Kjeldsen, S, Kreutz, R, Gjesdal, K, Narkiewicz, K, Burnier, M, Oparil, S, Mancia, G, Brunstrom M., Kjeldsen S. E., Kreutz R., Gjesdal K., Narkiewicz K., Burnier M., Oparil S., and Mancia G.

Published
2021

28. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis

Author

Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, R, Chalmers, J, Cushman, W, Cutler, J, Davis, B, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington R. P., Chalmers J., Cushman W. C., Cutler J., Davis B. R., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pepine C. J., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, R, Chalmers, J, Cushman, W, Cutler, J, Davis, B, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington R. P., Chalmers J., Cushman W. C., Cutler J., Davis B. R., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pepine C. J., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., and Wang J.

Abstract

Background: The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods: We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat. Findings: Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/8

Published
2021

32. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

Author

Nazarzadeh, Milad, primary, Bidel, Zeinab, additional, Canoy, Dexter, additional, Copland, Emma, additional, Bennett, Derrick A, additional, Dehghan, Abbas, additional, Davey Smith, George, additional, Holman, Rury R, additional, Woodward, Mark, additional, Gupta, Ajay, additional, Adler, Amanda I, additional, Wamil, Malgorzata, additional, Sattar, Naveed, additional, Cushman, William C, additional, McManus, Richard J, additional, Teo, Koon, additional, Davis, Barry R, additional, Chalmers, John, additional, Pepine, Carl J, additional, Rahimi, Kazem, additional, Agodoa, L, additional, Algra, A, additional, Asselbergs, F W, additional, Beckett, N, additional, Berge, E, additional, Black, H, additional, Brouwers, F P J, additional, Brown, M, additional, Bulpitt, C J, additional, Byington, B, additional, Cutler, J, additional, Devereaux, R B, additional, Dwyer, J, additional, Estacio, R, additional, Fagard, R, additional, Fox, K, additional, Fukui, T, additional, Imai, Y, additional, Ishii, M, additional, Julius, S, additional, Kanno, Y, additional, Kjeldsen, S E, additional, Kostis, J, additional, Kuramoto, K, additional, Lanke, J, additional, Lewis, E, additional, Lewis, J, additional, Lievre, M, additional, Lindholm, L H, additional, Lueders, S, additional, MacMahon, S, additional, Mancia, G, additional, Matsuzaki, M, additional, Mehlum, M H, additional, Nissen, S, additional, Ogawa, H, additional, Ogihara, T, additional, Ohkubo, T, additional, Palmer, C, additional, Patel, A, additional, Pfeffer, M, additional, Poulter, N R, additional, Rakugi, H, additional, Reboldi, G, additional, Reid, C, additional, Remuzzi, G, additional, Ruggenenti, P, additional, Saruta, T, additional, Schrader, J, additional, Schrier, R, additional, Sever, P, additional, Sleight, P, additional, Staessen, J A, additional, Suzuki, H, additional, Thijs, L, additional, Ueshima, K, additional, Umemoto, S, additional, van Gilst, W H, additional, Verdecchia, P, additional, Wachtell, K, additional, Whelton, P, additional, Wing, L, additional, Yui, Y, additional, Yusuf, S, additional, Zanchetti, A, additional, Zhang, Z Y, additional, Anderson, C, additional, Baigent, C, additional, Brenner, BM, additional, Collins, R, additional, de Zeeuw, D, additional, Lubsen, J, additional, Malacco, E, additional, Neal, B, additional, Perkovic, V, additional, Pitt, B, additional, Rodgers, A, additional, Rothwell, P, additional, Salimi-Khorshidi, G, additional, Sundström, J, additional, Turnbull, F, additional, Viberti, G, additional, and Wang, J, additional

Published
2022
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38. Diverse pharmacological properties, trial results, comorbidity prescribing and neural pathophysiology suggest European hypertension guideline downgrading of beta-blockers is not justified

Author

Esler, M, Kjeldsen, S, Pathak, A, Grassi, G, Kreutz, R, Mancia, G, Esler M, Kjeldsen SE, Pathak A, Grassi G, Kreutz R, Mancia G, Esler, M, Kjeldsen, S, Pathak, A, Grassi, G, Kreutz, R, Mancia, G, Esler M, Kjeldsen SE, Pathak A, Grassi G, Kreutz R, and Mancia G

Abstract

Beta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trials. Hypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rate. Beta-blockers represent a heterogenous class of drugs with regard to both pharmacodynamic and pharmacokinetic properties. This position is manifest by reference to another clinical context, beta-blocker treatment of heart failure, where unequivocally there is no class effect (no similar benefit from all beta-blockers); there are good and less good beta-blockers for heart failure. Analogous differences in beta-blocker efficacy is also likely in hypertension. Beta-blockers are widely used for the treatment of diseases comorbid with hypertension, in approximately 50 different concomitant medical conditions that are frequent in patients with hypertension, leading to many de facto beta-blocker first choices in clinical practice. Thus, beta-blockers should be regarded as relevant first choices for hypertension in clinical practice, particularly if characterised by a long half-life, highly selective beta-1 blocking activity and no intrinsic agonist properties.SUMMARYBeta-blockers have solid documentation in preventing cardiovascular complications in the treatment of hypertension; atenolol, metoprolol, oxprenolol and propranolol demonstrate proven cardiovascular prevention in hypertension mega-trialsHypertension is characterised by activation of the sympathetic nervous system from early to late phases, which makes beta-blockers an appropriate treatment seen from a pathophysiological viewpoint, especially in patients with an elevated heart rateBeta-blockers represent a heterogenous class of drug

Published
2022

39. Individualized Beta-Blocker Treatment for High Blood Pressure Dictated by Medical Comorbidities: Indications Beyond the 2018 European Society of Cardiology/European Society of Hypertension Guidelines

Author

Mancia, G, Kjeldsen, S, Kreutz, R, Pathak, A, Grassi, G, Esler, M, Mancia, Giuseppe, Kjeldsen, Sverre E, Kreutz, Reinhold, Pathak, Atul, Grassi, Guido, Esler, Murray, Mancia, G, Kjeldsen, S, Kreutz, R, Pathak, A, Grassi, G, Esler, M, Mancia, Giuseppe, Kjeldsen, Sverre E, Kreutz, Reinhold, Pathak, Atul, Grassi, Guido, and Esler, Murray

Abstract

Several hypertension guidelines have removed beta-blockers from their previous position as first-choice drugs for the treatment of hypertension. However, this downgrading may not be justified by available evidence because beta-blockers lower blood pressure as effectively as other major antihypertensive drugs and have solid documentation in preventing cardiovascular complications. Suspected inconveniences of beta-blockers such as increased risk of depression or erectile dysfunction may have been overemphasized, while patients with chronic obstructive pulmonary disease or peripheral artery disease, that is, conditions in which their use was previously restricted, will benefit from beta-blocker therapy. Besides, evidence that from early to late phases, hypertension is accompanied by activation of the sympathetic nervous system makes beta-blockers pathophysiologically an appropriate treatment in hypertension. Beta-blockers have favorable effects on a variety of clinical conditions that may coexist with hypertension, making their use either as specific treatment or as co-treatment potentially common in clinical practice. Guidelines typically limit recommendations on specific beta-blocker use to cardiac conditions including angina pectoris, postmyocardial infarction, or heart failure, with little or no mention of the additional cardiovascular or noncardiovascular conditions in which these drugs may be needed or preferred. In the present narrative review, we focus on multiple additional diseases and conditions that may occur and affect patients with hypertension, often more frequently than people without hypertension, and that may favor the choice of beta-blocker. Notwithstanding, beta-blockers represent an in-homogenous group of drugs and choosing beta-blockers with documented effect in prevention and treatment of disease is important for first choice in guidelines.

Published
2022

41. Blood Pressure-Lowering Profiles and Clinical Effects of Angiotensin Receptor Blockers Versus Calcium Channel Blockers

Author

Mehlum, M, Liestol, K, Kjeldsen, S, Wyller, T, Julius, S, Rothwell, P, Mancia, G, Parati, G, Weber, M, Berge, E, Mehlum M. H., Liestol K., Kjeldsen S. E., Wyller T. B., Julius S., Rothwell P. M., Mancia G., Parati G., Weber M. A., Berge E., Mehlum, M, Liestol, K, Kjeldsen, S, Wyller, T, Julius, S, Rothwell, P, Mancia, G, Parati, G, Weber, M, Berge, E, Mehlum M. H., Liestol K., Kjeldsen S. E., Wyller T. B., Julius S., Rothwell P. M., Mancia G., Parati G., Weber M. A., and Berge E.

Abstract

Blood pressure-lowering drugs have different blood pressure-lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg (P values <0.0001). The higher risks of myocardial infarction and stroke in the valsartan group was attenuated after adjustment for mean and variability of systolic blood pressure, from HR 1.19 (95% CI, 1.02-1.39) to 1.11 (0.96-1.30) and from HR 1.13 (0.96-1.33) to 1.00 (0.85-1.18), respectively. The lower risk of congestive heart failure in the valsartan group was accentuated after adjustment, from HR 0.86 (0.74-1.00) to 0.76 (0.65-0.89). A smaller effect was seen on risk of death, from 1.01 (0.92-1.12) to 0.94 (0.85-1.04). In conclusion, the higher risks of myocardial infarction and stroke in patients randomized to valsartan versus amlodipine were related to the drugs' different blood pressure modulating profiles. The risk of congestive heart failure with valsartan was lower, independent of the less favorable blood pressure modulating profile.

Published
2020

42. Circadian variations in blood pressure and their implications for the administration of antihypertensive drugs: Is dosing in the evening better than in the morning?

Author

Burnier, M, Kreutz, R, Narkiewicz, K, Kjeldsen, S, Oparil, S, Mancia, G, Burnier M., Kreutz R., Narkiewicz K., Kjeldsen S., Oparil S., Mancia G., Burnier, M, Kreutz, R, Narkiewicz, K, Kjeldsen, S, Oparil, S, Mancia, G, Burnier M., Kreutz R., Narkiewicz K., Kjeldsen S., Oparil S., and Mancia G.

Abstract

Blood pressure (BP) follows a circadian rhythm with a physiological decrease during the night. Studies have demonstrated that nocturnal BP as well as its dipping pattern during night-time have a significant prognostic importance for mortality and the occurrence of cardiovascular events. Therefore, hypertension management guidelines recommend to ascertain that patients treated for hypertension have well controlled BP values around the clock. To improve hypertension control during the night and eventually further reduce cardiovascular events, it has been proposed by some to prescribe at least one antihypertensive medication at bedtime. In this review, we have examined the data which could support the benefits of prescribing BP-lowering drugs at bedtime. Our conclusion is that there is no convincing evidence that the administration of BP-lowering drugs in the evening provides any significant advantage in terms of quality of BP control, prevention of target organ damage or reduction of cardiovascular events. Before changing practice for unproven benefits, it would be wise to wait for the results of the ongoing trials that are addressing this issue.

Published
2020

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