Beta‐bloqueantes para la hipertensión
Resumen
Antecedentes
Los betabloqueantes hacen referencia a un grupo mixto de fármacos con diversas propiedades farmacodinámicas y farmacocinéticas. Han demostrado tener efectos beneficiosos a largo plazo sobre la mortalidad y las enfermedades cardiovasculares (ECV) cuando se utilizan en personas con insuficiencia cardíaca o infarto agudo de miocardio. Se pensaba que los betabloqueantes tenían efectos beneficiosos similares cuando se utilizaban como terapia de primera línea para la hipertensión. Sin embargo, el beneficio de los betabloqueantes como terapia de primera línea para la hipertensión sin indicaciones convincentes es controvertido. Esta revisión es una actualización de una revisión Cochrane publicada inicialmente en 2007 y actualizada en 2012.
Objetivos
Evaluar los efectos de los betabloqueantes en las variables de evaluación de morbilidad y la mortalidad en adultos con hipertensión.
Métodos de búsqueda
El Especialista en Información sobre la Hipertensión de la Cochrane buscó en las siguientes bases de datos ensayos controlados aleatorios hasta junio de 2016: el Registro Especializado Cochrane de Hipertensión, el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (2016, número 6), MEDLINE (desde 1946), Embase (desde 1974) y ClinicalTrials.gov. Se verificaron las listas de referencias de las revisiones pertinentes y las listas de referencias de los estudios potencialmente elegibles para su inclusión en esta revisión, y también se realizaron búsquedas en la Plataforma de Registro Internacional de Ensayos Clínicos de la Organización Mundial de la Salud el 06 de julio de 2015.
Criterios de selección
Ensayos controlados aleatorizados (ECA) de al menos un año de duración, que evaluaron los efectos de los betabloqueantes en comparación con el placebo u otros fármacos, como tratamiento de primera línea para la hipertensión, sobre la mortalidad y la morbilidad en adultos.
Obtención y análisis de los datos
Los estudios y la extracción de datos fue realizada por duplicado, resolviendo las discrepancias por consenso. Los resultados de los estudios se expresaron como riesgo relativo (RR) con intervalos de confianza (IC) del 95% y se realizaron metanálisis de efectos fijos o aleatorios, según correspondiera. Para evaluar la certeza de la evidencia se utilizó GRADE. GRADE clasifica la certeza de la evidencia como alta (si estamos seguros de que el verdadero efecto se aproxima al de la estimación del efecto), moderada (si es probable que el verdadero efecto se aproxime a la estimación del efecto), baja (si el verdadero efecto puede ser sustancialmente diferente de la estimación del efecto), y muy baja (si estamos muy inseguros sobre la estimación del efecto).
Resultados principales
Trece ECAs cumplieron los criterios de inclusión. Compararon los betabloqueantes con el placebo (4 ECA, 23.613 participantes), los diuréticos (5 ECA, 18.241 participantes), los bloqueadores de los canales de calcio (BCC): 4 ECA, 44.825 participantes), y los inhibidores del sistema renina‐angiotensina (SRA) (3 ECA, 10.828 participantes). Estos ECA se realizaron entre los decenios de 1970 y 2000 y la mayoría de ellos presentaban un alto riesgo de sesgo debido a las limitaciones en el diseño, la realización y el análisis de los datos de los estudios. Había 40.245 participantes tomando beta‐bloqueantes, tres cuartas partes de ellos tomando atenolol. No se encontraron resultados que incluyeran los nuevos betabloqueantes vasodilatadores (por ejemplo, el nebivolol).
No hubo diferencias en la mortalidad por todas las causas entre los betabloqueantes y el placebo (RR 0,99; IC del 95%: 0,88 a 1,11), los diuréticos o los inhibidores del SRA, pero fue mayor para los betabloqueantes en comparación con los BCC (RR 1,07; IC del 95%: 1,00 a 1,14). La evidencia sobre la mortalidad fue de una certeza moderada en todas las comparaciones.
La ECV total fue menor para los betabloqueantes en comparación con el placebo (RR 0,88; IC del 95%: 0,79 a 0,97; baja certeza de la evidencia), lo que refleja la disminución de los accidentes cerebrovasculares (RR 0,80; IC del 95%: 0,66 a 0,96; baja certeza de la evidencia), ya que no hubo diferencias en la enfermedad coronaria (ECC: RR 0,93, IC del 95%: 0,81 a 1,07, moderada certeza de la evidencia). El efecto de los betabloqueantes en las ECV fue peor que el de los BCC (RR 1,18; IC del 95%: 1,08 a 1,29; moderada certeza de la evidencia), pero no fue diferente del de los diuréticos (certeza moderada) o los inhibidores del SRA (certeza baja). Además, hubo un aumento de los accidentes cerebrovasculares en los betabloqueantes en comparación con los BCC (RR 1,24; IC del 95%: 1,11 a 1,40; moderada certeza de la evidencia) y los inhibidores del SRA (RR 1,30; IC del 95%: 1,11 a 1,53; moderada certeza de la evidencia). Sin embargo, había poca o ninguna diferencia en la ECC entre los betabloqueantes y los diuréticos (baja certeza de la evidencia), los BCC (moderada certeza de la evidencia) o los inhibidores del SRA (baja certeza de la evidencia). En el único ensayo que incluyó participantes de 65 años de edad o más, el atenolol se asoció con una mayor incidencia de cardiopatía coronaria en comparación con los diuréticos (RR 1,63; IC del 95%: 1,15 a 2,32). Los participantes que tomaban betabloqueantes tenían más probabilidades de interrumpir el tratamiento debido a eventos adversos que los participantes que tomaban inhibidores del SRA (RR 1,41; IC del 95%: 1,29 a 1,54; moderada certeza de la evidencia), pero había poca o ninguna diferencia con el placebo, los diuréticos o los BCC (baja certeza de la evidencia).
Conclusiones de los autores
La mayoría de los resultados de los ECA sobre betabloqueantes como terapia inicial para la hipertensión tienen un alto riesgo de sesgo. El atenolol fue el beta‐bloqueante más utilizado. La evidencia actual indica que el inicio del tratamiento de la hipertensión con betabloqueantes da lugar a una modesta reducción de las ECV y a poco o ningún efecto en la mortalidad. Estos efectos de los betabloqueantes son inferiores a los de otros medicamentos antihipertensivos. Las futuras investigaciones deben ser de alta calidad y deben explorar si existen diferencias entre los diferentes subtipos de betabloqueantes o si los betabloqueantes tienen efectos diferenciales en los jóvenes y los ancianos.
PICO
Resumen en términos sencillos
Beta‐bloqueantes para la hipertensión
¿Cuál era el objetivo de esta revisión?
El objetivo de esta revisión Cochrane fue evaluar si los betabloqueantes disminuyen el número de muertes, accidentes cerebrovasculares e infartos de miocardio asociados con la hipertensión arterial en adultos. Se recopilaron y analizaron todos los estudios relevantes para responder a esta pregunta y se encontraron 13 estudios pertinentes.
¿Son los betabloqueantes tan buenos como otros medicamentos cuando se utilizan para el tratamiento de adultos con hipertensión?
Los betabloqueantes no fueron tan buenos para prevenir el número de muertes, accidentes cerebrovasculares y ataques cardíacos como otras clases de medicamentos como los diuréticos, los bloqueadores del canal de calcio y los inhibidores del sistema renina‐angiotensina. La mayoría de estos hallazgos provienen de un tipo de beta‐bloqueador llamado atenolol. Sin embargo, los betabloqueantes son un grupo diverso de medicinas con diferentes propiedades, y se necesita más investigación bien realizada en esta área.
¿Qué se estudió en la revisión?
Millones de personas con hipertensión arterial sufren accidentes cerebrovasculares, ataques cardíacos y otras enfermedades, y muchos de ellos mueren. Esta situación podría prevenirse con un tratamiento adecuado. Los investigadores han probado diferentes medicamentos para tratar la presión arterial alta.
¿Cuáles son los principales resultados de la revisión?
Se encontraron 13 estudios de países de ingresos altos, principalmente de Europa occidental y América del Norte. En los estudios, se compararon personas que recibían betabloqueantes con personas que no recibían ningún tratamiento u otros medicamentos. Los estudios revelaron lo siguiente.
Los betabloqueantes probablemente tienen poca o ninguna diferencia en el número de muertes entre las personas que reciben tratamiento para la hipertensión. Este efecto parece ser similar al de los diuréticos y los inhibidores del sistema renina‐angiotensina, pero los betabloqueantes probablemente no son tan buenos para prevenir las muertes por hipertensión como los bloqueantes del canal del calcio.
Los betabloqueantes pueden reducir el número de accidentes cerebrovasculares, un efecto que parece ser similar al de los diuréticos. Sin embargo, los betabloqueantes pueden no ser tan buenos en la prevención de los accidentes cerebrovasculares como los inhibidores del sistema renina‐angiotensina o los bloqueadores del canal de calcio.
Los betabloqueantes pueden marcar una diferencia mínima o nula en el número de ataques cardíacos entre las personas con hipertensión. La evidencia sugiere que este efecto puede no ser diferente del de los diuréticos, los inhibidores del sistema renina‐angiotensina o los bloqueadores del canal del calcio. Sin embargo, entre las personas de 65 años o más, la evidencia sugiere que los betabloqueantes pueden no ser tan buenos para reducir los ataques cardíacos como los diuréticos.
Las personas que reciben betabloqueantes tienen más probabilidades de sufrir efectos secundarios y de interrumpir el tratamiento que las personas que toman inhibidores del sistema renina‐angiotensina, pero puede haber poca o ninguna diferencia en los efectos secundarios entre los betabloqueantes y los diuréticos o los bloqueadores del canal del calcio.
¿Cuán actualizada está esta revisión?
Los autores de la revisión buscaron estudios que se habían publicado hasta junio 2016.
Authors' conclusions
Summary of findings
| Beta‐blockers versus placebo as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Beta‐blockers | ||||
| Total mortality | 52 per 1000 | 51 per 1000 | RR 0.99 | 23613 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 64 per 1000 | 57 per 1000 | RR 0.88 | 23613 | ⊕⊕⊝⊝ |
| Total stroke | 23 per 1000 | 18 per 1000 | RR 0.80 | 23613 | ⊕⊕⊝⊝ |
| Total coronary heart disease | 37 per 1000 | 34 per 1000 | RR 0.93 | 23613 | ⊕⊕⊕⊝ |
| Withdrawal due to adverse effect | 74 per 1000 | 249 per 1000 | RR 3.38 | 22729 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The two studies that contribute to the most weight of the pooled RR have high risk of bias (especially incomplete outcome reporting due to attrition bias): downgraded by 1 point. | |||||
| Beta‐blockers compared to diuretics as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Diuretics | Beta‐blockers | ||||
| Total mortality | 41 per 1000 | 43 per 1000 | RR 1.04 | 18241 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 45 per 1000 | 51 per 1000 | RR 1.13 | 18135 | ⊕⊕⊕⊝ |
| Total stroke | 12 per 1000 | 14 per 1000 | RR 1.17 | 18135 | ⊕⊕⊝⊝ |
| Total coronary heart disease | 33 per 1000 | 37 per 1000 | RR 1.12 | 18135 | ⊕⊕⊝⊝ |
| Withdrawal due to adverse effect | 109 per 1000 | 184 per 1000 | RR 1.69 | 11566 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The two studies that contribute to the most weight of the pooled RR have high risk of bias (especially incomplete outcome reporting due to attrition bias): downgraded by 1 point. | |||||
| Beta‐blockers compared to calcium‐channel blockers as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Calcium‐channel blockers | Beta‐blockers | ||||
| Total mortality | 73 per 1000 | 78 per 1000 | RR 1.07 | 44825 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 81 per 1000 | 96 per 1000 | RR 1.18 | 19915 | ⊕⊕⊕⊝ |
| Total stroke | 23 per 1000 | 29 per 1000 | RR 1.24 | 44167 | ⊕⊕⊕⊝ |
| Total coronary heart disease | 39 per 1000 | 41 per 1000 | RR 1.05 | 44167 | ⊕⊕⊕⊝ |
| Withdrawal due to adverse effect | 33 per 1000 | 40 per 1000 | RR 1.20 | 21591 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The RR is too close to 1 and could easily include 1 if more trials are added: downgraded by 1 point. 2 Only 2 hypertension trials comparing beta‐blockers to calcium‐channel blockers have reported data on this outcome: downgraded by 1 point. 4 Inconsistent results across studies (I2 = 93%): downgraded by 1 point. | |||||
| Beta‐blockers compared to renin‐angiotensin system inhibitors as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Renin‐angiotensin system inhibitors | Beta‐blockers | ||||
| Total mortality | 84 per 1000 | 92 per 1000 | RR 1.10 | 10828 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 115 per 1000 | 115 per 1000 | RR 1.0 | 10828 | ⊕⊕⊝⊝ |
| Total stroke | 51 per 1000 | 66 per 1000 | RR 1.30 | 9951 | ⊕⊕⊕⊝ |
| Total coronary heart disease | 54 per 1000 | 49 per 1000 | RR 0.90 | 9951 | ⊕⊕⊝⊝ |
| Withdrawal due to adverse effect | 137 per 1000 | 194 per 1000 | RR 1.41 | 9951 | ⊕⊕⊕⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Only 3 hypertension trials comparing beta‐blockers to RAS inhibitors have reported data on this outcome: downgraded by 1 point. 4 Imprecise results, as the effect ranges from a clinically important benefit to a small increase in harm: downgraded by 1 point. | |||||
Background
Description of the condition
Hypertension is one of the leading causes of disability and premature deaths worldwide (GBD 2015). The rationale for treating hypertension achieved great impetus with the finding that even small reductions in blood pressure can significantly reduce associated morbidity and mortality risks (Collins 1990; Staessen 2003; Thomopoulos 2015). The major classes of drugs for treating hypertension include beta‐blockers, calcium‐channel blockers (CCBs), diuretics, and renin‐angiotensin system (RAS) inhibitors (Wiysonge 2013).
Description of the intervention
Beta‐blockers refer to a diverse group of drugs which block the action of endogenous catecholamines on beta‐adrenergic receptors, part of the autonomic (or sympathetic) nervous system (Wiysonge 2007a). The autonomic nervous system has been known to play a role in blood pressure control since 1949 (Smithwick 1949). The principal adrenergic receptors present in the human cardiovascular system are the β1, β2, and α1 receptors (Fergus 2015; Pucci 2016). Beta‐blockers vary in their β1/β2‐adrenergic receptor selectivity and vasodilatory properties, and this diversity has given rise to their classification into first, second, and third generation. First‐generation beta‐blockers exercise identical affinity for β1 and β2 receptors and are thus classified as non‐selective beta‐blockers (e.g. propranolol). Second‐generation beta‐blockers are more attracted to β1 than β2 receptors, and are thus termed selective beta‐blockers (e.g. atenolol). The third‐generation of beta‐blockers are known for their intrinsic vasodilatory properties (e.g. nebivolol) (Weber 2005).
How the intervention might work
Beta‐blockers have been used as first‐line therapy for hypertension since the late 1960s, apparently because activation of the sympathetic nervous system is important in the aetiology and maintenance of hypertension (Berglund 1981; JNC‐6 1997; Larochelle 2014; Philipp 1997; Psaty 1997; Ramsay 1999; Wiysonge 2013); but the robustness of the evidence for use of beta‐blockers as first‐line therapy for hypertension without compelling indications is controversial (Carlberg 2004; Khan 2006; Lindhom 2005; Messerli 2003; Opie 1997; Opie 2014; Wiysonge 2007a; Wright 2000). From 2004 to 2006, three meta‐analyses were published which found that beta‐blockers were less effective in reducing the incidence of stroke (Lindhom 2005), and the composite of major cardiovascular outcomes including stroke, myocardial infarction, and death (Khan 2006), compared to all drugs for treating hypertension. However, beta‐blockers might have different comparative outcomes versus the various other classes of drugs. For instance, several studies have claimed that CCBs are better than other antihypertensive agents in preventing stroke but less good at preventing coronary heart disease (CHD; Angeli 2004; Opie 2002; Verdecchia 2005). Thus, it is important to know to what extent the comparisons made by Lindholm and colleagues (Carlberg 2004; Lindhom 2005) and Khan and co‐authors (Khan 2006; Kuyper 2014) relate to beta‐blockers versus specific classes of antihypertensive drugs such as diuretics, CCBs, or RAS inhibitors. RAS inhibitors refer to angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRI). In general, beta‐blockers might be better or worse than one specific class of drugs for specific endpoints so that comparing beta‐blockers with all other classes could be misleading (Carlberg 2004; Lindhom 2005; Khan 2006). In addition, the safety of a medication is as important to the clinician and the person as is the effectiveness; but neither Lindholm and colleagues (Carlberg 2004; Lindhom 2005) nor Khan and co‐authors (Khan 2006; Kuyper 2014) provided data on this aspect when comparing beta‐blockers to other antihypertensive agents (see also Table 1).
| Identification | Comparison | Trials included | Comments |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992; Coope 1986; STOP 1991 trials | STOP 1991 classified as beta‐blocker trial as 68% in active group were taking a beta‐blocker. | |
| Beta‐blocker vs placebo in older people | Coope 1986; MRCOA 1992 | The review concluded that beta‐blockers should not be used in elderly people with hypertension. | |
| Beta‐blocker vs diuretic | Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP 1982 | IPPPSH not included because 67% of participants taking beta‐blocker were taking a diuretic. | |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992 | Coope 1986 and STOP excluded because of high use of diuretic. | |
| Atenolol vs placebo, and atenolol vs other antihypertensive drugs | Placebo: Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995) Other antihypertensive drugs: HAPPHY 1987; MRCOA 1992; UKPDS‐39‐1998; LIFE 2002; ELSA 2002 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with atenolol. | |
| Beta‐blockers vs placebo, thiazide diuretics, calcium‐channel blockers, ACE inhibitors, and angiotensin receptor blockers | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995; STOP‐2 1999 Thiazide diuretics: MRC 1985; HAPPHY 1987; MAPHY 1988; MRCOA 1992 Calcium‐channel blockers: CONVINCE 1998; STOP‐2 1999; NORDIL 2000; ELSA 2002; INVEST 2003 ACE inhibitors: CAPP 1999; STOP‐2 1999 Angiotensin receptor blockers: LIFE 2002 | Included MAPPHY which is a subset of HAPPHY study. Included some studies in which only a proportion of participants were assigned to start treatment on a beta‐blocker. | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with a beta‐blocker. | |
| Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics: Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Excluded Dutch TIA 1993 and TEST 1995 because not all participants in these 2 trials were had hypertension. | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; CAPP 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with a beta‐blocker. | |
| Beta‐blockers vs thiazide diuretics, calcium‐channel blockers, ACE inhibitors, and angiotensin receptor blockers | Thiazide diuretics: MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: ASCOT 2005; ELSA 1992; INVEST 2003 ACE inhibitors: no studies meeting criteria Angiotensin receptor blockers: LIFE 2002 | Updated NICE 2004 review by evaluating head‐to‐head trials only. ASCOT new study added and excluded CONVINCE; NORDIL; and CAPP due to confounded use. | |
| Beta‐blockers with or without diuretics vs placebo or no treatment | Coope 1986; MRC 1985; MRCOA 1992; STOP 1991; UKPDS‐39 | IPPPSH 1985 not included. STOP 1991 included because > 85% of participants on active treatment received beta‐blocker as first‐line or second‐line therapy. Regarded the 'control group' in the UKPDS‐39 as placebo, even though the group permitted antihypertensive therapy (other than | |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992; Dutch TIA 1993; TEST 1995; UKPDS‐39 1998 | IPPPSH 1985 and Coope 1986 excluded because of high use of diuretics in beta‐blocker group. UKPDS‐39 included using 'less tight control group' as placebo, but participants took antihypertensive treatments for 57% of total person‐years. | |
| Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics (Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Previously published version of this systematic review | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; STOP 1991; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; CAPP 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Compared the efficacy of atenolol vs non‐atenolol beta‐blockers in clinical trials enrolling young (aged < 60 years) and older people with hypertension. The review concluded that atenolol should not be used in | |
| Wiysonge 2017 | Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics: Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Current systematic review |
ACE: angiotensin‐converting enzyme.
Why it is important to do this review
Proper understanding of the evidence for beta‐blocker therapy in hypertension requires a regularly updated systematic, comprehensive, and appropriate analysis of all currently available data. In 2007, we published a Cochrane Review which re‐assessed the place of beta‐blockers as first‐line therapy for hypertension relative to each of the other major classes of antihypertensive drugs. An update of the review was published in 2012. The current review is an update of the 2012 review.
Objectives
To assess the effects of beta‐blockers on morbidity and mortality endpoints in adults with hypertension.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) with a duration of one year or more.
Types of participants
Men and non‐pregnant women, aged 18 years and over, with hypertension as defined by cut‐off points operating at the time of the study under consideration.
Types of interventions
The treatment group must have received a beta‐blocker drug either as monotherapy or as a first‐line drug in a stepped‐care approach. The control group could have been a placebo, no treatment, or another antihypertensive drug (including a different beta‐blocker or the same beta‐blocker at a different dose).
Types of outcome measures
Primary outcomes
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Mortality.
Secondary outcomes
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Total (i.e. fatal and non‐fatal) stroke.
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Total coronary heart disease (myocardial infarction, sudden death).
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Total cardiovascular disease (CVD: i.e. fatal and non‐fatal CHD, stroke, congestive heart failure, and transient ischaemic attacks).
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Adverse events leading to discontinuation of allocated treatment.
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Degree of reduction in systolic and diastolic blood pressure achieved by beta‐blocker therapy in relation to each comparator treatment.
We used the definitions employed by the investigators of the study under consideration.
Search methods for identification of studies
Electronic searches
The Cochrane Hypertension Information Specialist conducted systematic searches in the following databases for randomised controlled trials without language, publication year or publication status restrictions:
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the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web) (searched 14 June 2016);
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the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) via the Cochrane Register of Studies (CRS‐Web) (searched 14 June 2016);
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MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 14 June 2016);
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Embase Ovid (searched 14 June 2016);
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ClinicalTrials.gov (www.clinicaltrials.gov) searched 14 June 2016);
The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)). Search strategies from 19 January 2015 are found in Appendix 1. Search strategies for all major databases are provided in Appendix 2.
Searches for previous versions of the review were conducted in June 2006, May 2011, December 2011, and November 2012 (Bradley 2006; Wiysonge 2007b; Wiysonge 2012; Wiysonge 2013). In the previous search conducted in June 2006 (Bradley 2006; Wiysonge 2007b), we searched PubMed, Embase, Cochrane Database of Systematic Reviews, and the York Database of Abstracts of Reviews of Effectiveness for previous reviews and meta‐analyses of antihypertensive treatments that included beta‐blockers. Reports of relevant trials referred to in these reviews were obtained. We then carried out an exhaustive search for eligible RCTs in MEDLINE (for the period 1966 to June 2006) using the terms "adrenergic beta‐antagonists" [MESH], "beta (blockers)" and exp "hypertension" [MESH] combined with the optimally sensitive strategy for identifying RCTs recommended by Cochrane (Higgins 2011); Embase (for the period 1980 to June 2006) using a search strategy similar to that used for MEDLINE; and CENTRAL (the Cochrane Library, 2016, Issue 2). Finally, experts in the field of hypertension and drug companies manufacturing beta‐blockers were contacted for unpublished trials. After reaching consensus on the search strategy for each electronic database, the information specialist of the South African Cochrane Centre conducted the respective electronic searches.
Searching other resources
The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE for systematic reviews) to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.
Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.
We did not perform a separate search for adverse effects of interventions used for the treatment of hypertension. We considered adverse effects described in included studies only.
We also screened the reference lists of 41 potentially eligible studies and 25 relevant reviews and guidelines (Balamuthusamy 2009; Bangalore 2007; Bangalore 2008; Bath 2014; Carlberg 2004; Chen 2010; Dahlöf 2007; ESH‐ESC 2013; Gradman 2010; Howlett 2014; James 2014; Jennings 2013; Khan 2006; Kuyper 2014; Larochelle 2014; NICE 2006; Poirier 2014; Pucci 2016; Ripley 2014; Sander 2011; Sciarretta 2011; Thomopoulos 2015; Wong 2014a; Wong 2014b; Wright 2009). In addition, we searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) using the terms (beta‐blocker OR beta‐blockers) AND hypertension on 06 July 2015.
Data collection and analysis
For the current update, two review authors (CSW and HB) independently examined the eligibility of all titles and abstracts of studies identified by electronic or bibliographic scanning. The two review authors then independently assessed the risk of bias within included studies and extracted data. At each stage, the they resolved differences by discussion and consensus. If any discrepancies had persisted, JV would have arbitrated.
We assessed the risk of bias by addressing seven specific domains, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The seven domains were random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias'. For each included study, we described what the study authors reported that they did for each domain and then made a decision relating to the risk of bias for that domain; by assigning a judgement of 'low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias.
The data extracted for each study were: methods, including means of assigning participants to trial interventions, blinding of those receiving and providing care and outcome assessors, losses to follow‐up and how they were handled, and length of trial follow‐up; participant characteristics, including gender, ethnicity and comorbid conditions; interventions, including type and dose of beta‐blocker and other medications used; outcome measures, including morbidity and mortality endpoints, and adverse events.
We conducted quantitative analyses according to standard Cochrane guidelines (Higgins 2011). We analysed trial participants in groups to which they were randomised, regardless of which or how much treatment they actually received, and expressed study results as risk ratios (RR) with 95% confidence intervals (CI). We assessed heterogeneity between studies by graphical inspection of results and, more formally followed by, the Chi2 test of homogeneity. In the absence of significant statistical heterogeneity between studies (P > 0.1), we performed meta‐analysis using a fixed‐effect method (Breslow 1980; Mantel 1959). When there was significant heterogeneity between study results, we used the random‐effects method (DerSimonian 1986), and investigated the cause of heterogeneity by stratified analysis with reference to the characteristics of the studies included in the meta‐analysis. The study characteristics considered in the subgroup analyses were age (less than 65 years versus 65 years and older), type of beta‐blockade (cardioselective versus non‐selective), control group (placebo versus no treatment), and risk of bias (high versus low risk of bias). In addition, we used the I2 statistic to describe the percentage of between‐study variability in effect estimates (for each outcome) attributable to true heterogeneity rather than chance (Higgins 2003).
Various related reviews differ from ours in their inclusion or exclusion of various studies (Carlberg 2004; Dahlöf 2007; Khan 2006; Lindhom 2005; Wright 2009). We conducted sensitivity analyses to confirm that those different decisions did not lead to different conclusions.
Results
Description of studies
Figure 1 shows the search and selection of studies for this review, in line with the statement of preferred reporting items for systematic reviews and meta‐analyses (Moher 2009).
PRISMA flow diagram showing the search and selection of studies.
Results of the search
We obtained 4453 records from the search conducted in January 2015; including 696 duplicates. Of the remaining 3757 records, 1263 were new records. We screened these and found no potentially eligible studies. The search conducted on 6 July 2015 found 450 studies in Clinicaltrials.gov and 283 records of 257 studies in the WHO International Clinical Trials Registry Platform. None of these 'ongoing' studies was potentially eligible. Finally, the search conducted in June 2016 yielded 2716 records, with 596 being duplicates. We screened the remaining 2120 records (of which 1551 were new records) and found no potentially eligible studies.
From the search conducted in June 2006, we identified 21 potentially eligible RCTs (AASK 2002; ASCOT 2005; Berglund 1981; Coope 1986; ELSA 2002; HAPPHY 1987; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS‐39‐1998; VA COOP 1982; CAPP 1999; CONVINCE 1998; Dutch TIA 1993; MAPHY 1988; NORDIL 2000; STOP 1991; STOP‐2 1999; TEST 1995), from which we excluded eight. In five of the six RCTs, participants in the 'beta‐blocker' group were not randomly allocated to a beta‐blocker at baseline but to conventional therapy, which referred to either a beta‐blocker or a diuretic (CAPP 1999; CONVINCE 1998; NORDIL 2000; STOP 1991; STOP‐2 1999). None of the five RCTs reported data separately for the participants taking beta‐blockers and participants taking diuretics. We excluded two studies because not all participants had hypertension at baseline (Dutch TIA 1993; TEST 1995). We excluded the eighth RCT (MAPHY 1988), because it was a subset of an included RCT (HAPPHY 1987).
The remaining 13 RCTs with 91,561 participants meet our inclusion criteria (AASK 2002; ASCOT 2005; Berglund 1981; Coope 1986; ELSA 2002; HAPPHY 1987; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS‐39‐1998; VA COOP 1982), and we included them in the previous review (Bradley 2006; Wiysonge 2007b).
The May 2011 search yielded 1566 records from the electronic databases (after removing duplicates), which we screened and identified 19 potentially eligible studies (ACCORD 2010; ADaPT 2008; APSIS 2006; CAPRICORN 2001; CARDHIAC 2008; CHHIPS 2009; CIBIS‐II 1999; COMET 2003; COPE 2005; COPERNICUS 2004; COSMOS 2010; Dietz 2008; GEMINI 2008; IMPACT‐HF 2004; MERIT‐HF 2002; Nilsson 2007; REASON 2009; RESOLVD 2000; SENIORS 2005). Following review of the full‐text articles of the 19 studies, we found that none of them met our inclusion criteria.
Finally, we obtained 508 abstracts from the December 2011 search; with one potentially eligible study (Marazzi 2011). This study did not met our inclusion criteria and was excluded.
Included studies
The 13 included RCTs compared a beta‐blocker to a placebo or no treatment (Coope 1986; IPPPSH 1985; MRC 1985; MRCOA 1992), a diuretic (Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP 1982), a CCB (AASK 2002; ASCOT 2005; ELSA 2002; INVEST 2003), an ACE inhibitor (AASK 2002; UKPDS‐39‐1998), or an ARB (LIFE 2002).
Unlike two related reviews (Dahlöf 2007; Wright 2009), we did not consider the UKPDS‐39‐1998 as a placebo‐controlled trial because participants in the 'less tight control group' (which these reviews consider as placebo) took antihypertensive treatment for 57% of total person‐years.
Ten RCTs recruited participants of both sexes (AASK 2002; ASCOT 2005; Coope 1986; ELSA 2002; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS‐39‐1998). Six RCTs included participants up to the age of 65 years (Berglund 1981; HAPPHY 1987; IPPPSH 1985; MRC 1985; UKPDS‐39‐1998; VA COOP 1982), and the rest included participants aged 18 to 70 years (AASK 2002), 40 to 79 years (ASCOT 2005), 45 to 75 years (ELSA 2002), more than 50 years (INVEST 2003), 55 to 80 years (LIFE 2002), 60 to 79 years (Coope 1986), and 65 to 74 years (MRCOA 1992).
All 13 studies were conducted in industrialised countries, mainly Western Europe and North America. Nine RCTs provided information on race or ethnicity: AASK 2002 (0% white), INVEST 2003 (44% white), VA COOP 1982 (48% white), UKPDS‐39‐1998 (86% white), IPPPSH 1985 (92% white), LIFE 2002 (92% white), ASCOT 2005 (95.0% white), ELSA 2002 (98.2% white), and HAPPHY 1987 (more than 99% white).
We have described the 13 RCTs included in this review in detail in the Characteristics of included studies table, and summarised their main features below:
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AASK 2002. This RCT compared the effects of an ACE inhibitor (ramipril), a CCB (amlodipine), and a beta‐blocker (metoprolol) on hypertensive renal disease progression in African American people aged 18 to 70 years. Additional antihypertensive agents were added sequentially to achieve blood pressure goals. Cardiovascular events, cardiovascular mortality. and all‐cause mortality were reported. The trial followed 1094 participants for a mean duration of 4.1 years.
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ASCOT 2005. The participants were randomised to a CCB (amlodipine) adding an ACE inhibitor (perindopril) as required to reach blood pressure targets or a beta‐blocker (atenolol) adding a diuretic (bendroflumethiazide) as required. The participants were men and women with hypertension aged 40 to 79 years. The main outcome measure was combined non‐fatal myocardial infarction and fatal CHD, and secondary endpoints included all‐cause mortality, cardiovascular mortality, and total stroke. At the end of the trial, 78% of participants were taking at least two antihypertensive medications and only 15% were taking amlodipine and 9% were taking atenolol monotherapy. The study enrolled 19,257 participants and followed them for a median duration of 5.5 years.
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Berglund 1981. This RCT evaluated the long‐term effects of a thiazide diuretic (bendroflumethiazide) compared to a beta‐blocker (propranolol) in men with hypertension aged 47 to 54 years. Hydralazine and other antihypertensive medications were added to achieve blood pressure goals. The investigators reported total mortality. At the end of the trial, 70% of participants taking diuretic and 74% taking beta‐blockers were on assigned treatment and 40% of participants taking diuretic and 42% taking beta‐blocker were on monotherapy. The study enrolled 106 participants and the study lasted 10 years.
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Coope 1986. The trial was designed to determine whether the treatment of hypertension using beta‐blocker therapy (atenolol) in a stepped‐care approach compared to no treatment reduced the incidence of stroke, CHD, cardiovascular death, or all‐cause mortality. Step one was monotherapy with atenolol, step two added a thiazide diuretic (bendrofluazide), and steps three and four added other antihypertensive agents. At the end of the trial, 70% of participants in the beta‐blocker group were taking assigned treatment, 17% were taking atenolol alone, and 53% were taking atenolol plus bendrofluazide. The trial followed up 884 participants aged 60 to 79 years for a mean duration of 4.4 years.
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ELSA 2002. The trial was designed to compare the effects of a beta‐blocker (atenolol) and a CCB (lacidipine) on the change in mean maximum intima‐media thickness and plaque number in men and women with hypertension. The investigators also reported data on fatal and non‐fatal cardiovascular events and total mortality. If satisfactory blood pressure control was not achieved, trial medication could be increased, and when necessary open‐label hydrochlorothiazide was added. At the end of the trial, 85% of participants in the beta‐blocker group and 78% in the CCB group were known to be on assigned treatment. The participants on monotherapy at the end of the trial were 43% in the beta‐blocker group and 42% in the CCB group. The trial followed up 2334 participants aged 45 to 75 years for a mean duration of 3.75 years.
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HAPPHY 1987. The trial was designed to compare the effects of beta‐blockers (mainly atenolol, 1599 participants or metoprolol, 1631 participants) and thiazide diuretics (bendroflumethiazide or hydrochlorothiazide) on the incidence of non‐fatal myocardial infarction, CHD mortality, and total mortality in men with mild to moderate hypertension. Other drugs were added to reduce blood pressure as necessary. At the end of the trial, 86% of participants in the beta‐blocker group and 83% in the diuretic group were on assigned treatment. More participants in the beta‐blocker group (68%) than in the diuretic group (62%) were on monotherapy. The trial followed up 6569 participants aged 40 to 64 years for a mean duration of 45.1 months.
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INVEST 2003. The trial was designed to compare the effect of a CCB (verapamil sustained release, SR), and a beta‐blocker (atenolol) in hypertensive participants with documented coronary artery disease, on all‐cause and cardiovascular death, and various non‐fatal cardiovascular events. Other drugs, mainly trandolapril (to the verapamil SR group) and hydrochlorothiazide (to the atenolol group), were added to achieve blood pressure control as required. At two years, 77.5% of participants in the beta‐blocker group and 81.5% in the CCB group were on the assigned treatment (18.1% taking beta‐blocker and 17.4% taking CCB monotherapy). The trial followed up 22,576 participants aged 50 years and older for a mean duration of 2.7 years.
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IPPPSH 1985. The trial was designed to evaluate the effect of antihypertensive therapy with a beta‐blocker (oxprenolol) on the incidence of cardiac events (myocardial infarction and sudden death) and cerebrovascular accidents. Trial medication could be increased or other non‐beta‐blocker antihypertensive drugs added according to predefined recommendations, as necessary, to reduce blood pressure. During the trial, 30% of participants remained on beta‐blocker monotherapy while 15% remained on placebo only. The trial followed up 6357 participants aged 40 to 64 years for three to five years.
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LIFE 2002. The trial was designed to evaluate the effects of an ARB (losartan) compared to a beta‐blocker (atenolol) in people with hypertension with documented left ventricular hypertrophy on the combined incidence of cardiovascular mortality and morbidity. Other drugs were added to reduce blood pressure as necessary. At the end of the trial, 63% of participants in the beta‐blocker group and 67% in the ARB group were on assigned treatment; 11% of participants were on monotherapy in each group. The trial followed up 9193 participants aged 55 to 80 years for a mean duration of 4.8 years.
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MRC 1985. The trial was designed to determine whether drug treatment of mild hypertension reduced the rates of fatal and non‐fatal stroke and of coronary events. Participants were randomised to active treatment (propranolol or bendrofluazide) or placebo. At the end of the study, the proportion of participants on assigned treatment in the beta‐blocker group was 59%, in the diuretic group was 62%, and placebo group was 56%. The trial followed up 17,354 participants aged 35 to 64 years for a mean duration of 4.9 years.
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MRCOA 1992. The trial was designed to establish whether treatment of hypertension in older adults reduced the risk of stroke, CHD, and death from all causes. Participants were randomised to a beta‐blocker (atenolol), a diuretic (amiloride and hydrochlorothiazide), or placebo. Other drugs were added as necessary. At five years, 52% of participants assigned to beta‐blockers required supplementary drugs compared to 38% in the diuretic group. At the end of the study, 37% of participants in the beta‐blocker group, 52% in the diuretic group, and 47% in the placebo group were on the assigned treatment. The trial followed up 4396 participants aged 65 to 74 years for 5.8 years.
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UKPDS‐39‐1998. The trial was designed to determine whether tight control of blood pressure with either a beta‐blocker (atenolol) or an ACE inhibitor (captopril) prevents macrovascular and microvascular complications in participants with type 2 diabetes. Participants were randomised to study drugs, with other drugs added as required. At the end of the trial, 65% of participants in the beta‐blocker group and 78% in the ACE inhibitor group were on assigned treatment. The trial followed up 758 participants aged 25 to 65 years for 8.4 years.
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VA COOP 1982. This trial compared a beta‐blocker (propranolol) and a diuretic (hydrochlorothiazide) for the initial treatment of hypertension in men aged 21 to 65 years. During treatment, fewer participants receiving hydrochlorothiazide required termination as compared with men receiving propranolol. A total of 683 men were recruited. During the initial 10 weeks (i.e. dose‐finding period), the clinic staff titrated the blinded drug upward until the target blood pressure was reached. Participants were withdrawn from the study if, on any follow‐up visit, diastolic blood pressure was 120 mmHg or more. The trial lasted one year.
Excluded studies
We excluded 28 potentially eligible studies because of the very short duration of relevant interventions (CHHIPS 2009; Dietz 2008), a beta‐blocker was not given as monotherapy or first‐line therapy (ACCORD 2010; CAPP 1999; CAPRICORN 2001; CARDHIAC 2008; CIBIS‐II 1999; CONVINCE 1998; COPE 2005; GEMINI 2008; Marazzi 2011; NORDIL 2000; STOP 1991; STOP‐2 1999), the study was not an RCT (ADaPT 2008), the study was a subset of an included RCT (MAPHY 1988), the study has not reported data on mortality or hard cardiovascular endpoints (COSMOS 2010; Nilsson 2007), or not all enrolled participants had hypertension (APSIS 2006; CIBIS‐II 1999; CAPRICORN 2001; COMET 2003; COPERNICUS 2004; Dutch TIA 1993; IMPACT‐HF 2004; MERIT‐HF 2002; RESOLVD 2000; SENIORS 2005; TEST 1995).The trials where not all enrolled participants had hypertension were of beta‐blockers in people with heart failure (CIBIS‐II 1999; COMET 2003; COPERNICUS 2004; IMPACT‐HF 2004; Marazzi 2011; MERIT‐HF 2002; RESOLVD 2000; SENIORS 2005), angina pectoris (APSIS 2006), post‐myocardial infarction (CAPRICORN 2001), or transient ischaemic attack or stroke (Dutch TIA 1993; TEST 1995).
We have described each of the 28 excluded studies in greater detail in the Characteristics of excluded studies table.
Risk of bias in included studies
The risk of bias in included studies is summarised in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Seven trials reported the method used to generate the randomisation sequence adequately (ASCOT 2005; Coope 1986; ELSA 2002; INVEST 2003; IPPPSH 1985; LIFE 2002; UKPDS‐39‐1998). It was unclear in the remaining six (AASK 2002; Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP 1982).
Five trials had adequate allocation concealment (ASCOT 2005; Coope 1986; INVEST 2003; IPPPSH 1985; UKPDS‐39‐1998), while in the remaining eight, the information provided was insufficient to assess this aspect of risk of bias (AASK 2002; Berglund 1981; ELSA 2002; HAPPHY 1987; LIFE 2002; MRC 1985; MRCOA 1992; VA COOP 1982).
Blinding
Outcome assessors were blinded in 11 studies (AASK 2002; ASCOT 2005; Coope 1986; ELSA 2002; HAPPHY 1987; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; VA COOP 1982), and two trials were completely unblinded (Berglund 1981; UKPDS‐39‐1998). However, in the Berglund 1981 study, the outcome assessed (i.e. death) is unlikely to be influenced by lack of blinding.
Participants were also blinded in seven trials (AASK 2002; ELSA 2002; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; VA COOP 1982), but healthcare workers were only blinded in five trials (AASK 2002; ELSA 2002; IPPPSH 1985; LIFE 2002; VA COOP 1982) .
Incomplete outcome data
Loss to follow‐up was negligible in AASK 2002 (0%), ASCOT 2005 (0.3%), IPPPSH 1985 (0.6%), HAPPHY 1987 (1%), LIFE 2002 (2%), INVEST 2003 (2.5%), ELSA 2002 (4%), UKPDS‐39‐1998 (4%), Berglund 1981 (7%), and VA COOP 1982 (8%), but high in MRC 1985 (19%) and MRCOA 1992 (25%) trials. Coope 1986 did not report loss to follow‐up.
The following trials stated the proportions of participants taking assigned beta‐blocker treatment at the end of the trial: HAPPHY 1987 (86%), ELSA 2002 (85%), Berglund 1981 (74%), Coope 1986 (70%), UKPDS‐39‐1998 (65%), LIFE 2002 (63%), MRC 1985 (59%), VA COOP 1982 (39%), MRCOA 1992 (37%), and IPPPSH 1985 (30%).
Selective reporting
Ten studies reported outcomes as stated in the respective study protocols (AASK 2002; ASCOT 2005; ELSA 2002; HAPPHY 1987; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS‐39‐1998). We did not have access to the study protocols of the remaining studies (Berglund 1981; Coope 1986; VA COOP 1982).
Other potential sources of bias
All the studies added other antihypertensive drugs to the first‐line treatment to help achieve the blood pressure goals. The observed effects may equally have resulted from the additional drugs used. In addition, two studies were stopped early for data‐dependent reasons (AASK 2002; ASCOT 2005).
The high risk of bias in most of the included studies limits our confidence in the effect estimates for beta‐blockers as first‐line therapy for hypertension (Balshem 2011; Guyatt 2011), as shown in the 'Summary of findings' tables (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4).
Effects of interventions
See: Summary of findings for the main comparison Beta‐blockers versus placebo as first‐line therapy for hypertension; Summary of findings 2 Beta‐blockers compared to diuretics as first‐line therapy for hypertension; Summary of findings 3 Beta‐blockers compared to calcium‐channel blockers as first‐line therapy for hypertension; Summary of findings 4 Beta‐blockers compared to renin‐angiotensin system inhibitors as first‐line therapy for hypertension
Due to the small number of participants in trials with ACE inhibitors (2 trials with 1635 participants (AASK 2002; UKPDS‐39‐1998)) and ARBs (1 trial with 9193 participants (LIFE 2002)), we combined data for the two classes of RAS inhibitors. We excluded the trial that compared the effects of atenolol and aliskiren, the first DRI to be approved for the treatment of hypertension (Dietz 2008), because of the very short duration (12 weeks) of relevant interventions.
Mortality
The effect of beta‐blocker therapy on total mortality was not significantly different from that of placebo (4 trials, 23,613 participants: RR 0.99, 95% CI 0.88 to 1.11; I2 = 0%; moderate certainty evidence).
Apart from the four studies included in our placebo comparison, previous related reviews included four other studies (Dutch TIA 1993; STOP 1991; TEST 1995; UKPDS‐39‐1998). When we added these studies in a sensitivity analysis, there was still no evidence of a significant effect of beta‐blockers on mortality (8 trials, 28,181 participants: RR 0.93, 95% CI 0.85 to 1.02, I2 = 39%).
In addition, total mortality was not significantly different between beta‐blockers and diuretics (5 trials, 18,241 participants: RR 1.04, 95% CI 0.91 to 1.19, I2 = 0%; moderate certainty evidence), and beta‐blockers and RAS inhibitors (3 trials, 10,828 participants: RR 1.10, 95% CI 0.98 to 1.24, I2 = 54%; moderate certainty evidence).
Total mortality was significantly higher for beta‐blockers compared to CCBs (4 trials, 44,825 participants: RR 1.07, 95% CI 1.00 to 1.14, I2 = 2%; moderate certainty evidence) corresponding to an absolute risk increase (ARI) of 0.5% and number of participants needed to treat for an additional harmful outcome (NNTH) with a beta‐blocker rather than a CCB treated for five years of 200.
Total stroke
Participants treated with a beta‐blocker had a significantly lower risk of developing a stroke than participants taking placebo (4 trials, 23,613 participants: RR 0.80, 95% CI 0.66 to 0.96, I2 = 0%; low certainty evidence). A sensitivity analysis adding the four studies included in related reviews yielded similar results (8 trials, 28,181 participants: RR 0.79, 95% CI 0.70 to 0.90, I2 = 31%).
Expressed as absolute risk reduction (ARR), beta‐blockers reduced the risk of stroke by 0.5% (compared to placebo). The corresponding number of participants needed to treat for an additional beneficial outcome (NNTB) with a beta‐blocker for approximately five years to prevent one stroke was 200.
We found no statistically significant difference in stroke events between participants treated with a beta‐blocker and participants treated with a diuretic (4 trials, 18,135 participants: RR (random effects) 1.17, 95% CI 0.65 to 2.09, I2 = 73%; moderate certainty evidence). However, participants treated with a beta‐blocker (atenolol) had more stroke events than participants treated with a CCB (3 trials, 44,167 participants: RR 1.24, 95% CI 1.11 to 1.40, I2 = 0%; ARI = 0.6%, NNTH 180; moderate certainty evidence) or an RAS inhibitor (2 trials, 9951 participants: RR 1.30, 95% CI 1.11 to 1.53, I2 = 29%; ARI = 1.5%, NNTH 65; moderate certainty evidence).
The heterogeneity among trials comparing beta‐blockers to diuretics may be related to the type of beta‐blockade (I2 = 73%, P = 0.01). There was an increase in the risk of stroke with the non‐selective beta‐blocker, propranolol, in the MRC 1985 trial (RR 2.28, 95% CI 1.31 to 3.95) with an ARI of 0.5% and NNTH with a beta‐blocker for approximately five years of 200; but no difference with the cardio‐selective beta‐blockers, atenolol or metoprolol (RR 1.00, 95% CI 0.74 to 1.33, I2 = 60).
Total coronary heart disease
The effect of beta‐blocker therapy on CHD was not significantly different from that of a placebo (4 trials, 23,613 participants: RR 0.93, 95% CI 0.81 to 1.07, I2 = 0%; moderate certainty evidence). A sensitivity analysis adding the four studies included in related reviews yielded similar results (8 trials, 28,181 participants: RR 0.91, 95% CI 0.81 to 1.02, I2 = 0%).
The beta‐blocker effect was similar to that of a diuretic (4 trials, 18,135 participants: RR (random effects) 1.12, 95% CI 0.82 to 1.54, I2 = 66%; low certainty evidence), a CCB (3 trials, 44,167 participants: RR 1.05, 95% CI 0.96 to 1.15, I2 = 32%; moderate certainty evidence), or a RAS inhibitor (2 trials, 9951 participants: RR 0.90, 95% CI 0.76 to 1.06, I2 = 42%; low certainty evidence).
There was significant statistical heterogeneity between trials comparing beta‐blockers to diuretics (I2 = 66%, P = 0.03), which may be explained by differences in age. The pooled RR in the trials whose participants were less than 65 years of age was 0.97 (95% CI 0.81 to 1.17, I2 = 5%, P = 0.35), while in the single trial involving participants aged 65 years and older atenolol was associated with an increased CHD incidence (RR 1.63, 95% CI 1.15 to 2.32) (MRCOA 1992). The difference between the subgroups was statistically significant (test for subgroup differences: Chi2 = 6.70, degrees of freedom (df) = 1, P = 0.01, I2 = 85.1%).
Total cardiovascular disease
Compared to participants taking placebo, participants taking beta‐blockers had a significantly reduced risk of having a cardiovascular event (4 trials, 23,613 participants: RR 0.88, 95% CI 0.79 to 0.97, I2 = 21%; ARR 0.7%, NNTB 140 for 5 years; low certainty evidence). A sensitivity analysis adding studies included in related reviews yielded similar results.
The effect of beta‐blockers on total cardiovascular events was not significantly different from that of diuretics (4 trials, 18,135 participants: RR 1.13, 95% CI 0.99 to 1.28, I2 = 45%; moderate certainty evidence) and RAS inhibitors (3 trials, 10,828 participants: RR (random effects) 1.00, 95% CI 0.72 to 1.38, I2 = 74%; low certainty evidence). Beta‐blockers increased total cardiovascular disease as compared to CCBs (2 trials, 19,915 participants: RR 1.18, 95% CI 1.08 to 1.29, I2 = 0%; ARI = 1.3%, NNTH 80; moderate certainty evidence).
The significant heterogeneity of effect on total cardiovascular disease between beta‐blockers and RAS inhibitors (I2 = 74%, P = 0.02) was explained by the effect of beta‐blockers being similar to that of ACE inhibitors (2 trials, 635 participants: RR 0.82, 95% CI 0.64 to 1.05, I2 = 0%) but worse than that of an ARB (1 trial, 9193 participants: RR 1.16, 95% CI 1.04 to 1.30) with an ARI of 1.8% and NNTH of 56.
Adverse events leading to discontinuation of allocated treatment
We analysed data on the rate of withdrawal from randomly assigned treatment due to any adverse events, and also report on the frequency of specific adverse events including depression, fatigue, and sexual dysfunction.
Trial participants on a beta‐blocker were no more likely than participants receiving a placebo to discontinue treatment due to adverse events (3 trials, 22,729 participants: RR (random effects) 3.38, 95% CI 0.82 to 13.95; low certainty evidence). However, there was significant heterogeneity of effect between the trials (I2 = 100%, P < 0.00001); with no difference in the likelihood of discontinuing treatment with oxprenolol (1 trial, 6357 participants: RR 0.95, 95% CI 0.87 to 1.04) and an increased likelihood with propranolol or atenolol (2 trials, 16,372; RR (random effects) 6.35, 95% CI 3.94 to 10.22, I2 = 91%). A sensitivity analysis adding studies included in related reviews also revealed significant heterogeneity of effect (I2 = 99%, P < 0.00001).
Participants taking a beta‐blocker were more likely to discontinue treatment due to adverse events than participants taking a RAS inhibitor (2 trials, 9951 participants: RR 1.41, 95% CI 1.29 to 1.54, I2 = 12%; ARI 5.5%, NNTH 18; low certainty evidence), but there was no significant difference with a diuretic (3 trials, 11,566 participants: RR (random effects) 1.69, 95% CI 0.95 to 3.00, I2 = 95%; low certainty evidence) or a CCB (2 trials, 21,591 participants: RR (random effects) 1.20, 95% CI 0.71 to 2.04, I2 = 93%; low certainty evidence).
There was no significant difference in the incidence of depressive symptoms between beta‐blockers and placebo (2 trials, 7082 participants: RR (random effects) 1.03, 95% CI 0.65 to 1.63, I2 = 83.0) or RAS inhibitors (1 trial, 758 participants: RR 1.12, 95% CI 0.07 to 17.80).
Beta‐blockers did not increase the risk of fatigue compared to placebo or no treatment (2 trials, 13,782 participants: RR (random effects) 4.35, 95% CI 0.17 to 108.74, I2 = 99.0%). However, trial participants taking a beta‐blocker were more likely to develop fatigue than participants taking a diuretic (1 trial, 8700 participants: RR 2.48, 95% CI 1.73 to 3.54), a CCB (1 trial, 19,257 participants: RR 1.99, 95% CI 1.84 to 2.16), or a RAS inhibitor (2 trials, 9951 participants: RR 1.17, 95% CI 1.06 to 1.28, I2 = 0%).
The risk of sexual dysfunction was not different between beta‐blockers and placebo (2 trials, 19,414 participants: RR (random effects) 1.95, 95% CI 0.33 to 11.59, I2 = 97.5%). However, beta‐blockers decreased the risk of sexual dysfunction when compared to diuretics (1 trial, 8700 participants: RR 0.50, 95% CI 0.36 to 0.70); but increased the risk relative to CCBs (1 trial, 19,257 participants: RR 1.27, 95% CI 1.14 to 1.42) and RAS inhibitors (2 trials, 9951 participants: RR 1.34, 95% CI 1.10 to 1.63, I2 = 56.2%).
Degree of reduction in systolic and diastolic blood pressure achieved by beta‐blocker therapy in relation to each comparator treatment
Compared to placebo, first‐line beta‐blockers plus supplementary antihypertensive drugs reduced systolic blood pressure by about 11 mmHg and diastolic blood pressures by about 6 mmHg (Table 2). However, compared to diuretics, CCBs, or RAS inhibitors, the mean systolic and diastolic blood pressures at the end of the trials were 0 to 2 mmHg higher in the beta‐blocker group (Table 2).
| Trial identification | Beta‐blocker | Comparison drug | Baseline BP (SBP/DBP; mmHg) | Mean BP difference (SBP/DBP)* |
| Beta‐blocker vs placebo/no treatment | ||||
| Atenolol | No treatment | 196.7/99.7 | ‐18.0/‐11.0 | |
| Atenolol | Placebo | 184.0/91.0 | ‐13.0/‐7.0 | |
| Propranolol | Placebo | 162.0/98.5 | ‐9.5/‐5.0 | |
| Oxprenolol | Placebo | 173.2/107.9 | ‐4.1/‐1.5 | |
| Beta‐blocker vs diuretic | ||||
| Atenolol | Diuretic | 184.0/91.0 | +1.0/‐0.5 | |
| Atenolol or metoprolol or propranolol | Diuretic | 166.0/107.9 | 0.0/‐1.0 | |
| Propranolol | Diuretic | 174.0/105.5 | ‐4.0/+2.0 | |
| Propranolol | Diuretic | 146.3/101.5 | +7.0/+1.6 | |
| Propranolol | Diuretic | 162.0/98.5 | +3.5/+1.0 | |
| Beta‐blocker vs calcium‐channel blocker | ||||
| Atenolol | Calcium‐channel blocker | 163.1/101.3 | +0.2/‐0.1 | |
| Atenolol | Calcium‐channel blocker | 150.8/87.2 | +0.3/+0.2 | |
| Atenolol | Calcium‐channel blocker | 164.0/94.7 | +1.6/+1.8 | |
| Metoprolol | Calcium‐channel blocker | 150.0/96.0 | +2.0/0.0 | |
| Beta‐blocker vs renin‐angiotensin system inhibitor | ||||
| Atenolol | Renin‐angiotensin system inhibitor (ACE inhibitor) | 159.0/93.0 | ‐1.0/‐1.0 | |
| Atenolol | Renin‐angiotensin system inhibitor (ARB) | 174.5/97.7 | +1.1/‐0.2 | |
| Metoprolol | Renin‐angiotensin system inhibitor (ACE inhibitor) | 150.0/96.0 | 0.0/‐1.0 | |
* 'Minus sign' means beta‐blocker group had lower BP, and 'plus sign' means beta‐blocker group had higher BP than control group.
ACE: angiotensin‐converting enzyme; ARB: angiotensin receptor blocker; BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure.
Discussion
Summary of main results
We included 13 eligible RCTs, which compared beta‐blockers to placebo, diuretics, CCBs, and RAS inhibitors. These RCTs generally had a high risk of bias resulting from limitations in study design, conduct, and data analysis.
We found little or no difference in all‐cause mortality between beta‐blockers and placebo, diuretics or RAS inhibitors, but all‐cause mortality was higher for beta‐blockers compared to CCBs. The evidence on mortality was of moderate‐certainty for all comparisons. Total cardiovascular disease was lower for beta‐blockers compared to placebo, which is a reflection of the significant decrease in stroke, since there was little or no difference in CHD between beta‐blockers and placebo. There were no significant differences between beta‐blockers and placebo in adverse events leading to withdrawal from assigned treatment (low‐certainty evidence).
The effect of beta‐blockers on cardiovascular disease was worse than that of CCBs (moderate‐certainty evidence), but was not different from that of diuretics (moderate‐certainty evidence) or RAS inhibitors (low‐certainty evidence). In addition, there was an increase in stroke with beta‐blockers compared to CCBs (moderate‐certainty evidence) and RAS inhibitors (moderate‐certainty evidence). However, there was little or no difference in CHD between beta‐blockers and diuretics (low‐certainty evidence), CCBs (moderate‐certainty evidence), or RAS inhibitors (low‐certainty evidence). Participants taking beta‐blockers were more likely to discontinue treatment due to adverse events than participants taking RAS inhibitors (moderate‐certainty evidence), but there was no significant difference with diuretics (low‐certainty evidence) or CCBs (low certainty evidence).
We demonstrated a high degree of homogeneity of effect for the comparisons of beta‐blockers versus CCBs for all‐cause mortality (I2 = 2%), stroke (I2 = 0%), and total cardiovascular events (I2 = 0%) but with less homogeneity for CHD (I2 = 32%). For the comparison of beta‐blockers versus RAS inhibitors, the I2 values for stroke and withdrawal rates also demonstrate a high degree of consistency across the studies making our conclusions more secure (Higgins 2003; Higgins 2011). For the comparison with diuretics, there were no statistically significant differences in any morbidity or mortality outcome.
Overall completeness and applicability of evidence
Though beta‐blockers are a heterogeneous group of pharmacological agents, differing in beta‐adrenergic receptor selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities (Kamp 2010; Pedersen 2007; Polónia 2010), we found no outcome trials with head‐to‐head comparisons between beta‐blockers for the treatment of hypertension (Poirier 2014). Of the 40,245 participants using beta‐blockers in this review, atenolol was used by 30,150 participants (75%). Due to the paucity of data using beta‐blockers other than atenolol, it is not possible to say whether the (lack of) effectiveness and (in)tolerability of beta‐blockers seen in this review is a property of atenolol or is a class effect of beta‐blockers. From this review, we cannot support the claim by Lindhom and colleagues that cardioselective beta‐blockers may be inferior to non‐selective beta‐blockers in the treatment of hypertension (Carlberg 2004).
A limitation of both previous reviews and ours is the absence of trials assessing the effects of the new vasodilating beta‐blockers (e.g. carvedilol, bucindolol, and nebivolol) on mortality and hard cardiovascular outcomes. Possible mechanisms to explain the poor ability of beta‐blockers to reduce stroke include a propensity to cause diabetes (Opie 2004), a failure to decrease central aortic pressure as much as brachial pressure, and others. Diabetes likely requires years to develop cardiovascular complications (Verdecchia 2004), so we favour the mechanism involving lesser reduction of central aortic pressure by beta‐blockers. Vasodilating beta‐blockers (Broeders 2000; Kalinowski 2003; Pucci 2016) have been shown to reduce central pressures better than conventional beta‐blockers (Kamp 2010; Polónia 2010); most probably because vasodilatation favourably alters the pattern of the pressure wave reflecting back from the periphery, thereby lowering the central pressure. Nonetheless, carvedilol and nebivolol also cause bradycardia, which is thought to be the principal mechanism whereby atenolol with or without thiazide may be less able to lower the central pressure than amlodipine with or without perindopril (Williams 2006). At any rate, high‐quality outcome studies are required to show that hard cardiovascular endpoints such as stroke and CHD are significantly reduced by beta‐blockers not studied in this review.
Information reported in the trials considered in this review was insufficient to explore the effect of race or ethnicity, as most trial participants were white (Park 2007). However, the finding that beta‐blockers are less effective than diuretics in older people, is most likely to be applicable to older black people as well (Materson 1993).
Quality of the evidence
The certainty of the evidence on the effects of beta‐blockers was generally moderate to low (Balshem 2011). In the GRADE system, RCTs without important limitations constitute high‐certainty evidence. However, the system considers five factors that can lower the certainty of the evidence: study limitations, heterogeneity, indirectness, imprecision, and publication bias. Overall, the GRADE system classifies research evidence into high‐, moderate‐, low‐, or very low‐certainty. Low‐certainty evidence implies that the "true effect is likely to be different from the estimate of effect" found in the review.
Our major concern with the evidence related to inherent shortcomings in the included primary studies. The emphasis was often on the results with the first drug used, whereas most studies used stepped‐up therapy to help achieve the blood pressure goals. Thus poorer outcomes with first‐line beta‐blockers may equally have resulted from the use of other drugs; explaining why other authors restricted their systematic reviews of beta‐blocker therapy to trials where confounding supplementary drug classes were administered to less than half of participants (Wright 1999; Wright 2000; Wright 2009). Although we were less restrictive than Wright and colleagues (Wright 1999; Wright 2000), we included only trials in which all the participants in one group received a beta‐blocker at baseline, whether or not other antihypertensive drug classes were later added to achieve blood pressure targets. This requirement was in contrast to other systematic reviews (Carlberg 2004; Dahlöf 2007; Khan 2006; Lindhom 2005). The dropout rates were high in two of the studies of diuretics, potentially introducing attrition bias (MRC 1985; MRCOA 1992).
It may be that only people with complicated hypertension or advanced disease are included in most studies, thereby ignoring the possible differing benefits of different antihypertensive medications on different organs and on different stages of disease development (Zanchetti 2005). A further problem is that in the two groups of the studies we analysed, and especially in the case of the comparison with diuretics, there were discrepancies between the achieved blood pressure levels (Table 2), and even small blood pressure differences may be linked to significant differences in outcomes (Collins 1990; Staessen 2003). However, there were no consistent differences in the blood pressure reduction between beta‐blockers and the other agents used to explain the outcome differences we found (Table 2). Yet another limitation is that (due to the scarcity of relevant trials) we combined the potentially different classes of RAS inhibitors (i.e. ACE inhibitors (captopril and lisinopril) and ARB (losartan). However, we believe that the similarities between these agents as antihypertensive drugs outweigh any potential differences.
Potential biases in the review process
We minimised potential biases in the review process by adhering to the Cochrane guidelines (Higgins 2011). We conducted a comprehensive search for eligible studies, without limiting the search to a specific language. Two review authors independently assessed study eligibility, extracted data, and assessed the risk of bias in each included study.
Agreements and disagreements with other studies or reviews
We showed that beta‐blockers are inferior to various CCBs for all‐cause mortality, stroke, and total cardiovascular events, and to RAS inhibition for stroke. By comparing beta‐blockers with all other therapies, Lindholm and colleagues were only able to show an inferiority of beta‐blockade on stroke reduction (Carlberg 2004; Lindhom 2005). In a similar meta‐analysis, Khan and McAlister found beta‐blockers to be inferior to all other therapies in effects on a composite outcome of major cardiovascular events (stroke, myocardial infarction, and death) and stroke for older people with hypertension but found no difference in effects for younger people (Khan 2006). The claim by Khan 2006 that the defects of beta‐blockade are limited to older people relies heavily on the Medical Research Council trial in older people with hypertension in which the beta‐blocker was atenolol and where the dropout rate was 25% (MRCOA 1992). In addition, Khan 2006 classified trials which enrolled participants as young as 40 (ASCOT 2005), 45 (ELSA 2002), and 50 (INVEST 2003) years as trials of older people with hypertension. At present, there are insufficient data to make a valid comparison of beta‐blocker effects on younger versus older people, although this is an important hypothesis.
We used the I2 statistic to evaluate the consistency in study results (Higgins 2003; Higgins 2011). In our meta‐analyses, heterogeneity was very low for the outcomes of beta‐blockers versus placebo or no treatment. We found a modest 20% relative reduction in stroke by beta‐blockers compared to placebo with six studies, which is similar to the relative reduction reported by Lindholm and colleagues using seven studies (Lindhom 2005). With their wider inclusion criteria, Lindholm and colleagues included three studies not considered by us (Dutch TIA 1993; STOP 1991; TEST 1995), which resulted in significant heterogeneity of effect in their findings. By contrast, there was excellent homogeneity of effect with the four studies included in our comparison of beta‐blockers to placebo as shown by an I2 value of 0% (Coope 1986; IPPPSH 1985; MRC 1985; MRCOA 1992). Thus, we were able to give additional validation to one of the crucial findings of Lindholm and colleagues (Lindhom 2005), namely that stroke reduction by beta‐blockade is suboptimal.
Two other reviews also differed from ours in their inclusion or exclusion of various studies (Dahlöf 2007; Wright 2009). Both considered the UKPDS‐39‐1998 as a placebo‐controlled trial and excluded IPPPSH 1985. In addition, Wright 2009 excluded Coope 1986 because of high use of diuretics in the beta‐blocker group while Dahlöf 2007 included STOP 1991 because more than 85% of participants on active treatment received beta‐blocker as first‐line or second‐line therapy. Both reviews considered the "less tight control group" in UKPDS‐39‐1998 as "placebo" because the target for blood pressure reduction in this group was not as low as in the beta‐blocker group. However, participants in this control group took antihypertensive treatment for 57% of their total person‐years in the UKPDS‐39‐1998 trial.
We combined trials of low‐dose and high‐dose thiazide diuretics because of the paucity of trials comparing beta‐blockers to diuretics (Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP 1982). This may be the reason for the lack of a statistical difference between beta‐blockers and diuretics in our review, since Wright and Musini have shown that first‐line low‐dose thiazides reduce stroke, CHD, and mortality outcomes while first‐line high‐dose thiazides have no significant effects on mortality and CHD (Wright 2009).
We conducted sensitivity analyses and found our results to be consistent with those of the related reviews, despite differences in inclusion and exclusion criteria (Effects of interventions). Overall, despite a variation in the studies included in other beta‐blocker reviews arising from different interpretations of inclusion criteria, all the reviews arrived at similar conclusions that the available evidence does not support the use of beta‐blockers as first‐line drugs in the treatment of hypertension.
PRISMA flow diagram showing the search and selection of studies.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 1 Mortality.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 2 Total stroke.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 3 Total coronary heart disease.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 4 Cardiovascular death.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 5 Total cardiovascular disease.
Comparison 1 Beta‐blocker versus placebo or no treatment, Outcome 6 Withdrawal due to adverse effects.
Comparison 2 Beta‐blocker versus diuretic, Outcome 1 Mortality.
Comparison 2 Beta‐blocker versus diuretic, Outcome 2 Total stroke.
Comparison 2 Beta‐blocker versus diuretic, Outcome 3 Total coronary heart disease.
Comparison 2 Beta‐blocker versus diuretic, Outcome 4 Cardiovascular death.
Comparison 2 Beta‐blocker versus diuretic, Outcome 5 Total cardiovascular disease.
Comparison 2 Beta‐blocker versus diuretic, Outcome 6 Withdrawal due to adverse effects.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 1 Mortality.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 2 Total stroke.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 3 Total coronary heart disease.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 4 Cardiovascular death.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 5 Total cardiovascular disease.
Comparison 3 Beta‐blocker versus calcium‐channel blocker (CCB), Outcome 6 Withdrawal due to adverse effects.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 1 Mortality.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 2 Total stroke.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 3 Total coronary heart disease.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 4 Cardiovascular death.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 5 Total cardiovascular disease.
Comparison 4 Beta‐blocker versus renin‐angiotensin system (RAS) inhibitor, Outcome 6 Withdrawal due to adverse effects.
| Beta‐blockers versus placebo as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Placebo | Beta‐blockers | ||||
| Total mortality | 52 per 1000 | 51 per 1000 | RR 0.99 | 23613 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 64 per 1000 | 57 per 1000 | RR 0.88 | 23613 | ⊕⊕⊝⊝ |
| Total stroke | 23 per 1000 | 18 per 1000 | RR 0.80 | 23613 | ⊕⊕⊝⊝ |
| Total coronary heart disease | 37 per 1000 | 34 per 1000 | RR 0.93 | 23613 | ⊕⊕⊕⊝ |
| Withdrawal due to adverse effect | 74 per 1000 | 249 per 1000 | RR 3.38 | 22729 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The two studies that contribute to the most weight of the pooled RR have high risk of bias (especially incomplete outcome reporting due to attrition bias): downgraded by 1 point. | |||||
| Beta‐blockers compared to diuretics as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Diuretics | Beta‐blockers | ||||
| Total mortality | 41 per 1000 | 43 per 1000 | RR 1.04 | 18241 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 45 per 1000 | 51 per 1000 | RR 1.13 | 18135 | ⊕⊕⊕⊝ |
| Total stroke | 12 per 1000 | 14 per 1000 | RR 1.17 | 18135 | ⊕⊕⊝⊝ |
| Total coronary heart disease | 33 per 1000 | 37 per 1000 | RR 1.12 | 18135 | ⊕⊕⊝⊝ |
| Withdrawal due to adverse effect | 109 per 1000 | 184 per 1000 | RR 1.69 | 11566 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The two studies that contribute to the most weight of the pooled RR have high risk of bias (especially incomplete outcome reporting due to attrition bias): downgraded by 1 point. | |||||
| Beta‐blockers compared to calcium‐channel blockers as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Calcium‐channel blockers | Beta‐blockers | ||||
| Total mortality | 73 per 1000 | 78 per 1000 | RR 1.07 | 44825 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 81 per 1000 | 96 per 1000 | RR 1.18 | 19915 | ⊕⊕⊕⊝ |
| Total stroke | 23 per 1000 | 29 per 1000 | RR 1.24 | 44167 | ⊕⊕⊕⊝ |
| Total coronary heart disease | 39 per 1000 | 41 per 1000 | RR 1.05 | 44167 | ⊕⊕⊕⊝ |
| Withdrawal due to adverse effect | 33 per 1000 | 40 per 1000 | RR 1.20 | 21591 | ⊕⊕⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The RR is too close to 1 and could easily include 1 if more trials are added: downgraded by 1 point. 2 Only 2 hypertension trials comparing beta‐blockers to calcium‐channel blockers have reported data on this outcome: downgraded by 1 point. 4 Inconsistent results across studies (I2 = 93%): downgraded by 1 point. | |||||
| Beta‐blockers compared to renin‐angiotensin system inhibitors as first‐line therapy for hypertension | |||||
| Participants: people with hypertension | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Certainty of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Renin‐angiotensin system inhibitors | Beta‐blockers | ||||
| Total mortality | 84 per 1000 | 92 per 1000 | RR 1.10 | 10828 | ⊕⊕⊕⊝ |
| Total cardiovascular disease | 115 per 1000 | 115 per 1000 | RR 1.0 | 10828 | ⊕⊕⊝⊝ |
| Total stroke | 51 per 1000 | 66 per 1000 | RR 1.30 | 9951 | ⊕⊕⊕⊝ |
| Total coronary heart disease | 54 per 1000 | 49 per 1000 | RR 0.90 | 9951 | ⊕⊕⊝⊝ |
| Withdrawal due to adverse effect | 137 per 1000 | 194 per 1000 | RR 1.41 | 9951 | ⊕⊕⊕⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Only 3 hypertension trials comparing beta‐blockers to RAS inhibitors have reported data on this outcome: downgraded by 1 point. 4 Imprecise results, as the effect ranges from a clinically important benefit to a small increase in harm: downgraded by 1 point. | |||||
| Identification | Comparison | Trials included | Comments |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992; Coope 1986; STOP 1991 trials | STOP 1991 classified as beta‐blocker trial as 68% in active group were taking a beta‐blocker. | |
| Beta‐blocker vs placebo in older people | Coope 1986; MRCOA 1992 | The review concluded that beta‐blockers should not be used in elderly people with hypertension. | |
| Beta‐blocker vs diuretic | Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP 1982 | IPPPSH not included because 67% of participants taking beta‐blocker were taking a diuretic. | |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992 | Coope 1986 and STOP excluded because of high use of diuretic. | |
| Atenolol vs placebo, and atenolol vs other antihypertensive drugs | Placebo: Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995) Other antihypertensive drugs: HAPPHY 1987; MRCOA 1992; UKPDS‐39‐1998; LIFE 2002; ELSA 2002 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with atenolol. | |
| Beta‐blockers vs placebo, thiazide diuretics, calcium‐channel blockers, ACE inhibitors, and angiotensin receptor blockers | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995; STOP‐2 1999 Thiazide diuretics: MRC 1985; HAPPHY 1987; MAPHY 1988; MRCOA 1992 Calcium‐channel blockers: CONVINCE 1998; STOP‐2 1999; NORDIL 2000; ELSA 2002; INVEST 2003 ACE inhibitors: CAPP 1999; STOP‐2 1999 Angiotensin receptor blockers: LIFE 2002 | Included MAPPHY which is a subset of HAPPHY study. Included some studies in which only a proportion of participants were assigned to start treatment on a beta‐blocker. | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with a beta‐blocker. | |
| Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics: Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Excluded Dutch TIA 1993 and TEST 1995 because not all participants in these 2 trials were had hypertension. | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; CAPP 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Included trials in which only a proportion (> 50%) of participants were assigned to start treatment with a beta‐blocker. | |
| Beta‐blockers vs thiazide diuretics, calcium‐channel blockers, ACE inhibitors, and angiotensin receptor blockers | Thiazide diuretics: MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: ASCOT 2005; ELSA 1992; INVEST 2003 ACE inhibitors: no studies meeting criteria Angiotensin receptor blockers: LIFE 2002 | Updated NICE 2004 review by evaluating head‐to‐head trials only. ASCOT new study added and excluded CONVINCE; NORDIL; and CAPP due to confounded use. | |
| Beta‐blockers with or without diuretics vs placebo or no treatment | Coope 1986; MRC 1985; MRCOA 1992; STOP 1991; UKPDS‐39 | IPPPSH 1985 not included. STOP 1991 included because > 85% of participants on active treatment received beta‐blocker as first‐line or second‐line therapy. Regarded the 'control group' in the UKPDS‐39 as placebo, even though the group permitted antihypertensive therapy (other than | |
| Beta‐blocker vs placebo | MRC 1985; MRCOA 1992; Dutch TIA 1993; TEST 1995; UKPDS‐39 1998 | IPPPSH 1985 and Coope 1986 excluded because of high use of diuretics in beta‐blocker group. UKPDS‐39 included using 'less tight control group' as placebo, but participants took antihypertensive treatments for 57% of total person‐years. | |
| Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics (Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Previously published version of this systematic review | |
| Beta‐blocker vs placebo, and beta‐blocker vs other antihypertensive drugs | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; STOP 1991; MRCOA 1992; Dutch TIA 1993; TEST 1995 Other antihypertensive drugs: Berglund 1981; MRC 1985; HAPPHY 1987; STOP 1991; MRCOA 1992; Yurenev 1992; UKPDS‐39‐1998; STOP‐2 1999; CAPP 1999; NORDIL 2000; LIFE 2002; ELSA 2002; CONVINCE 2003; ASCOT 2005 | Compared the efficacy of atenolol vs non‐atenolol beta‐blockers in clinical trials enrolling young (aged < 60 years) and older people with hypertension. The review concluded that atenolol should not be used in | |
| Wiysonge 2017 | Beta‐blocker vs placebo, diuretics, calcium‐channel blockers, and renin‐angiotensin system inhibitors | Placebo: IPPPSH 1985; MRC 1985; Coope 1986; MRCOA 1992 Diuretics: Berglund 1981; VA COOP 1982; MRC 1985; HAPPHY 1987; MRCOA 1992 Calcium‐channel blockers: AASK 2002; ELSA 2002; INVEST 2003; ASCOT 2005 Renin‐angiotensin system inhibitors: UKPDS‐39‐1998; AASK 2002; LIFE 2002 | Current systematic review |
| ACE: angiotensin‐converting enzyme. | |||
| Trial identification | Beta‐blocker | Comparison drug | Baseline BP (SBP/DBP; mmHg) | Mean BP difference (SBP/DBP)* |
| Beta‐blocker vs placebo/no treatment | ||||
| Atenolol | No treatment | 196.7/99.7 | ‐18.0/‐11.0 | |
| Atenolol | Placebo | 184.0/91.0 | ‐13.0/‐7.0 | |
| Propranolol | Placebo | 162.0/98.5 | ‐9.5/‐5.0 | |
| Oxprenolol | Placebo | 173.2/107.9 | ‐4.1/‐1.5 | |
| Beta‐blocker vs diuretic | ||||
| Atenolol | Diuretic | 184.0/91.0 | +1.0/‐0.5 | |
| Atenolol or metoprolol or propranolol | Diuretic | 166.0/107.9 | 0.0/‐1.0 | |
| Propranolol | Diuretic | 174.0/105.5 | ‐4.0/+2.0 | |
| Propranolol | Diuretic | 146.3/101.5 | +7.0/+1.6 | |
| Propranolol | Diuretic | 162.0/98.5 | +3.5/+1.0 | |
| Beta‐blocker vs calcium‐channel blocker | ||||
| Atenolol | Calcium‐channel blocker | 163.1/101.3 | +0.2/‐0.1 | |
| Atenolol | Calcium‐channel blocker | 150.8/87.2 | +0.3/+0.2 | |
| Atenolol | Calcium‐channel blocker | 164.0/94.7 | +1.6/+1.8 | |
| Metoprolol | Calcium‐channel blocker | 150.0/96.0 | +2.0/0.0 | |
| Beta‐blocker vs renin‐angiotensin system inhibitor | ||||
| Atenolol | Renin‐angiotensin system inhibitor (ACE inhibitor) | 159.0/93.0 | ‐1.0/‐1.0 | |
| Atenolol | Renin‐angiotensin system inhibitor (ARB) | 174.5/97.7 | +1.1/‐0.2 | |
| Metoprolol | Renin‐angiotensin system inhibitor (ACE inhibitor) | 150.0/96.0 | 0.0/‐1.0 | |
| * 'Minus sign' means beta‐blocker group had lower BP, and 'plus sign' means beta‐blocker group had higher BP than control group. ACE: angiotensin‐converting enzyme; ARB: angiotensin receptor blocker; BP: blood pressure; DBP: diastolic blood pressure; SBP: systolic blood pressure. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 4 | 23613 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.88, 1.11] |
| 2 Total stroke Show forest plot | 4 | 23613 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.66, 0.96] |
| 3 Total coronary heart disease Show forest plot | 4 | 23613 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.81, 1.07] |
| 4 Cardiovascular death Show forest plot | 4 | 23613 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.80, 1.09] |
| 5 Total cardiovascular disease Show forest plot | 4 | 23613 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.79, 0.97] |
| 6 Withdrawal due to adverse effects Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 Oxprenolol | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Propranolol | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Atenolol | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 5 | 18241 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.91, 1.19] |
| 2 Total stroke Show forest plot | 4 | 18135 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.65, 2.09] |
| 2.1 Cardio‐selective beta‐blocker | 3 | 9435 | Risk Ratio (M‐H, Random, 95% CI) | 0.92 [0.55, 1.54] |
| 2.2 Non‐selective beta‐blocker | 1 | 8700 | Risk Ratio (M‐H, Random, 95% CI) | 2.28 [1.31, 3.95] |
| 3 Total coronary heart disease Show forest plot | 4 | 18135 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [0.82, 1.54] |
| 3.1 Aged < 65 years | 3 | 15952 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.81, 1.17] |
| 3.2 Aged > 65 years | 1 | 2183 | Risk Ratio (M‐H, Random, 95% CI) | 1.63 [1.15, 2.32] |
| 4 Cardiovascular death Show forest plot | 3 | 17452 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.90, 1.32] |
| 5 Total cardiovascular disease Show forest plot | 4 | 18135 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.99, 1.28] |
| 6 Withdrawal due to adverse effects Show forest plot | 3 | 11566 | Risk Ratio (M‐H, Random, 95% CI) | 1.69 [0.95, 3.00] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 4 | 44825 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [1.00, 1.14] |
| 2 Total stroke Show forest plot | 3 | 44167 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [1.11, 1.40] |
| 3 Total coronary heart disease Show forest plot | 3 | 44167 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.96, 1.15] |
| 4 Cardiovascular death Show forest plot | 4 | 44825 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.92, 1.46] |
| 5 Total cardiovascular disease Show forest plot | 2 | 19915 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [1.08, 1.29] |
| 6 Withdrawal due to adverse effects Show forest plot | 2 | 21591 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.71, 2.04] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 3 | 10828 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.98, 1.24] |
| 2 Total stroke Show forest plot | 2 | 9951 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.30 [1.11, 1.53] |
| 3 Total coronary heart disease Show forest plot | 2 | 9951 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.76, 1.06] |
| 4 Cardiovascular death Show forest plot | 3 | 10828 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.92, 1.29] |
| 5 Total cardiovascular disease Show forest plot | 3 | 10828 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.72, 1.38] |
| 5.1 Angiotensin‐converting enzyme inhibitors | 2 | 1635 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.63, 1.04] |
| 5.2 Angiotensin receptor blockers | 1 | 9193 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [1.04, 1.30] |
| 6 Withdrawal due to adverse effects Show forest plot | 2 | 9951 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.41 [1.29, 1.54] |
