Effect of the combination of diuretics, renin-angiotensin-aldosterone system inhibitors, and non-steroidal anti-inflammatory drugs or metamizole (triple whammy) on hospitalisation due to acute kidney injury: A nested case-control study.

PURPOSE: Concomitant use of diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) or metamizole, known as 'triple whammy' (TW), has been associated with an increased risk of acute kidney injury (AKI). Nevertheless, there is still uncertainty on its impact in hospitalisation and mortality. The aim of the study was to analyse the association between exposure to TW and the risk of hospitalisation for AKI, all-cause mortality and the need for renal replacement therapy (RRT). METHODS: A case-control study nested in a cohort of adults exposed to at least one diuretic or RAAS inhibitor between 2009 and 2018 was carried out within the Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Patients hospitalised for AKI between 2010 and 2018 (cases) were matched with up to 10 patients of the same age, sex and region of Spain who had not been hospitalised for AKI as of the date of hospitalisation for AKI of the matching case (controls). The association between TW exposure versus non-exposure to TW and outcome variables was analysed using logistic regression models. RESULTS: A total of 480 537 participants (44 756 cases and 435 781 controls) were included (mean age: 79 years). The risk of hospitalisation for AKI was significantly higher amongst those exposed to TW [adjusted odds ratio (aOR) 1.36, 95% confidence interval (95%CI) 1.32-1.40], being higher with current (aOR 1.60, 95%CI 1.52-1.69) and prolonged exposure (aOR 1.65, 95%CI 1.55-1.75). No significant association was found with the need of RRT. Unexpectedly, mortality was lower in those exposed to TW (aOR 0.81, 95%CI 0.71-0.93), which may be influenced by other causes. CONCLUSION: Vigilance should be increased when diuretics, RAAS inhibitors, and NSAIDs or metamizole are used concomitantly, especially in patients at risk such as elderly patients.

Impact of COVID-19 Pandemic in Antibiotic Consumption in Navarre (Spain): An Interrupted Time Series Analysis.

On 11 March 2020, the World Health Organization declared coronavirus disease 19 (COVID-19) a global pandemic. This exceptional situation changed the world not only in terms of mortality and morbidity, but also in terms of epidemiology and health system resources consumption. The objective of this work was to analyze the consumption of antibiotics during the period around the pandemic in our region. A drug utilization study was performed comparing the antibiotic consumption in the community during the years 2018, 2019, 2020, and 2021. Quarterly antibiotic use (defined daily doses (DDD) per 1000 inhabitants per day (DID)) and number of patients treated were the outcomes. Interrupted time series regression analysis was performed to estimate the statistical significance of the change in level of consumption before and after the COVID-19 pandemic. The drop of global antibiotic consumption was statistically significant, both in number of patients and in DID when analyzing pre-pandemic period versus pandemic period. The use of strategic antibiotics for respiratory infections such as amoxicillin, amoxicillin-clavulanic acid, and levofloxacin also decreased significantly. Seasonal pattern of use of antibiotics disappeared due to the global measures imposed over the world to work against COVID-19.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

BACKGROUND: This is the third update of the review first published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. OBJECTIVES: To determine if lower blood pressure targets (systolic/diastolic 135/85 mmHg or less) are associated with reduction in mortality and morbidity compared with standard blood pressure targets (140 mmHg to 160mmHg/90 mmHg to 100 mmHg or less) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). SEARCH METHODS: For this updated review, we used standard, extensive Cochrane search methods. The latest search date was January 2022. We applied no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) with more than 50 participants per group that provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (135/85 mmHg or less) compared with standard targets for blood pressure (140 mmHg to 160 mmHg/90 mmHg to 100 mmHg or less). Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included seven RCTs that involved 9595 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). Six of seven RCTs provided individual participant data. None of the included studies was blinded to participants or clinicians because of the need to titrate antihypertensive drugs to reach a specific blood pressure goal. However, an independent committee blinded to group allocation assessed clinical events in all trials. Hence, we assessed all trials at high risk of performance bias and low risk of detection bias. We also considered other issues, such as early termination of studies and subgroups of participants not predefined, to downgrade the certainty of the evidence. We found there is probably little to no difference in total mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.91 to 1.23; 7 studies, 9595 participants; moderate-certainty evidence) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; 6 studies, 9484 participants; moderate-certainty evidence). Similarly, we found there may be little to no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; 7 studies, 9595 participants; low-certainty evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure (CHF)) (RR 0.89, 95% CI 0.80 to 1.00; 7 studies, 9595 participants; low-certainty evidence). The evidence was very uncertain about withdrawals due to adverse effects. However, studies suggest more participants may withdraw due to adverse effects in the lower target group (RR 8.16, 95% CI 2.06 to 32.28; 3 studies, 801 participants; very low-certainty evidence). Systolic and diastolic blood pressure readings were lower in the lower target group (systolic: mean difference (MD) -8.77 mmHg, 95% CI -12.82 to -4.73; 7 studies, 8657 participants; diastolic: MD -4.50 mmHg, 95% CI -6.35 to -2.65; 6 studies, 8546 participants). More drugs were needed in the lower target group (MD 0.56, 95% CI 0.16 to 0.96; 5 studies, 7910 participants), but blood pressure targets at one year were achieved more frequently in the standard target group (RR 1.20, 95% CI 1.17 to 1.23; 7 studies, 8699 participants). AUTHORS' CONCLUSIONS: We found there is probably little to no difference in total mortality and cardiovascular mortality between people with hypertension and cardiovascular disease treated to a lower compared to a standard blood pressure target. There may also be little to no difference in serious adverse events or total cardiovascular events. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on withdrawals due to adverse effects, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (135/85 mmHg or less) in people with hypertension and established cardiovascular disease. Several trials are still ongoing, which may provide an important input to this topic in the near future.

Association between benzodiazepine use and development of dementia

Objective: To evaluate the association between use of benzodiazepines and incident dementia.MethodsAnalytical prospective nested case-control study for which the Spanish database for pharmacoepidemiological research in primary care (BIFAP) of the Spanish Agency of Medicines and Medical Devices (AEMPS) was used. A total of 15,212 subjects diagnosed with dementia of the Alzheimer type and 62,397 controls were identified. Exposure was retrieved retrospectively with a 3-year lag time before the index date. Adjusted odd ratios (OR) were calculated.ResultsBenzodiazepines use increased the risk of suffering Alzheimer's disease (OR=1.05, 95% CI, 1.01–1.10). No statistical differences were shown between short-acting and long-acting drugs. The risk is more evident with longer exposure times.ConclusionsThere seems to be a weak association between benzodiazepine use and the development of dementia, the risk increases with greater exposure. (AU)

Objetivo: Evaluar la asociación entre el uso de benzodiacepinas y la incidencia de demencia.MétodosEstudio analítico prospectivo de caso-control anidado, utilizando la base de datos española para investigación farmacoepidemiológica en atención primaria (BIFAP) de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Se identificó un total de 15.212 sujetos diagnosticados de demencia tipo Alzheimer, y 62.397 controles. Los datos sobre la exposición se recuperaron retrospectivamente con un lapso de tiempo de 3 años anterior a la fecha del índice. Se calcularon los odds ratios (OR) ajustados.ResultadosEl uso de benzodiacepinas incrementó el riesgo de padecer Alzheimer (OR=1,05; IC 95%, 1,01-1,10). No se encontraron diferencias estadísticas entre los fármacos de acción corta y acción prolongada. El riesgo es más evidente cuando se incrementan los tiempos de exposición.ConclusionesParece existir una débil asociación entre el uso de benzodiacepinas y el desarrollo de demencia, incrementándose el riesgo cuando se aumenta la exposición. (AU)

Association between benzodiazepine use and development of dementia.

OBJECTIVE: To evaluate the association between use of benzodiazepines and incident dementia. METHODS: Analytical prospective nested case-control study for which the Spanish database for pharmacoepidemiological research in primary care (BIFAP) of the Spanish Agency of Medicines and Medical Devices (AEMPS) was used. A total of 15,212 subjects diagnosed with dementia of the Alzheimer type and 62,397 controls were identified. Exposure was retrieved retrospectively with a 3-year lag time before the index date. Adjusted odd ratios (OR) were calculated. RESULTS: Benzodiazepines use increased the risk of suffering Alzheimer's disease (OR=1.05, 95% CI, 1.01-1.10). No statistical differences were shown between short-acting and long-acting drugs. The risk is more evident with longer exposure times. CONCLUSIONS: There seems to be a weak association between benzodiazepine use and the development of dementia, the risk increases with greater exposure.

Alcohol intake reduction for controlling hypertension.

BACKGROUND: High blood pressure constitutes one of the leading causes of mortality and morbidity all over the world. At the same time, heavy drinking increases the risk for developing cardiovascular diseases, including cardiomyopathy, hypertension, atrial arrhythmias, or stroke. Several studies have already assessed specifically the relationship between alcohol intake and hypertension. However, the potential effect on blood pressure of alcohol intake reduction interventions is largely unknown. OBJECTIVES: To assess the effect of any intervention to reduce alcohol intake in terms of blood pressure decrease in hypertensive people with alcohol consumption compared to a control intervention or no intervention at all. To determine additional effects related to mortality, major cardiovascular events, serious adverse events, or quality of life. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to June 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 5, 2020), MEDLINE Ovid (from 1946), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In-Process, Embase Ovid (from 1974), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. Trial authors were contacted when needed and no language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials with minimum 12 weeks duration and including 50 or more subjects per group with quantitative measurement of alcohol consumption and/or biological measurement of the outcomes of interest. Participants were adults (16 years of age or older) with systolic blood pressure (SBP) greater than 140 mmHg and diastolic blood pressure (DBP) greater than 90 mmHg, and SBP ≥ 130 or DBP ≥ 80 mmHg in participants with diabetes. We included any intervention implemented to reduce their alcohol intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and extracted data using standard methodological procedures adopted by Cochrane. MAIN RESULTS: A total of 1210 studies were screened. We included one randomised controlled trial involving a total of 269 participants with a two-year follow-up. Individual patient data for all participants were provided and used in this review. No differences were found between the cognitive-behavioural intervention group and the control group for overall mortality (RR 0.72, 95% CI 0.16 to 3.17; low-certainty evidence), cardiovascular mortality (not estimable) and cardiovascular events (RR 0.80, 95% CI 0.36 to 1.79; very low-certainty evidence). There was no statistical difference in systolic blood pressure (SBP) reduction (Mean Difference (MD) -0.92 mmHg, 95% confidence interval (CI) -5.66 to 3.82 mmHg; very low-certainty evidence) or diastolic blood pressure (DBP) decrease (MD 0.98 mmHg, 95% CI -1.69 to 3.65 mmHg; low-certainty evidence) between the cognitive-behavioural intervention group and the control group. We also did not find any differences in the proportion of subjects with SBP < 140 mmHg and DBP < 90 mmHg (Risk Ratio (RR) 1.21, 95% CI 0.88 to 1.65; very low-certainty evidence). Concerning secondary outcomes, the alcohol intake was significantly reduced in the cognitive-behavioural intervention compared with the control group (MD 191.33 g, 95% CI 85.36 to 297.30 g). We found no differences between the active and control intervention in the proportion of subjects with lower-risk alcohol intake versus higher-risk and extreme drinkers at the end of the study (RR 1.04, 95% CI 0.68 to 1.60). There were no estimable results for the quality of life outcome. AUTHORS' CONCLUSIONS: An intervention for decreasing alcohol intake consumption did not result in differences in systolic and diastolic blood pressure when compared with a control intervention, although there was a reduction in alcohol intake favouring the active intervention. No differences were found either for overall mortality, cardiovascular mortality or cardiovascular events. No data on serious adverse events or quality of life were available to assess. Adequate randomised controlled trials are needed to provide additional evidence on this specific question.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

BACKGROUND: This is the second update of the review first published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. OBJECTIVES: To determine if lower blood pressure targets (135/85 mmHg or less) are associated with reduction in mortality and morbidity as compared with standard blood pressure targets (140 to 160/90 to 100 mmHg or less) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to November 2019: Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. SELECTION CRITERIA: We included RCTs with more than 50 participants per group that provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (135/85 mmHg or less) compared with standard targets for blood pressure (140 to 160/90 to 100 mmHg or less). Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. We used GRADE to assess the quality of the evidence. MAIN RESULTS: We included six RCTs that involved 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data. None of the included studies was blinded to participants or clinicians because of the need to titrate antihypertensives to reach a specific blood pressure goal. However, an independent committee blinded to group allocation assessed clinical events in all trials. Hence, we assessed all trials at high risk of performance bias and low risk of detection bias. Other issues such as early termination of studies and subgroups of participants not predefined were also considered to downgrade the quality evidence. We found there is probably little to no difference in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23; 6 studies, 9484 participants; moderate-quality evidence) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; 6 studies, 9484 participants; moderate-quality evidence). Similarly, we found there may be little to no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; 6 studies, 9484 participants; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; 6 studies, 9484 participants; low-quality evidence). The evidence was very uncertain about withdrawals due to adverse effects. However, studies suggest more participants may withdraw due to adverse effects in the lower target group (RR 8.16, 95% CI 2.06 to 32.28; 2 studies, 690 participants; very low-quality evidence). Systolic and diastolic blood pressure readings were lower in the lower target group (systolic: mean difference (MD) -8.90 mmHg, 95% CI -13.24 to -4.56; 6 studies, 8546 participants; diastolic: MD -4.50 mmHg, 95% CI -6.35 to -2.65; 6 studies, 8546 participants). More drugs were needed in the lower target group (MD 0.56, 95% CI 0.16 to 0.96; 5 studies, 7910 participants), but blood pressure targets were achieved more frequently in the standard target group (RR 1.21, 95% CI 1.17 to 1.24; 6 studies, 8588 participants). AUTHORS' CONCLUSIONS: We found there is probably little to no difference in total mortality and cardiovascular mortality between people with hypertension and cardiovascular disease treated to a lower compared to a standard blood pressure target. There may also be little to no difference in serious adverse events or total cardiovascular events. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on withdrawals due to adverse effects, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (135/85 mmHg or less) in people with hypertension and established cardiovascular disease. Several trials are still ongoing, which may provide an important input to this topic in the near future.

Telmisartan-induced sprue-like enteropathy: a case report.

A possible case of sprue-like enteropathy (SLE) induced by the use of telmisartan is reported. Telmisartan is an angiotensin-receptor II blocker (type 1) used for the treatment of hypertension. Several cases of SLE associated with olmesartan and other drugs of the same group have been reported. In all cases, SLE resolved following therapy withdrawal. We describe the case of an 80-year-old woman who presented with diarrhoea and abdominal pain. In the past 5 years she had been treated with telmisartan 40 mg once a day for hypertension, so we hypothesised that symptoms might be caused by telmisartan. After treatment discontinuation, diarrhoea disappeared. Three causality algorithms were applied and revealed a possible or likely causal relationship. At present, the patient remains asymptomatic. There is a causal relationship between the use of telmisartan and SLE. This association should be taken into account by physicians when prescribing and reviewing drug therapies.

First-line combination therapy versus first-line monotherapy for primary hypertension.

BACKGROUND: This is the first update of a review originally published in 2017. Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown. OBJECTIVES: To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2019: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 2005), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We used no language restrictions. We also searched clinical studies repositories of pharmaceutical companies, reviews of combination drugs on the US Food and Drug Administration and European Medicines Agency websites, and lists of references in reviews and clinical practice guidelines. SELECTION CRITERIA: We included randomised, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drugs with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events, or serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, evaluated the risk of bias, and performed data entry. The primary outcomes were mortality, serious adverse events, cardiovascular events, and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial), and blood pressure change from baseline. Analyses were based on the intention-to-treat principle. We summarised data on dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: This update included one new study in which a subgroup of participants met our inclusion criteria. As none of the four included studies focused solely on people initiating antihypertensive treatment, we asked investigators for data for this subgroup. One study (PREVER-treatment 2016) used a combination of thiazide-type diuretic/potassium-sparing diuretic; as the former is not indicated in monotherapy, we analysed this study separately. The three original trials in the main comparison (monotherapy: 335 participants; combination therapy: 233 participants) included outpatients, mostly European and white people. Two trials only included people with type 2 diabetes; the remaining trial excluded people treated with diabetes, hypocholesterolaemia, or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. It is very uncertain whether combination therapy versus monotherapy reduces total mortality (RR 1.35, 95% CI 0.08 to 21.72), cardiovascular mortality (zero events reported), cardiovascular events (RR 0.98, 95% CI 0.22 to 4.41), serious adverse events (RR 0.77, 95% CI 0.31 to 1.92), or withdrawals due to adverse effects (RR 0.85, 95% CI 0.53 to 1.35); all outcomes had 568 participants, and the evidence was rated as of very low certainty due to serious imprecision and for using a subgroup that was not defined in advance. The confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. The PREVER-treatment 2016 trial, which used a combination therapy with potassium-sparing diuretic (monotherapy: 84 participants; combination therapy: 116 participants), included outpatients. This trial was conducted in Brazil and had a follow-up of 18 months. The number of events was very low and confidence intervals very wide, with zero events reported for cardiovascular mortality and withdrawals due to adverse events. It is very uncertain if there are differences in clinical outcomes between monotherapy and combination therapy in this trial. AUTHORS' CONCLUSIONS: The numbers of included participants, and hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the review question and report clinically relevant endpoints.

Use of methylphenidate and risk for valvular heart disease: A case-control study nested in the BIFAP cohort.

PURPOSE: To examine the association between use of methylphenidate and the risk for valvular heart disease (VHD) in the Spanish primary care database BIFAP. METHODS: Case-control study nested in a cohort of patients aged 5 to 25 years between 2002 and 2014, based in a general practice research database. Cases were people with a validated diagnosis of VHD. Ten controls per case were matched on age, sex, and calendar year. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) of VHD comparing patients ever treated with methylphenidate vs never users, as well as by time since last use, treatment duration, and variations in case inclusion criteria. RESULTS: From a cohort of 1 596 284 patients, we identified 262 valid cases of VHD. No difference in the incidence of VHD was observed when comparing "ever users" of methylphenidate with "never users" (adjusted OR 0.52, 95%CI 0.16-1.69). A similar result was found comparing current, recent, or past users of methylphenidate. Differences were not significant when both valid and probable cases were included as events of interest (adjusted OR 0.59, 95%CI 0.22-1.63). CONCLUSIONS: In this first-ever population-based study on this issue, association between methylphenidate and the incidence of VHD among persons in the 5 to 25 years age range was neither confirmed nor excluded. Additional studies may be required to clarify the presence or absence of this relationship.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

BACKGROUND: This is the first update of the review published in 2017. Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure to below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. OBJECTIVES: To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2018: Cochrane Hypertension Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), and Latin American Caribbean Health Sciences Literature (LILACS) (from 1982), along with the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. We applied no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that included more than 50 participants per group and provided at least six months' follow-up. Trial reports had to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions involved lower targets for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard targets for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension and adults receiving treatment for hypertension with a cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease, or angina pectoris. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and extracted data using standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six RCTs that involved a total of 9484 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). All RCTs provided individual participant data.We found no change in total mortality (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.91 to 1.23) or cardiovascular mortality (RR 1.03, 95% CI 0.82 to 1.29; moderate-quality evidence). Similarly, we found no differences in serious adverse events (RR 1.01, 95% CI 0.94 to 1.08; low-quality evidence) or total cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization, or death from congestive heart failure) (RR 0.89, 95% CI 0.80 to 1.00; low-quality evidence). Studies reported more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower target group by 8.9/4.5 mmHg. More drugs were needed in the lower target group, but blood pressure targets were achieved more frequently in the standard target group. AUTHORS' CONCLUSIONS: We found no evidence of a difference in total mortality, serious adverse events, or total cardiovascular events between people with hypertension and cardiovascular disease treated to a lower or to a standard blood pressure target. This suggests that no net health benefit is derived from a lower systolic blood pressure target. We found very limited evidence on adverse events, which led to high uncertainty. At present, evidence is insufficient to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to examine this topic.

Blood pressure targets for the treatment of people with hypertension and cardiovascular disease.

BACKGROUND: Hypertension is a prominent preventable cause of premature morbidity and mortality. People with hypertension and established cardiovascular disease are at particularly high risk, so reducing blood pressure below standard targets may be beneficial. This strategy could reduce cardiovascular mortality and morbidity but could also increase adverse events. The optimal blood pressure target in people with hypertension and established cardiovascular disease remains unknown. OBJECTIVES: To determine if 'lower' blood pressure targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with 'standard' blood pressure targets (≤ 140 to 160/ 90 to 100 mmHg) in the treatment of people with hypertension and a history of cardiovascular disease (myocardial infarction, angina, stroke, peripheral vascular occlusive disease). SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to February 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the Latin American and Caribbean Health Science Literature Database (from 1982) and contacted authors of relevant papers regarding further published and unpublished work. There were no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) with more than 50 participants per group and at least six months follow-up. Trial reports needed to present data for at least one primary outcome (total mortality, serious adverse events, total cardiovascular events, cardiovascular mortality). Eligible interventions were lower target for systolic/diastolic blood pressure (≤ 135/85 mmHg) compared with standard target for blood pressure (≤ 140 to 160/90 to 100 mmHg).Participants were adults with documented hypertension or who were receiving treatment for hypertension and cardiovascular history for myocardial infarction, stroke, chronic peripheral vascular occlusive disease or angina pectoris. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and extracted data using standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included six RCTs that involved a total of 9795 participants. Mean follow-up was 3.7 years (range 1.0 to 4.7 years). Five RCTs provided individual patient data for 6775 participants.We found no change in total mortality (RR 1.05, 95% CI 0.90 to 1.22) or cardiovascular mortality (RR 0.96, 95% CI 0.77 to 1.21; moderate-quality evidence). Similarly, no differences were found in serious adverse events (RR 1.02, 95% CI 0.95 to 1.11; low-quality evidence). There was a reduction in fatal and non fatal cardiovascular events (including myocardial infarction, stroke, sudden death, hospitalization or death from congestive heart failure) with the lower target (RR 0.87, 95% CI 0.78 to 0.98; ARR 1.6% over 3.7 years; low-quality evidence). There were more participant withdrawals due to adverse effects in the lower target arm (RR 8.16, 95% CI 2.06 to 32.28; very low-quality evidence). Blood pressures were lower in the lower' target group by 9.5/4.9 mmHg. More drugs were needed in the lower target group but blood pressure targets were achieved more frequently in the standard target group. AUTHORS' CONCLUSIONS: No evidence of a difference in total mortality and serious adverse events was found between treating to a lower or to a standard blood pressure target in people with hypertension and cardiovascular disease. This suggests no net health benefit from a lower systolic blood pressure target despite the small absolute reduction in total cardiovascular serious adverse events. There was very limited evidence on adverse events, which lead to high uncertainty. At present there is insufficient evidence to justify lower blood pressure targets (≤ 135/85 mmHg) in people with hypertension and established cardiovascular disease. More trials are needed to answer this question.

Use of oral antidiabetic agents and risk of community-acquired pneumonia: a nested case-control study.

AIMS: To evaluate the association between use of different oral antidiabetic agents (OAD) and the risk of community-acquired pneumonia (CAP) in patients with type-2 diabetes (T2DM). METHODS: Case-control study nested in a cohort of patients with T2DM and use of OAD between 2002 and 2013, based in a Spanish general practice research database. Cases were people diagnosed with T2DM, aged >18 years and with a validated diagnosis of CAP between 2002 and 2013. Ten controls were matched on age, sex and calendar year. Odds ratio (OR) of CAP was estimated comparing patients treated with: (1) metformin vs. other monotherapies or no antidiabetic treatment; (2) metformin + sulfonylureas vs. other antidiabetic combinations. OR of CAP was also assessed according to antidiabetic treatment duration. RESULTS: From a cohort of 76 009 T2DM patients, we identified 1803 cases of CAP. No difference in the incidence of CAP was observed when comparing any OAD in monotherapy with metformin. Compared with current use of metformin + sulfonylurea, thiazolidinediones + metformin was associated with an increased risk of CAP (adjusted OR = 2.48, 95% CI 1.40-4.38). The use of any combination with thiazolidinediones was also associated with higher risk of CAP (adjusted OR = 2.00, 95% CI 1.22-3.28). Current use of DPP-4 inhibitors was not associated with an increased risk of CAP. CONCLUSIONS: No differences in the incidence of CAP were observed between the use of OAD in monotherapy vs. metformin. Thiazolidinedione use in combination was associated with an increase in the risk of CAP when compared to metformin + sulfonylureas. The use of DPP-4 inhibitors was not associated with an increased risk of CAP.

First-line combination therapy versus first-line monotherapy for primary hypertension.

BACKGROUND: Starting with one drug and starting with a combination of two drugs are strategies suggested in clinical guidelines as initial treatment of hypertension. The recommendations are not based on evidence about clinically relevant outcomes. Some antihypertensive combinations have been shown to be harmful. The actual harm-to-benefit balance of each strategy is unknown. OBJECTIVES: To determine if there are differences in clinical outcomes between monotherapy and combination therapy as initial treatment for primary hypertension. SEARCH METHODS: We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 2), Ovid MEDLINE, Ovid Embase, LILACS, ClinicalTrials.gov, Current Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2016. We searched in clinical studies repositories of pharmaceutical companies, reviews of combination drugs in Food and Drug Administration and European Medicines Agency, and lists of references in reviews and clinical practice guidelines. SELECTION CRITERIA: Randomized, double-blind trials with at least 12 months' follow-up in adults with primary hypertension (systolic blood pressure/diastolic blood pressure 140/90 mmHg or higher, or 130/80 mmHg or higher if participants had diabetes), which compared combination of two first-line antihypertensive drug with monotherapy as initial treatment. Trials had to include at least 50 participants per group and report mortality, cardiovascular mortality, cardiovascular events or serious adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, evaluated the risk of bias and entered the data. Primary outcomes were mortality, serious adverse events, cardiovascular events and cardiovascular mortality. Secondary outcomes were withdrawals due to drug-related adverse effects, reaching blood pressure control (as defined in each trial) and blood pressure change from baseline. Analyses were based on the intention-to-treat principle. We summarized data on dichotomous outcomes as risk ratios with 95% confidence intervals. MAIN RESULTS: We found three studies in which a subgroup of participants met our inclusion criteria. None of the studies focused solely on people initiating antihypertensive treatment so we asked investigators for data for this subgroup (monotherapy: 335 participants; combination therapy: 233 participants). They included outpatients, and mostly European and white people. Two trials included only people with type 2 diabetes, whereas the other trial excluded people treated with diabetes, hypocholesterolaemia or cardiovascular drugs. The follow-up was 12 months in two trials and 36 months in one trial. Certainty of evidence was very low due to the serious imprecision, and for using a subgroup not defined in advance. Confidence intervals were extremely wide for all important outcomes and included both appreciable harm and benefit. AUTHORS' CONCLUSIONS: The numbers of included participants and, hence the number of events, were too small to draw any conclusion about the relative efficacy of monotherapy versus combination therapy as initial treatment for primary hypertension. There is a need for large clinical trials that address the question and report clinically relevant endpoints.