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The Cochrane Database of Systematic... Oct 2014Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of... (Review)
Review
BACKGROUND
Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of blood pressure, which can reduce the recurrence of stroke.
OBJECTIVES
To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development of diabetes mellitus.
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (May 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2014, Issue 5), the Database of Abstracts of Reviews of Effects (DARE) (May 2014), MEDLINE (1966 to May 2014), EMBASE (1980 to May 2014), and Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to May 2014). We also searched ongoing trials registers and reference lists.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism. The intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the trials identified, appraised quality, and extracted data.
MAIN RESULTS
We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo and were of a high methodological quality. We noted no statistical differences among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.76 to 1.18). For other outcomes analysed (major vascular events, death from all causes, death from cardiovascular causes) , we observed no significant differences between the groups. There were minor blood pressure reductions in the intervention group. Neither of the included studies reported the occurrence of diabetes among their outcomes or assessed quality of life. Adverse events were significantly more frequent in participants taking atenolol than in those given placebo, and were the most common reason given for discontinuing treatment (RR 1.85, 95% CI 1.45 to 2.35).
AUTHORS' CONCLUSIONS
To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed.
Topics: Adrenergic beta-1 Receptor Antagonists; Atenolol; Humans; Ischemic Attack, Transient; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention; Stroke
PubMed: 25317988
DOI: 10.1002/14651858.CD007890.pub3 -
The Cochrane Database of Systematic... Aug 2012This review is an update of the Cochrane Review published in 2007, which assessed the role of beta-blockade as first-line therapy for hypertension. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review is an update of the Cochrane Review published in 2007, which assessed the role of beta-blockade as first-line therapy for hypertension.
OBJECTIVES
To quantify the effectiveness and safety of beta-blockers on morbidity and mortality endpoints in adults with hypertension.
SEARCH METHODS
In December 2011 we searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and reference lists of previous reviews; for eligible studies published since the previous search we conducted in May 2006.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of at least one year duration, which assessed the effects of beta-blockers compared to placebo or other drugs, as first-line therapy for hypertension, on mortality and morbidity in adults.
DATA COLLECTION AND ANALYSIS
We selected studies and extracted data in duplicate. We expressed study results as risk ratios (RR) with 95% confidence intervals (CI) and combined them using the fixed-effects or random-effects method, as appropriate.
MAIN RESULTS
We included 13 RCTs which compared beta-blockers to placebo (4 trials, N=23,613), diuretics (5 trials, N=18,241), calcium-channel blockers (CCBs: 4 trials, N=44,825), and renin-angiotensin system (RAS) inhibitors (3 trials, N=10,828). Three-quarters of the 40,245 participants on beta-blockers used atenolol. Most studies had a high risk of bias; resulting from various limitations in study design, conduct, and data analysis.Total mortality was not significantly different between beta-blockers and placebo (RR 0.99, 95%CI 0.88 to 1.11; I(2)=0%), diuretics or RAS inhibitors, but was higher for beta-blockers compared to CCBs (RR 1.07, 95%CI 1.00 to 1.14; I(2)=2%). Total cardiovascular disease (CVD) was lower for beta-blockers compared to placebo (RR 0.88, 95%CI 0.79 to 0.97; I(2)=21%). This is primarily a reflection of the significant decrease in stroke (RR 0.80, 95%CI 0.66 to 0.96; I(2)=0%), since there was no significant difference in coronary heart disease (CHD) between beta-blockers and placebo. There was no significant difference in withdrawals from assigned treatment due to adverse events between beta-blockers and placebo (RR 1.12, 95%CI 0.82 to 1.54; I(2)=66%).The effect of beta-blockers on CVD was significantly worse than that of CCBs (RR 1.18, 95%CI 1.08-1.29; I(2)=0%), but was not different from that of diuretics or RAS inhibitors. In addition, there was an increase in stroke in beta-blockers compared to CCBs (RR 1.24, 95%CI 1.11-1.40; I(2)=0%) and RAS inhibitors (RR 1.30, 95%CI 1.11 to 1.53; I(2)=29%). However, CHD was not significantly different between beta-blockers and diuretics, CCBs or RAS inhibitors. Participants on beta-blockers were more likely to discontinue treatment due to adverse events than those on RAS inhibitors (RR 1.41, 95% CI 1.29 to 1.54; I(2)=12%), but there was no significant difference with diuretics or CCBs.
AUTHORS' CONCLUSIONS
Initiating treatment of hypertension with beta-blockers leads to modest reductions in cardiovascular disease and no significant effects on mortality. These effects of beta-blockers are inferior to those of other antihypertensive drugs. The GRADE quality of this evidence is low, implying that the true effect of beta-blockers may be substantially different from the estimate of effects found in this review. Further research should be of high quality and should explore whether there are differences between different sub-types of beta-blockers or whether beta-blockers have differential effects on younger and elderly patients.
Topics: Adrenergic beta-Antagonists; Adult; Aged; Angiotensin Receptor Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Diuretics; Humans; Hypertension; Middle Aged; Randomized Controlled Trials as Topic; Stroke
PubMed: 22895924
DOI: 10.1002/14651858.CD002003.pub3 -
Journal of Pharmaceutical Sciences Sep 2017In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides... (Review)
Review
In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration-time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.
Topics: Beverages; Drug Interactions; Food-Drug Interactions; Humans; Intestinal Absorption; Intestinal Mucosa; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 28414144
DOI: 10.1016/j.xphs.2017.04.004 -
BMC Medicine Apr 2012We conducted a systematic review of evidence from randomized controlled trials to answer the following research question: What are the relative effects of different... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
We conducted a systematic review of evidence from randomized controlled trials to answer the following research question: What are the relative effects of different classes of antihypertensive drugs in reducing the incidence of cardiovascular disease outcomes for healthy people at risk of cardiovascular disease?
METHODS
We searched MEDLINE, EMBASE, AMED (up to February 2011) and CENTRAL (up to May 2009), and reference lists in recent systematic reviews. Titles and abstracts were assessed for relevance and those potentially fulfilling our inclusion criteria were then assessed in full text. Two reviewers made independent assessments at each step. We selected the following main outcomes: total mortality, myocardial infarction and stroke. We also report on angina, heart failure and incidence of diabetes. We conducted a multiple treatments meta-analysis using random-effects models. We assessed the quality of the evidence using the GRADE-instrument.
RESULTS
We included 25 trials. Overall, the results were mixed, with few significant differences, and with no drug-class standing out as superior across multiple outcomes. The only significant finding for total mortality based on moderate to high quality evidence was that beta-blockers (atenolol) were inferior to angiotensin receptor blockers (ARB) (relative risk (RR) 1.14; 95% credibility interval (CrI) 1.02 to 1.28). Angiotensin converting enzyme (ACE)-inhibitors came out inferior to calcium-channel blockers (CCB) regarding stroke-risk (RR 1.19; 1.03 to 1.38), but superior regarding risk of heart failure (RR 0.82; 0.69 to 0.94), both based on moderate quality evidence. Diuretics reduced the risk of myocardial infarction compared to beta-blockers (RR 0.82; 0.68 to 0.98), and lowered the risk of heart failure compared to CCB (RR 0.73; 0.62 to 0.84), beta-blockers (RR 0.73; 0.54 to 0.96), and alpha-blockers (RR 0.51; 0.40 to 0.64). The risk of diabetes increased with diuretics compared to ACE-inhibitors (RR 1.43; 1.12 to 1.83) and CCB (RR 1.27; 1.05 to 1.57).
CONCLUSION
Based on the available evidence, there seems to be little or no difference between commonly used blood pressure lowering medications for primary prevention of cardiovascular disease. Beta-blockers (atenolol) and alpha-blockers may not be first-choice drugs as they were the only drug-classes that were not significantly superior to any other, for any outcomes. Review registration: CRD database ("PROSPERO") CRD42011001066.
Topics: Antihypertensive Agents; Chemoprevention; Humans; Incidence; Myocardial Infarction; Primary Prevention; Randomized Controlled Trials as Topic; Stroke; Survival Analysis; Treatment Outcome
PubMed: 22480336
DOI: 10.1186/1741-7015-10-33 -
Frontiers in Neuroscience 2018Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are...
Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these. This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment. A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug, antipsychotic, schizophrenia, schizophren, psychos, psychotic, mental ill, mental disorder, neuroleptic, cardiovascular, cardiovascular diseases, clozapine, clozaril, autonomic, sympathetic, catecholamine, norepinephrine, noradrenaline, epinephrine, adrenaline. The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports. The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects.
PubMed: 29670504
DOI: 10.3389/fnins.2018.00203 -
International Journal of Health Sciences 2019Uncontrolled hypertension is a main predisposing risk factor leading to chronic atrial fibrillation (AF). Although several treatment methods for patients with HTN and AF... (Review)
Review
OBJECTIVES
Uncontrolled hypertension is a main predisposing risk factor leading to chronic atrial fibrillation (AF). Although several treatment methods for patients with HTN and AF were developed in past decades, further investigations of their efficacies are needed. This systematic narrative review presents an overview of studies reporting treatment efficacies in patients with HTN and/or AF.
METHODS
A narrative-based systematic review was performed using EMBASE, Medline, PubMed, Google Scholar, and the Cochrane Library searching for relevant papers published between October 2008 and October 2018. Out of 4481 studies, only 15 studies could be included following the inclusion criteria.
RESULTS
Included studies reported treatment measures, measured outcomes, and efficacies in adult patients with HTN and AF with defined interventions and methodologies. Treatment methods with effective outcomes were administration of hydrochlorothiazide, losartan or atenolol, telmisartan or amlodipine, or general anti-hypertensive drugs. Treatment methods that showed the most effective outcomes (lowering AF recurrence and improving BP control) were those containing pulmonary vein (or antrum) isolation (PVI/PVAI) (6 studies) and/or in conjunction with renal denervation (RDN)(6 studies). Treatment methods showing the most effective outcomes were PVI/PVAI in conjunction with RDN.
CONCLUSION
The latest evidence shows that PVI (in conjunction with RDN in some instances) was more efficacious among patients suffering from HTN and/or AF.
PubMed: 31745397
DOI: No ID Found -
The Cochrane Database of Systematic... May 2013Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of blood pressure, which can reduce the recurrence of stroke.
OBJECTIVES
To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development of diabetes mellitus.
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2011, Issue 12), the Database of Abstracts of Reviews of Effects (DARE) (December 2011), MEDLINE (1966 to December 2011), EMBASE (1980 to December 2011), and Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to December 2011). We also searched ongoing trials registers and reference lists.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism.The intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the trials identified, appraised quality, and extracted data.
MAIN RESULTS
We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo. No statistical differences were noted among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.75 to 1.17). For all other outcomes analysed (death from all causes, cardiac death, non-fatal myocardial infarction, major vascular events), we observed no significant differences between the groups.
AUTHORS' CONCLUSIONS
To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed.
Topics: Adrenergic beta-1 Receptor Antagonists; Atenolol; Cause of Death; Humans; Ischemic Attack, Transient; Myocardial Infarction; Secondary Prevention; Stroke
PubMed: 23728669
DOI: 10.1002/14651858.CD007890.pub2 -
The Cochrane Database of Systematic... Sep 2013Beta (β) blockers are indicated for use in coronary artery disease (CAD). However, optimal therapy for people with CAD accompanied by intermittent claudication has been... (Review)
Review
BACKGROUND
Beta (β) blockers are indicated for use in coronary artery disease (CAD). However, optimal therapy for people with CAD accompanied by intermittent claudication has been controversial because of the presumed peripheral haemodynamic consequences of beta blockers, leading to worsening symptoms of intermittent claudication. This is an update of a review first published in 2008.
OBJECTIVES
To quantify the potential harmful effects of beta blockers on maximum walking distance, claudication distance, calf blood flow, calf vascular resistance and skin temperature when used in patients with peripheral arterial disease (PAD).
SEARCH METHODS
For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched March 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 2).
SELECTION CRITERIA
Randomised controlled trials (RCTs) evaluating the role of both selective (β1) and non-selective (β1 and β2) beta blockers compared with placebo. We excluded trials that compared different types of beta blockers.
DATA COLLECTION AND ANALYSIS
Primary outcome measures were claudication distance in metres, time to claudication in minutes and maximum walking distance in metres and minutes (as assessed by treadmill).Secondary outcome measures included calf blood flow (mL/100 mL/min), calf vascular resistance and skin temperature (ºC).
MAIN RESULTS
We included six RCTs that fulfilled the above criteria, with a total of 119 participants. The beta blockers studied were atenolol, propranolol, pindolol and metoprolol. All trials were of poor quality with the drugs administered over a short time (10 days to two months). None of the primary outcomes were reported by more than one study. Similarly, secondary outcome measures, with the exception of vascular resistance (as reported by three studies), were reported, each by only one study. Pooling of such results was deemed inappropriate. None of the trials showed a statistically significant worsening effect of beta blockers on time to claudication, claudication distance and maximal walking distance as measured on a treadmill, nor on calf blood flow, calf vascular resistance and skin temperature, when compared with placebo. No reports described adverse events associated with the beta blockers studied.
AUTHORS' CONCLUSIONS
Currently, no evidence suggests that beta blockers adversely affect walking distance, calf blood flow, calf vascular resistance and skin temperature in people with intermittent claudication. However, because of the lack of large published trials, beta blockers should be used with caution, if clinically indicated.
Topics: Adrenergic beta-Antagonists; Atenolol; Humans; Intermittent Claudication; Metoprolol; Peripheral Vascular Diseases; Pindolol; Propranolol; Randomized Controlled Trials as Topic; Regional Blood Flow; Walking
PubMed: 24027118
DOI: 10.1002/14651858.CD005508.pub3 -
American Journal of Cardiovascular... Mar 2021Cardiovascular diseases are the main cause of mortality worldwide, and systemic arterial hypertension is associated with a large number of these cases. The objective of... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Cardiovascular diseases are the main cause of mortality worldwide, and systemic arterial hypertension is associated with a large number of these cases. The objective of health professionals and health policies should be searching for the best therapeutics to control this disease. A recent consensus indicated that β-blockers have recently lost their place in initial indications for the treatment of systemic arterial hypertension and are now more indicated for the treatment of hypertension in association with other clinical situations such as angina, heart failure and arrhythmia; however, it is known that this approach was based on studies that evaluated older β-blockers such as atenolol.
OBJECTIVE
The main objective of this study was to perform a systematic review with subsequent meta-analysis on the use of nebivolol for hypertensive disease treatment, comparing it with drugs of the main antihypertensive classes.
METHODS
This systematic review was based on a search of the MEDLINE (via Pubmed), Scopus, Cochrane, International Pharmaceuticals Abstracts (IPA), and Lilacs databases for randomized and double-blind clinical trials. In addition, we also searched for gray literature studies, to 31 July 2015. Next, a cumulative meta-analysis was performed, with studies being added in a sequential manner, evaluating their impact on the combined effect. For this project, we only meta-analyzed direct comparisons of random effect.
RESULTS
Overall, 981 clinical trials were included in this systematic review. After careful analysis, 34 randomized and double-blind clinical trials were included to investigate the efficacy of nebivolol on systolic (SBP) and diastolic blood pressure (DBP) control and adverse effects. The study population comprised 12,465 patients with systemic arterial hypertension (SAH) aged between 18 and 85 years; 17% of subjects were of Black ethnicity, approximately 55% were men, and almost 10% had diabetes. In SBP management, nebivolol was superior to other β-blockers and diuretics and showed no difference in efficacy when compared with angiotensin receptor blockers or calcium channel blockers. There were insufficient studies on angiotensin-converting enzyme inhibitors for adequate comparison of both SBP and DBP control. For DBP control, nebivolol was more efficient than other β-blockers, angiotensin receptor blockers, diuretics, and calcium channel blockers.
DISCUSSION
Nebivolol is a third-generation β-blocker with additional capabilities to improve blood pressure levels in patients with arterial hypertension, because it acts by additional mechanisms such as endothelium-dependent vasodilation associated with L-arginine and oxide nitric acid, nitric oxide activity on smooth muscle cells, decreasing platelet aggregation, and leukocyte adhesion in the endothelium, decreasing oxidative stress. Although nebivolol has shown good results in controlling hypertension in this study (with few adverse events when compared with placebo treatment) and has an unquestionable benefit in individuals with heart failure (mainly with reduced ejection fraction), there is a lack of studies proving the benefit of this drug for controlling hypertension and reducing clinical outcomes such as cardiovascular (or general) mortality, acute myocardial infarction, or stroke.
CONCLUSIONS
Nebivolol demonstrated at least similar control of blood pressure levels in hypertensive individuals when compared with drugs of the most used classes. In addition, in relation to the control of arterial hypertension, studies with clinical outcomes should be performed to ensure the use of this drug in detriment to others with these well-established results.
Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Age Factors; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Multicenter Studies as Topic; Nebivolol; Randomized Controlled Trials as Topic; Sex Factors; Socioeconomic Factors; Young Adult
PubMed: 32710438
DOI: 10.1007/s40256-020-00422-0 -
Lancet (London, England) Mar 2017Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Globally, most patients with hypertension are treated with monotherapy, and control rates are poor because monotherapy only reduces blood pressure by around 9/5 mm Hg on average. There is a pressing need for blood pressure-control strategies with improved efficacy and tolerability. We aimed to assess whether ultra-low-dose combination therapy could meet these needs.
METHODS
We did a randomised, placebo-controlled, double-blind, crossover trial of a quadpill-a single capsule containing four blood pressure-lowering drugs each at quarter-dose (irbesartan 37·5 mg, amlodipine 1·25 mg, hydrochlorothiazide 6·25 mg, and atenolol 12·5 mg). Participants with untreated hypertension were enrolled from four centres in the community of western Sydney, NSW, Australia, mainly by general practitioners. Participants were randomly allocated by computer to either the quadpill or matching placebo for 4 weeks; this treatment was followed by a 2-week washout, then the other study treatment was administered for 4 weeks. Study staff and participants were unaware of treatment allocations, and masking was achieved by use of identical opaque capsules. The primary outcome was placebo-corrected 24-h systolic ambulatory blood pressure reduction after 4 weeks and analysis was by intention to treat. We also did a systematic review of trials evaluating the efficacy and safety of quarter-standard-dose blood pressure-lowering therapy against placebo. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614001057673. The trial ended after 1 year and this report presents the final analysis.
FINDINGS
Between November, 2014, and December, 2015, 55 patients were screened for our randomised trial, of whom 21 underwent randomisation. Mean age of participants was 58 years (SD 11) and mean baseline office and 24-h systolic and diastolic blood pressure levels were 154 (14)/90 (11) mm Hg and 140 (9)/87 (8) mm Hg, respectively. One individual declined participation after randomisation and two patients dropped out for administrative reasons. The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14-23), and office blood pressure was reduced by 22/13 mm Hg (p<0·0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p=0·0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n=4721 participants) of one drug at quarter-dose and six trials (n=312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p<0·0001), and there were no side-effects from either regimen.
INTERPRETATION
The findings of our small trial in the context of previous randomised evidence suggest that the benefits of quarter-dose therapy could be additive across classes and might confer a clinically important reduction in blood pressure. Further examination of the quadpill concept is needed to investigate effectiveness against usual treatment options and longer term tolerability.
FUNDING
National Heart Foundation, Australia; University of Sydney; and National Health and Medical Research Council of Australia.
Topics: Female; Humans; Male; Middle Aged; Administration, Oral; Amlodipine; Antihypertensive Agents; Atenolol; Biphenyl Compounds; Blood Pressure; Cross-Over Studies; Double-Blind Method; Drug Combinations; Hydrochlorothiazide; Hypertension; Irbesartan; Medication Adherence; Tetrazoles; Treatment Outcome
PubMed: 28190578
DOI: 10.1016/S0140-6736(17)30260-X