Learn more: PMC Disclaimer | PMC Copyright Notice
Blood pressure targets for hypertension in older adults
Michael R Kolber, Christina S Korownyk, Rita K McCracken, Balraj S Heran, G Michael Allan, and Cochrane Hypertension GroupAbstract
Background
Eight out of 10 major antihypertensive trials in older adults attempted to achieve a target systolic blood pressure (BP) less than 160 mmHg. Collectively these trials demonstrated benefit for treatment, as compared to no treatment, for an older adult with BP greater than 160 mmHg. However an even lower BP target of less than 140 mmHg is commonly applied to all age groups. At the present time it is not known whether a lower or higher BP target is associated with better cardiovascular outcomes in older adults.
Objectives
To assess the effects of a higher (less than 150 to 160/95 to 105 mmHg) BP target compared to the lower BP target of less than 140/90 mmHg in hypertensive adults 65 years of age or older.
Search methods
The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Hypertension Specialised Register, MEDLINE, Embase, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also contacted authors of relevant papers regarding further published and unpublished work.
Selection criteria
Randomised trials, of at least one year's duration, conducted on hypertensive adults aged 65 years or older, which report the effect on mortality and morbidity of a higher systolic or diastolic BP treatment target (whether ambulatory, home, or office measurements) in the range of systolic BP less than 150 to 160 mmHg or diastolic BP less than 95 to 105 mmHg as compared to a lower BP treatment target of less than 140/90 mmHg or lower.
Data collection and analysis
Two authors independently screened and selected trials for inclusion, assessed risk of bias, and extracted data. We combined data for dichotomous outcomes using the risk ratio (RR) with 95% confidence interval (CI) and for continuous outcomes we used mean difference (MD). Primary outcomes were all‐cause mortality, stroke, institutionalisation, and cardiovascular serious adverse events. Secondary outcomes included cardiovascular mortality, non‐cardiovascular mortality, unplanned hospitalisation, each component of cardiovascular serious adverse events separately (including cerebrovascular disease, cardiac disease, vascular disease, and renal failure), total serious adverse events, total minor adverse events, withdrawals due to adverse effects, systolic BP achieved, and diastolic BP achieved.
Main results
We found and included three unblinded randomised trials in 8221 older adults (mean age 74.8 years), in which higher BP targets of less than 150/90 mmHg (two trials) and less than 160/90 mmHg (one trial) were compared to a lower target of less than 140/90 mmHg. Treatment to the two different BP targets over two to four years failed to produce a difference in any of our primary outcomes, including all‐cause mortality (RR 1.24 95% CI 0.99 to 1.54), stroke (RR 1.25 95% CI 0.94 to 1.67) and total cardiovascular serious adverse events (RR 1.19 95% CI 0.98 to 1.45). However, the 95% confidence intervals of these outcomes suggest the lower BP target is probably not worse, and might offer a clinically important benefit. We judged all comparisons to be based on low‐quality evidence. Data on adverse effects were not available from all trials and not different, including total serious adverse events, total minor adverse events, and withdrawals due to adverse effects.
Authors' conclusions
At the present time there is insufficient evidence to know whether a higher BP target (less than150 to 160/95 to 105 mmHg) or a lower BP target (less than 140/90 mmHg) is better for older adults with high BP. Additional good‐quality trials assessing BP targets in this population are needed.
Plain language summary
Blood pressure targets for hypertension in older adults
Review question
What is the optimal blood pressure (BP) target when treating older adults with high blood pressure?
Background
Elevated BP in older adults is common and higher pressures increase the risk of adverse health events such as stroke, heart attack, heart failure, and death. Lowering BP with drugs has been shown to reduce the risk of these serious health events but the optimal BP target when treating older adults is not known.
Study characteristics
We systematically retrieved all randomised trials that compared the effect of a higher BP target (upper BP number less than 150 to 160 mmHg) with a conventional lower BP target (upper BP number less than140 mmHg) in people over the age of 65 years. The evidence is current to February 2017.
Key results
We found three randomised trials (the 'gold standard' of medical evidence) that investigated this question in a total of 8221 older adults (average age 75 years, 59% female). We did not find a difference between the higher BP target and the conventional lower BP target, however an important difference favoring the lower BP target could not be ruled out.
Quality of the evidence
We judged the pooled evidence to be of low‐quality and not able to adequately answer the question as to which target BP was better. More good‐quality trials addressing this question are needed.
Summary of findings
Background
Description of the condition
Hypertension (elevated blood pressure (BP)) is a common condition and the second most frequent reason for visiting a family physician in Canada (Chan 2005). Although hypertensive individuals are generally asymptomatic, high BP is associated with higher rates of cardiovascular morbidity and mortality in the population at large (Lewington 2002) and it has been well demonstrated that lowering BP with antihypertensive drugs can reduce cardiovascular morbidity and mortality (Musini 2009; Wright 2009) in people with moderate to severe hypertension. Hence primary care visits for hypertension focus on prevention (lowering overall cardiovascular risk) and frequently involve the adding or adjusting of antihypertensive medication to obtain BPs in a range believed to put the patient at lowest risk for adverse health outcomes.
By convention the target BP for the treatment of otherwise healthy adults is the same as the threshold used to diagnose hypertension (i.e. a target BP less than 140/90 mmHg). Yet the risk and benefit of antihypertensive therapy can be expected to vary across patient populations. In people over the age of 80 years, for example, the evidence for a mortality benefit from BP lowering is conflicting (Beckett 2008; Musini 2009). The BP target that will minimise adverse events in older adults is unknown.
Eight out of 10 major antihypertensive trials in elderly people targeted a systolic BP of less than 160 mmHg (Mancia 2009). These trials (with the exception of the lone trial to target a systolic BP of less than 140 mmHg (JATOS 2008) show improvement in clinical endpoints and lend support to a systolic BP target for older adults of less than 160 mmHg. However a BP target of less than 140/90 mmHg is commonly applied to all people, irrespective of age and, according to a consensus document prepared by the American College of Cardiology Foundation and the American Heart Association, use of this lower BP target in older adults is based only on expert opinion and not on data from randomised controlled trials (RCTs) (Aronow 2011). By performing this review we hope to determine, for older adults, whether differences in BP targets lead to important differences in clinical outcomes.
Description of the intervention
Physicians tailor the introduction and dosing of BP‐lowering medication to a person's BP readings. Such readings can be obtained from automated 24‐hour ambulatory BP monitors, several days of recordings from patient‐actuated home BP machines or same day measurements in the physician's office (single or multiple readings, acquired either by a healthcare worker or an automated device). In practice BP targets (though not based on evidence) may vary with the setting in which BP is measured (e.g. home BP targets may be 5 mmHg lower) and may focus on systolic BP, diastolic BP, or both (Daskalopoulou 2012).
For the purpose of this review we compared a higher (intervention) systolic or diastolic BP target of less than 150 to 160/95 to 105 mmHg to a lower (control) BP target of less than 140/90 mmHg irrespective of how BP was measured.
How the intervention might work
The elderly are a distinct population with greater comorbidity, more polypharmacy, and greater potential risk from low organ perfusion pressure (e.g. cognitive impairment, or postural hypotension resulting in falls and fractures) (Hilmer 2007). More aggressive BP targets mean more medication use and greater potential for adverse drug‐drug and drug‐disease interactions (Cadieux 1989).
Occlusive vascular disease can also be expected to be more common in the elderly. Conceivably, in people with focal obstructions in blood flow, a reduction in overall BP may further compromise the perfusion, performance and health of that already under‐perfused organ ‐ increasing the potential for adverse effects beyond what is seen in typical clinical trial populations (which are generally comprised of younger and healthier participants) (Masoudi 2003; Van Spall 2007).
Cohort studies lend support to speculation that older adults may do better with less aggressive BP targets. In particular, adults over the age of 85 years have been shown to have slower rates of cognitive and physical decline when systolic BP is higher (Sabayan 2012) and the frailest older adults (as measured by gait speed) have lower mortality when hypertension is present (Odden 2012). Such studies have multiple potential explanations but one of these explanations is that the risk/benefit ratio of antihypertensive treatment may be different in the elderly ‐ with maximum overall benefit occurring when less aggressive antihypertensive therapy is pursued and somewhat higher BPs are achieved.
Why it is important to do this review
Given how common the treatment of hypertension is, given our aging population, and given how poorly represented older adults are in most of the large RCTs that guide clinical practice, it is important to explore whether older adults might do just as well, or better, with less aggressive pharmacotherapy for hypertension.
Objectives
To assess the effects of a higher BP target compared to a lower BP target of less than 140/90 mmHg in hypertensive adults 65 years of age or older.
Methods
Criteria for considering studies for this review
Types of studies
Open‐label RCTs (including parallel‐group or cross‐over trials) of at least one year's duration. As it is necessary for clinicians to know the BP target to which a patient is randomised in order to adjust their medication, it is assumed that any existing trials will not blind the participant or the care provider.
Types of participants
Adults 65 years of age or older who are either:
- already being treated for hypertension; or
- have elevated BP (BP 140/90 mmHg or higher) documented in a standard way on at least two occasions.
Types of interventions
A higher systolic or diastolic BP treatment target (whether ambulatory, home, or office measurements) in the range of systolic BP less than 150 to 160 mmHg or diastolic BP less than 95 to 105 mmHg. Valid comparators would include any BP treatment target that is less than 140/90 mmHg or lower.
Types of outcome measures
Primary outcomes
- All‐cause mortality
- Stroke (fatal and non‐fatal, excluding transient ischaemic attack)
- Institutionalisation (i.e. nursing home admission)
- Cardiovascular serious adverse events, including: cerebrovascular disease (infarction, haemorrhage, transient ischaemic attack), cardiac disease (myocardial infarction, new treatment for angina or congestive heart failure, sudden death), vascular disease (enlarging or rupturing or dissecting aneurysms of the aorta, treatment for occlusive arterial disease) and renal failure (acute or chronic doubling of serum creatinine or dialysis)
We chose the first three outcomes because we believe death (from any cause) and disability/loss of independence to be the most important outcomes from the perspective of older adults. We chose our fourth outcome because we believe a composite measure of serious cardiovascular events would have the greatest statistical power to show a difference between therapies.
Secondary outcomes
- Cardiovascular mortality
- Non‐cardiovascular mortality
- Unplanned hospitalisation
- Each component of 'cardiovascular serious adverse events' separately
- cerebrovascular disease
- cardiac disease
- vascular disease
- renal failure
- Total serious adverse events (death, hospitalisation and/or events requiring medical treatment)
- Total minor adverse events (symptoms not requiring medical treatment such as cough, fatigue or light‐headedness)
- Withdrawals due to adverse effects
- Systolic BP achieved (mean)
- Diastolic BP achieved (mean)
Search methods for identification of studies
Electronic searches
The Cochrane Hypertension Information Specialist conducted systematic searches in the following databases for RCTs without language, publication year or publication status restrictions:
- the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web) (searched 3 February 2017);
- the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) via the Cochrane Register of Studies (CRS‐Web) (searched 3 February 2017);
- MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 3 February 2017);
- Embase Ovid (searched 3 February 2017);
- ClinicalTrials.gov (www.clinicaltrials.gov) searched 3 February 2017);
- World Health Organization International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch) searched 3 February 2017).
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 sensitivity and precision‐maximising strategy designed by Cochrane for identifying randomised controlled trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.d. (Lefebvre 2011)). Search strategies for major databases are provided in Appendix 1.
Searching other resources
We checked all references in the relevant identified trials and attempted to contact the study authors to identify any additional published or unpublished data. We also searched ICTRP in an attempt to uncover unpublished trials; searched ISI Web of Science for papers citing the studies included in this review; and contacted the Food and Drug Administration (FDA) to ask if they had any related clinical trial information in their possession.
Data collection and analysis
Selection of studies
Two review authors independently screened the titles and abstracts of all articles identified by the search algorithm, obtained the full text of all potentially relevant studies and determined which studies met the inclusion criteria. A third author adjudicated any disagreements regarding study inclusion. A full accounting of the search results is provided in Figure 1 in the form of a PRISMA study flow diagram (Liberati 2009).
Data extraction and management
Two review authors independently extracted data onto specially designed forms. One review author entered the data into Review Manager 5 (RevMan 5) software (RevMan 2014) and a second review author independently checked the data entry.
Assessment of risk of bias in included studies
Two review authors independently assessed the risk of bias in the included studies using the Cochrane recommended tool (Higgins 2011). A third review author adjudicated any disagreements.
We assessed the risk of bias for each study according to six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and 'other sources of bias'. We rated each domain as high, low or unclear risk of bias. We presented the risk of bias assessment in a table for each study, and provided a graph displaying risk of bias across studies and domains, respectively (Figure 2).
Measures of treatment effect
We measured most of our outcomes as the proportion of participants suffering an event. This includes mortality (all‐cause, cardiovascular, non‐cardiovascular), stroke, institutionalisation, total serious adverse events, cardiovascular serious adverse events and its individual components, total minor adverse events, withdrawals due to adverse effects, and unplanned hospitalisation. For achieved systolic and diastolic BPs we used the intervention and control group means.
Unit of analysis issues
For each included study the unit of analysis and the unit of randomisation (expected to be the participant) needed to match to prevent the introduction of bias. For any study in which this was not the case, our intention was to qualitatively describe the findings but not include such studies in meta‐analyses. For all included studies the unit of analysis and the unit of randomisation matched.
Dealing with missing data
We attempted to contact authors of included studies for any necessary clarification, and to request any missing data. If data were still missing after author contact, and assumed to be missing at random (i.e. provided it appeared that the reason data were missing had nothing to do with the data values themselves) then our intention was to analyse only available data. If we believed that persistently missing data were missing for non‐random reasons, then our intention was to impute values for these missing data using methods such as assigning a poor value to each, assigning the mean value, or using the last value carried forward. The decision on how to impute such values was to depend on what was missing, and on the study design. No missing values were identified for which these steps were needed.
Assessment of heterogeneity
We assessed heterogeneity using a Chi2 test on n‐1 degrees of freedom and by calculating the I2 statistic (Higgins 2003). Where statistical heterogeneity was found we examined the trial methodology, the intervention, and the study populations with an eye to finding potential explanations for observed variation (Deeks 2011). Subgroup analysis was not possible as this information was not available for the included trials.
Assessment of reporting biases
We did not prepare any funnel plots as we only identified three studies (we had previously stated in the protocol that such a graph would be produced if 10 or more studies were found).
Data synthesis
We combined trial data identified for inclusion in this review using the most current version of the Cochrane statistical package, RevMan 5 (RevMan 2014). We anticipated a similar magnitude of effect across studies and accordingly performed only fixed‐effect meta‐analyses.
Subgroup analysis and investigation of heterogeneity
None of the three included trials reported outcomes in a way that permitted subgroup analysis. As stated in our protocol, when possible, we intended to use subgroup analysis to search for variation in treatment effect and to explore possible sources of heterogeneity. Prespecified subgroups related to clinical presentation included gender, age (under/over 75 years), and frailty (via a median split of either integrative physical measures such as gait speed or of composite clinical frailty scores). Prespecified subgroups related to method of treatment included the class of medication with which the treatment protocol began (e.g. calcium channel blocker versus angiotensin receptor blocker (ARB)). Although we identified that we may perform additional subgroup analyses we stated that such post‐hoc analyses would be merely hypothesis‐generating.
Sensitivity analysis
Where heterogeneity existed, we presented results both with and without the outlying trial(s). Where high risk of bias existed, we presented results both with and without the high‐risk trial(s).
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
A search of the Database of Abstracts of Reviews of Effects (DARE) revealed no prior reviews specific to BP targets in older adults. Search results from the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE, MEDLINE In‐Process, Embase, and ClinicalTrials.gov revealed 1669 citations (3088 prior to deduplication). We screened titles and abstracts for all 1669 citations. Of these, the review authors obtained and reviewed 24 full papers. We excluded 13 studies (see Characteristics of excluded studies) and 2 potentially eligible studies were ongoing (see Characteristics of ongoing studies). Of the remaining nine publications, only three were independent RCTs meeting our inclusion criteria. The other six publications were derived from these three RCTs in some way (one protocol, one protocol that included participant characteristics and BP results in the first year, three substudies, and one previously published abstract) (Characteristics of included studies). Contacting the FDA, searching ISS Web of Science for papers citing the studies included in this review, and a search of the International Clinical Trials Registry Platform (WHO‐ICTRP) revealed no additional published or unpublished studies.
Included studies
The two larger of the three included trials (4418 and 3079 participants in analysis) were in Japanese outpatients with either systolic hypertension irrespective of diastolic BP (JATOS 2008) or isolated systolic hypertension (VALISH 2010). These participants were in their mid 70s, and had baseline BPs of 170/90 (JATOS 2008) and 170/81 (VALISH 2010). Around 61% of these participants were women, around 12% had diabetes and around 16% smoked. The smaller trial (724 participants in analysis) enrolled Chinese general practice patients with either systolic or diastolic hypertension (Wei 2013). Mean baseline BP was 160/84 mmHg and these participants differed from the Japanese trials in being predominantly men (66%) with twice as many people with diabetes (23%) and more that smoked (25%).
The two Japanese trials compared conventional systolic BP targets of less than 140 mmHg to higher systolic targets of less than 150mmHg (VALISH 2010) or less than 160 mmHg (JATOS 2008). The Chinese trial compared a conventional strict mixed systolic and diastolic BP target of less than 140/90 mmHg to less than 150/90 mmHg (Wei 2013). Achieved BP was similar in the lower BP groups for all three trials (around 136/75 at study conclusion) but achieved BP differed substantially in the higher BP group, being 142/76.5 mmHg in VALISH 2010, 145.6/78.1 in JATOS 2008, and 149.7/82.1 in Wei 2013.
In two of the trials the study protocol mandated that participants be initially switched to, or started on (if previously untreated), a specified study medication. These medications were either the long‐acting dihydropyridine calcium antagonist efonidipine (JATOS 2008) or the angiotensin II type 1 receptor blocker valsartan (VALISH 2010). In Wei 2013 it is unclear how the initial choice of medication was made but could include single drug treatment of either an angiotensin‐converting‐enzyme (ACE) inhibitor (enalapril), a beta‐blocker (bisoprolol or metoprolol), a calcium channel blocker (amlodipine), or a diuretic (indapamide). In all three studies drug doses were adjusted upwards and numbers of drugs increased until BP control was achieved according to the allocated BP target. Trial protocols led to all JATOS 2008 subjects being on efonidipine with 36% of these subjects also receiving an ACE/ARB (plus 13% received a betablocker and 12% received a diuretic). VALISH 2010 subjects all took valsartan, with 37% also taking a calcium channel blocker (plus 12% taking a diuretic and 5% taking a betablocker). Wei 2013 subjects were more balanced as to use of different antihypertensive classes (ACEI 31%, calcium channel blocker 28%, beta blocker 20%, diuretic 20%).
All three studies were prospective, randomised, parallel, and open‐label with average follow‐up ranging from two years (JATOS 2008) to four years (Wei 2013). All studies used a primary outcome that was a composite of major adverse cardiovascular events and all composites included fatal and nonfatal stroke and myocardial infarction, and death from other cardiovascular causes (sudden death, congestive heart failure). The two Japanese trials also included within the composite other hospitalisations for cardiovascular disease (e.g. angina, aortic dissection) and renal dysfunction.
Excluded studies
In all cases, we excluded studies because they were not randomised trials using the conventional and relaxed BP targets identified for this review.
Risk of bias in included studies
We carried out the 'Risk of bias' assessment as outlined in the methods and summarised our assessments in Figure 2.
Allocation
The risk of allocation bias was unclear in two of the trials (VALISH 2010 and Wei 2013) largely because of inadequate description in the methods.
Blinding
We rated the risk from blinding high for all three trials, since neither clinicians nor participants could be blinded to the allocated BP target. However outcome assessors were blinded, which mitigates concerns to some degree.
Incomplete outcome data
Although it was generally unclear how participants who were lost to follow‐up were handled in the analysis, all trials had fairly low rates of attrition. The highest rate of attrition was in VALISH 2010 (5.9%), which we rated at unclear risk of bias because more participants dropped out than experienced the primary outcome and no sensitivity analysis was performed.
Selective reporting
Although we rated all trials as low risk of reporting bias for their identified primary and secondary outcomes, Wei 2013 did not provide total serious adverse events and reported adverse events only selectively.
Other potential sources of bias
We rated VALISH 2010 at unclear risk of bias because it did not describe how participants were selected for a per‐protocol analysis (with participants excluded "...according to a judging criteria drawn up by the Statistical Committee of this study"). We rated Wei 2013 as high risk of bias because an initial analysis of this study was published in abstract form with no mention of Wei (the lead author of the final publication) as a co‐investigator. E‐mail communication with authors of Wei 2013 confirm that the lead author was a late addition to the project and hence, in our view, unable to meaningfully take responsibility for study design and conduct.
Effects of interventions
See: Table 1
Summary of findings for the main comparison
| Higher BP target (< 150‐160/95‐105 mmHg) compared with lower BP target (< 140/90 mmHg) for cardiovascular risk reduction | ||||||
| Patient or population: older adults with primary hypertension Settings: outpatient Intervention: higher BP target < 150‐160)/95‐105 mmHg Comparison: lower BP target < 140/90 mmHg | ||||||
| Outcomes | Illustrative comparative risks1
(95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| Lower BP target | Higher BP target | |||||
| All‐cause mortality Mean follow‐up: 2.6 years | 31 per 1000 | 39 per 1000
(31 to 48) | RR 1.24 (0.99 to 1.54) | 8221 (3) | ⊕⊕⊝⊝ Low2,3 | |
| Stroke Mean follow‐up: 2.6 years | 20 per 1000 | 25 per 1000
(19 to 33) | RR 1.25 (0.94 to 1.67) | 8221 (3) | ⊕⊕⊝⊝ Low2,3 | |
| Cardiovascular serious adverse events Mean follow‐up: 2.6 years | 42 per 1000 | 50 per 1000
(41 to 61) | RR 1.19 (0.98 to 1.45) | 8221 (3) | ⊕⊕⊝⊝ Low2,3 | |
| Withdrawals due to adverse effects Mean follow‐up: 2.4 years | 17 per 1000 | 14 per 1000
(10 to 20) | RR 0.83 (0.58 to 1.19) | 7497 (2) | ⊕⊕⊝⊝ Low2,3 | |
| The basis for the assumed risk is provided in footnote below. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BP: blood pressure; CI: confidence interval; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | ||||||
1Rationale for our choice of assumed risk: the risk of cardiovascular events in a hypertensive general population varies considerably across countries (Finegold 2013). With no reason to favour one country over another we have opted to use (now and for future updates) an assumed risk, which is the average across studies included in this review.
2Downgraded due to high risk of bias.
3Downgraded due to heterogeneity and imprecision.
See: Table 1
Primary Outcomes
1. All‐cause mortality
Although all three studies provided data on total mortality, only results from Wei 2013 were statistically significant, finding the higher BP target to be inferior (RR 1.72, 95% CI 1.25 to 2.35). In contrast, JATOS 2008 found a non‐significant difference in the opposite direction, favouring the lower target (RR 0.78, 95% CI 0.52 to 1.16). Pooling data produced a nonsignificant difference (RR 1.24, 95% CI 0.99 to 1.54) with high heterogeneity (I2= 79%) (Figure 3, Analysis 1.1).
Forest plot of comparison higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, outcome 1. All‐cause mortality.
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 1 All‐cause mortality.
2. Stroke (fatal and non‐fatal, excluding transient ischaemic attack)
All three studies provided data on stroke and only results from Wei 2013 were statistically significant, finding the higher BP target to be inferior. Pooling data produced a nonsignificant difference (RR 1.25, 95% CI 0.94 to 1.67) with moderate heterogeneity (I2 = 38%) (Figure 4, Analysis 1.2).
Forest plot of comparison higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, outcome 2. Stroke
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 2 Stroke.
3. Institutionalisation (i.e. nursing home admission)
Although we believe this to be an important outcome for older adults it was not reported in any of the included studies.
4. Cardiovascular serious adverse events (cerebrovascular disease, cardiac disease, vascular disease and renal failure)
All three studies provided data on cardiovascular serious adverse events and only Wei 2013 was statistically significant, finding the higher BP target to be inferior. Pooling data produced a nonsignificant difference (RR 1.19, 95% CI 0.98 to 1.45) with high heterogeneity (I2 = 59%) (Figure 5, Analysis 1.3).
Forest plot of comparison higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, outcome 4. Cardiovascular serious adverse events
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 3 Cardiovascular serious adverse events.
Secondary Outcomes
1. Cardiovascular mortality
All three studies provided data on cardiovascular mortality and only results from Wei 2013 were statistically significant, finding the higher BP target to be inferior. Pooling data produced a statistically significant difference showing the higher target to be inferior (RR 1.52, 95% CI 1.06 to 2.19) with high heterogeneity (I2 = 52%) (Figure 6, Analysis 1.4).
Forest plot of comparison higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, outcome7. Withdrawals due to adverse effects
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 4 Cardiovascular mortality.
2. Non‐cardiovascular mortality
All three studies provided data on non‐cardiovascular mortality and none demonstrated statistically significant differences. Pooling data produced a non‐significant difference (RR 1.09, 95% CI 0.81 to 1.46) with high heterogeneity (I2 = 52%) (Analysis 1.5.)
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 5 Non‐cardiovascular mortality.
3. Unplanned hospitalisation
Only VALISH 2010 reported unplanned hospitalisation and no significant difference was found (RR 1.18, 95% CI 0.55 to 2.53) (Analysis 1.6).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 6 Unplanned hospitalisation.
4. Cardiovascular serious adverse events
4a. Cerebrovascular disease (infarction, haemorrhage or transient ischaemic attack)
All three studies provided data on cerebrovascular disease and only results from Wei 2013 were statistically significant, finding the higher BP target to be inferior. Pooling data produced a non‐significant difference (RR 1.22 95% CI 0.93 to 1.61) with moderate heterogeneity (I2 = 46%) (Analysis 1.7.1).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 7 Cardiovascular serious adverse events (by component).
4b. Cardiac disease (myocardial infarction, new treatment for angina or congestive heart failure, sudden death)
All three studies provided data on cardiac disease and only results from Wei 2013 were statistically significant, finding the higher BP target to be inferior. Pooling data produced a non‐significant difference (RR 1.21, 95% CI 0.82 to 1.79) with no heterogeneity (I2 = 0%) (Analysis 1.7.2). Differences between groups were largely accounted for by congestive heart failure.
4c. Vascular disease (enlarging or rupturing or dissecting aneurysms of the aorta, treatment for occlusive arterial disease)
Only one study provided information on vascular disease (JATOS 2008) and found a non‐significant difference (RR 2.01, 95% CI 0.37 to 10.94) (Analysis 1.7.3).
4d. Renal failure (acute or chronic doubling of serum creatinine or dialysis)
Only two studies provided information on renal failure (JATOS 2008, VALISH 2010) and neither demonstrated significant differences. Pooling data produced no significant difference (RR 0.85, 95% CI 0.38 to 1.89) with low heterogeneity (I2 = 12%) (Analysis 1.7.4).
5. Total serious adverse events (death, hospitalisation and/or events requiring medical treatment)
Only VALISH 2010 reported total serious adverse events, which showed no significant difference (RR 0.93, 95% CI 0.69 to 1.24) (Analysis 1.8).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 8 Total serious adverse events.
6. Total minor adverse events (symptoms not requiring medical treatment such as cough, fatigue or light‐headedness)
Only two studies provided information on total minor adverse events (JATOS 2008, VALISH 2010) and neither demonstrated significant differences. Pooling data produced no significant difference (RR 0.99, 95% CI 0.91 to 1.08) with low heterogeneity (I2 = 0%) (Analysis 1.9).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 9 Total minor adverse events.
7. Withdrawals due to adverse effects
Only two studies provided information on withdrawals due to adverse effects (JATOS 2008, VALISH 2010) and neither demonstrated significant differences. Pooling data produced no significant difference (RR 0.83, 95% CI 0.58 to 1.19) with moderate heterogeneity (I2 = 36%) (Figure 6, Analysis 1.10).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 10 Withdrawals due to adverse effects.
8. Systolic BP achieved (mean difference)
Pooling all three studies, the mean difference in achieved systolic BP was 8.88 mmHg (95% CI 8.38 to 9.39 mmHg) greater in the higher as compared to the lower BP target groups with high heterogeneity (I2 = 98%) (Analysis 1.11).
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 11 Mean systolic BP achieved.
9. Diastolic BP achieved (mean difference)
Pooling all three studies, the mean difference in achieved diastolic BP was 3.09 mmHg (95% CI 2.72 to 3.47 mmHg) greater in the higher as compared to the lower BP target groups with high heterogeneity (I2 = 96%) Analysis 1.12.
Comparison 1 Higher (< 150‐160/95‐100 mmHg) versus lower (< 140/90 mmHg) BP target, Outcome 12 Mean diastolic BP achieved.
Discussion
Overview
Three relatively large RCTs met our inclusion criteria, however we rated the quality of evidence for our pooled estimates of effect as low for all outcomes. In most cases this downgrade was because of high heterogeneity and imprecision. In some cases we downgraded the quality of evidence because of high risk of bias or because not all trials reported the outcome of interest.
How were these studies heterogeneous?
One of the three included trials (Wei 2013: 724 participants) was substantially smaller than the other two trials (JATOS 2008: 4418 participants; VALISH 2010: 3079 participants) but none of the three trials dominated the weight of the analysis because the smallest trial (Wei 2013) had much higher event rates. This is at least partially explained by the fact that Japan (where the two larger trials took place) has one of the lowest age‐standardised cardiovascular mortality rates in the world and China (where Wei 2013 was conducted) has an indirectly standardised mortality ratio for ischaemic heart disease which is four times higher than Japan (and marginally higher than the USA) (Finegold 2013). Although the methods in Wei 2013 did not describe attempts to select a higher risk population, the composite primary outcome event rate in the less‐than‐140 mmHg‐BP group of Wei 2013 (which we calculate to be 2.8% per year) was not that different than the composite cardiovascular event rate in the 75‐years‐or‐over subset of the recently completed SPRINT trial's less‐than‐140 mmHg arm (which we calculate to be 3.3% per year) (SPRINT 2015). SPRINT participants were Americans without diabetes, considered to be at high risk of cardiovascular disease.
Separate from the difference in the underlying event rates, these three trials found very different estimates of the direction and magnitude of effect. With only three studies to compare, it is difficult to consider any one trial an outlier. One study (VALISH 2010) found nonsignificant results that most often lay between the other two studies. These other two studies either statistically significantly favoured the lower BP target for many outcomes (Wei 2013) or found a nonsignificant difference that lay close to, and at times even on the opposite side of, the no‐effect line (JATOS 2008). Selectively excluding JATOS 2008 from the meta‐analysis removed the heterogeneity for all‐cause mortality (I2 79% →0%) and stroke (I2 38% →0%), while removing Wei 2013 removed the heterogeneity from cardiovascular serious adverse events (I2 59% →0%) and cardiovascular mortality (I2 52% →0%).
An exploration of the observed heterogeneity
Methodology
Although the methodology described in each trial was not sufficiently different to explain the observed heterogeneity, we considered the only trial reporting a statistically significant benefit (Wei 2013) to be at high risk of bias, because the lead author appeared to join the trial after the results had already been reported in a conference abstract. When we excluded Wei 2013 from the analysis, all trends towards a benefit for the lower target disappeared. In particular this included all‐cause mortality (RR 0.93, 95% CI 0.68 to 1.27), cardiovascular serious adverse events (RR 1.04, 95% CI 0.82 to 1.32), and cardiovascular mortality (RR 0.90, 95% CI 0.48 to 1.71).
Populations studied
Consistent with the observed differences in event rates between these trials, participants in Wei 2013 had substantially higher prevalence of cardiovascular risk factors than did participants in JATOS 2008. Specifically, Wei 2013 had a higher proportion of men (66% versus 40%), higher proportion of people with diabetes (23% versus 12%), higher proportion of people that smoked (25% versus 13.5%), and greater age (76.5 years versus 73.6 years). The discussion in Wei 2013 also offered other information on baseline characteristics compared to JATOS 2008 that were not included in the body of the text (all of which showed Wei 2013 participants to be at higher risk) including differences in prior stroke (6.9% versus 4.2%), prior coronary heart disease (7.5% versus 3%), and presence of atrial fibrillation (18% in Wei 2013, excluded in JATOS 2008).
Outcomes
It is important to note that the primary outcome in Wei 2013 was driven by differences in stroke and congestive heart failure (fatal and non‐fatal). Fatal and non‐fatal myocardial infarction, in contrast, was essentially identical for both BP targets in all three trials. Importantly, and separate from the relative benefit of the different BP targets, coronary events (which typically represent a large proportion of events in trials with younger, high cardiovascular‐risk, hypertensive populations) represented a minority of events in these three trials of older, hypertensive adults (Wei 2013 18/107 events = 16.8% of events were myocardial infarction; JATOS 2008 31/176 events = 17.6% of events were myocardial infarction or angina; VALISH 2010 9/99 events = 9.1% of events were myocardial infarction). The HYVET antihypertensive trial (Beckett 2008) in people over the age of 80 years, similarly found both stroke and congestive heart failure to be more frequent occurrences than myocardial infarction (fatal or nonfatal outcomes in the placebo group were: stroke 17.7%, heart failure 14.8%, myocardial infarction only 3.1%). This compares, for instance, to the ACCOMPLISH trial (Jamerson 2008) which compared benazepril plus amlodipine to benazepril plus hydrochlorothiazide. In this often‐cited trial of (relatively) younger, high‐risk, hypertensive adults (average age 68.4 yrs) coronary revascularisations accounted for 720/1231 = 58.5% of the composite primary outcome. Chronic disease surveillance carried out by the Canadian government is consistent with this age differential in cardiovascular events. Examining (and stratifying by age) hospitalisations for coronary artery disease, congestive heart failure and stroke in Canada, the majority of such admissions (78.2%) are for coronary artery disease in the 55 years to 65 years age group whereas coronary artery disease accounts for only 38.8% of such admissions in those over 85 years of age (Dai 2009).
Intervention
Two aspects of the intervention are likely to be relevant to the observed differences in trial results. The first is the difference in systolic BP in the lower BP target group, compared to the higher BP target group (‐14.0 mmHg in Wei 2013, ‐9.7 mmHg in JATOS 2008, ‐5.4 mmHg in VALISH 2010). Clearly the greater difference in BP between treatment arms in Wei 2013 could explain some of the difference in the degree of benefit seen. The other potentially important difference is in which medications were used. In JATOS 2008 (the trial that concluded no difference between BP targets), all participants initially started and continued to use the calcium channel blocker efonidipine and had other medications added if needed. Roughly half of the participants in this trial were on efonidipine as monotherapy. The most common add‐on medications in the lower BP group included ACEI/ARB (40.7% of participants), followed distantly by adrenoceptor‐blocking drugs (14.3%) and diuretics (15.3%). The heavy reliance on calcium channel blockers is important since they have been demonstrated in meta‐analysis to be inferior to other antihypertensives in preventing heart failure outcomes (Chen 2010; Ettehad 2016). In VALISH 2010 (the trial that reported a nonsignificant trend to benefit for the lower BP target) all participants initially started on the ARB, valsartan. Roughly 57% were on valsartan monotherapy with the most commonly added agents in the lower BP target group again being calcium channel blockers (37.1%), followed much more distantly by diuretics (13.0%) and beta‐blockers (6.0%). In contrast Wei 2013 (the trial demonstrating statistically significant benefit) started participants on a variety of medications and ended up with the lower BP target group having participants on the ACE inhibitor, enalapril (31.5%), the calcium channel blocker amlodipine (27.2%), the beta‐blockers metoprolol or bisoprolol (21.2%) and the diuretic, indapamide (21.2%). Although it is not stated how many participants were on monotherapy with each agent, we know from VALISH 2010 and JATOS 2008 that roughly 50% of participants ended up on monotherapy with one drug. Given the greater BP difference in this trial, the percentage of participants on monotherapy may be even smaller. If so, and if participants started on each drug class equally frequently, we estimate only 12% of Wei 2013 participants to have been on monotherapy with a calcium channel blocker.
Possible explanations for the observed heterogeneity
- Bias may have influenced the sole trial finding a statistically significant benefit. We considered Wei 2013, the smallest trial driving any trend to benefit, to be at high risk of bias.
- The effect of antihypertensive medication on outcomes that are common in the elderly may differ by medication class. The older adults participating in these three trials had stroke and heart failure (fatal and nonfatal) as their most common cardiovascular events. Each trial also differed in the extent to which they relied on medications indicated for use in heart failure. In Wei 2013 (the single study finding statistically significant benefit) close to 90% of participants were expected to have been on at least one, and possibly two or more drugs with established benefit to treat or prevent heart failure. In JATOS 2008 (the study finding no benefit) roughly half of these participants were on monotherapy with a calcium channel blocker, a medication class shown to be inferior to other antihypertensives for preventing heart failure outcomes (Chen 2010, Ettehad 2016). It is conceivable that the heavy reliance of JATOS 2008 on a calcium channel blocker might have led to less effective risk reduction for heart failure‐related events, which were one of the main contributors to the composite primary outcome in all three studies. The substantially more common cardiovascular risk factors in Wei 2013, including the 18% of participants with atrial fibrillation (which JATOS excluded), would also be expected to put the participants in Wei at substantially greater risk of stroke than those of JATOS 2008. Although calcium channel blockers have superior efficacy to other antihypertensives for the prevention of stroke (Chen 2010, Ettehad 2016), the low‐risk participants in JATOS 2008, and the relatively smaller difference in BP between study arms in that trial, may have diminished the opportunity for stroke benefit to be seen.
Summary of main results
See Table 1 for key results. Although none of our primary outcomes reached conventional statistical significance, two of these outcomes were numerically in favour of the lower BP target, these being all‐cause mortality (RR 1.24, 95% CI 0.99 to 1.54) and cardiovascular serious adverse events (RR 1.19, 95% CI 0.98 to 1.45). Consistent with the possibility that these differences might be real, cardiovascular mortality also favoured the lower BP target and was statistically significantly different (RR 1.52, 95% CI 1.06 to 2.19). Although this suggests the potential of a clinically important difference favouring the lower BP target, the high degree of unexplained heterogeneity amongst these trials (I2 of 38% to 79% for the primary outcomes), and the apparent disappearance of potential benefit when the single trial considered to be at high risk of bias was removed, prevents any conclusions being drawn.
Overall completeness and applicability of evidence
In this review we systematically searched all relevant electronic databases. It is unlikely that published RCTs meeting our inclusion criteria would have been missed, however unpublished studies could have gone undetected. There were too few studies to assess the likelihood of missing studies with a funnel plot. The study participants appear to have all been drawn from general practice populations, however these populations may have been somewhat atypical for general practice patients in many countries given that they appeared to be either at lower risk than average for cardiovascular events (JATOS 2008 and VALISH 2010), or higher risk than average (Wei 2013).
Quality of the evidence
We assessed the risk of bias for each of the RCTs included in this review (Figure 2), and we viewed one of the three included trials as having a higher overall risk of bias. While two large RCTs and one moderate‐sized RCT might normally be considered to provide high‐quality evidence, the high level of heterogeneity observed, and the higher potential for bias in the only trial finding benefit, led us to consider this evidence as low quality overall.
Potential biases in the review process
This review is limited to published trials. Conceivably smaller trials that were never published might exist (publication bias). The high heterogeneity also suggests that either Wei 2013 or JATOS 2008 may substantially over, or under‐estimate, the magnitude of the mean benefit conveyed by differing BP targets.
Agreements and disagreements with other studies or reviews
SPRINT 2015, an RCT in high cardiovascular disease risk, non‐diabetic hypertensive people, comparing a systolic BP target of less than 140 mmHg with less than 120 mmHg, does not meet the inclusion criteria for this review and has been excluded. For the subset of participants over the age of 75 years (2636 subjects, mean age 79.9 years), this trial reported a statistically significant difference in a composite CVD primary outcome that favoured the lower BP target (HR 0.67, 95% CI 0.51 to 0.86). For SPRINT 2015 as a whole, the average difference in BP between treatment groups was 14.8 mmHg. If a difference in BP targets can demonstrate risk reduction when those BPs are already fairly low (as in SPRINT 2015), it seems possible that benefit from a lower BP target might also be found when those targets are substantially higher (as in our review). Multiple systematic reviews (Chen 2010; Ettehad 2016; Wiysonge 2017; Xue 2015) have also demonstrated that antihypertensive drug classes differ in their efficacy for preventing various cardiovascular events. In particular diuretics appear superior at preventing heart failure compared to other drugs, calcium channel blockers appear inferior at preventing heart failure compared to other drugs, and both calcium channel blockers and ARBs appear superior at preventing stroke. Given our observation that heart failure admissions are a major driver of events in older adults, the body of literature suggesting that calcium channel blockers are inferior to other agents for the prevention of heart failure might explain why JATOS 2008 (in which half the subjects were on calcium channel blocker monotherapy) did not find benefit to the lower BP target.
Authors' conclusions
Acknowledgements
We would like to acknowledge the assistance provided us by Cochrane Hypertension ‐ in particular the assistance of Doug Salzwedel (Information Specialist), who designed and ran most of our electronic searches.
Appendices
Appendix 1. Search strategies
Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS‐Web)
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MeSH DESCRIPTOR Aged EXPLODE ALL TREES
#2 MeSH DESCRIPTOR Health Services for the Aged
#3 MeSH DESCRIPTOR Homes for the Aged
#4 MeSH DESCRIPTOR Long‐term Care
#5 MeSH DESCRIPTOR Nursing Care
#6 MeSH DESCRIPTOR Nursing Homes EXPLODE ALL TREES
#7 ((“advanced years” or ageing or aging or elder* or elderly or frail or geriatric* or gerontolog* or “later life” or “nursing care” or nursing home* or “old age” or “oldest old” or pensioner* or post‐menopausal or postmenopausal or senior or seniors))
#8 (old* NEAR3 (adult* or female* or male* or men or people or person or women))
#9 ((65 year* or "over 65" or "over 70" or "over 75" or "over 80" or "over 85" or 85 year*))
#10 ((aged or aging or ageing or elder* or geriatric* or gerontolog*)):SO
#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10
#12 ((goal* or intensive* or strict* or target* or tight*) NEAR5 (antihypertensive* anti‐hypertensive* or bp or control or dbp or diastolic or pressure* or sbp or systolic or treat*))
#13 MeSH DESCRIPTOR Antihypertensive Agents EXPLODE ALL TREES
#14 (ceiling diuretic* OR loop diuretic*)
#15 ((amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide*))
#16 ((chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide))
#17 (sodium chloride symporter inhibitor* or sodium potassium chloride symporter inhibitor*)
#18 #14 OR #15 OR #16 OR #17
#19 (angiotensin converting enzyme inhibit*)
#20 (ace NEAR2 inhibit*)
#21 acei
#22 ((alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril* or perindopril* or pivopril or quinapril* or ramipril* or rentiapril or saralasin or s nitrosocaptopril or spirapril* or temocapril* or teprotide or trandolapril* or utibapril* or zabicipril* or zofenopril* or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril))
#23 #19 OR #20 OR #21 OR #22
#24 (angiotensin NEAR3 (receptor antagon* or receptor block*))
#25 (arb or arbs)
#26 ((abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten))
#27 #24 OR #25 OR #26
#28 ((amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM))
#29 (calcium NEAR2 (antagonist* or block* or inhibit*))
#30 #28 OR #29
#31 ((methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or "methyl dopa" or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or "alpha methyl dopa"))
#32 ((reserpine or serpentina or rauwolfia or serpasil))
#33 ((clonidine or adesipress or arkamin or caprysin or catapres* or catasan or chlofazolin or chlophazolin or clinidine or clofelin* or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin* or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or "st 155" or "tesno timelets"))
#34 ((hydralazin* or hydrallazin* or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat))
#35 #31 OR #32 OR #33 OR #34
#36 ((acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol))
#37 (beta NEAR2 (adrenergic or antagonist* or block* or receptor*))
#38 #36 OR #37
#39 ((alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin))
#40 (adrenergic NEAR2 (alpha or antagonist*))
#41 ((adrenergic or alpha or receptor*) NEAR2 block*)
#42 #39 OR #40 OR #41
#43 #13 OR #18 OR #23 OR #27 OR #30 OR #35 OR #38 OR #42
#44 RCT:DE
#45 (Review OR Meta‐Analysis):MISC2
#46 #44 OR #45
#47 #11 AND #12 AND #43 AND #46 (129)
***************************
Database: Cochrane Central Register of Controlled Trials on Wiley <2017, Issue 2> via Cochrane Register of Studies (CRS‐Web)
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MeSH DESCRIPTOR Aged EXPLODE ALL TREES AND CENTRAL:TARGET
#2 MeSH DESCRIPTOR Health Services for the Aged AND CENTRAL:TARGET
#3 MeSH DESCRIPTOR Homes for the Aged AND CENTRAL:TARGET
#4 MeSH DESCRIPTOR Long‐term Care AND CENTRAL:TARGET
#5 MeSH DESCRIPTOR Nursing Care AND CENTRAL:TARGET
#6 MeSH DESCRIPTOR Nursing Homes EXPLODE ALL TREES AND CENTRAL:TARGET
#7 ((“advanced years” or ageing or aging or elder* or elderly or frail or geriatric* or gerontolog* or “later life” or “nursing care” or nursing home* or “old age” or “oldest old” or pensioner* or post‐menopausal or postmenopausal or senior or seniors)) AND CENTRAL:TARGET
#8 (old* NEAR3 (adult* or female* or male* or men or people or person or women)) AND CENTRAL:TARGET
#9 ((65 year* or "over 65" or "over 70" or "over 75" or "over 80" or "over 85" or 85 year*)) AND CENTRAL:TARGET
#10 ((aged or aging or ageing or elder* or geriatric* or gerontolog*)):SO AND CENTRAL:TARGET
#11 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 AND CENTRAL:TARGET
#12 ((goal* or intensive* or strict* or target* or tight*) NEAR5 (antihypertensive* anti‐hypertensive* or bp or control or dbp or diastolic or pressure* or sbp or systolic or treat*)) AND CENTRAL:TARGET
#13 MeSH DESCRIPTOR Antihypertensive Agents EXPLODE ALL TREES AND CENTRAL:TARGET
#14 (ceiling diuretic* OR loop diuretic*) AND CENTRAL:TARGET
#15 ((amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide*)) AND CENTRAL:TARGET
#16 ((chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide)) AND CENTRAL:TARGET
#17 (sodium chloride symporter inhibitor* or sodium potassium chloride symporter inhibitor*) AND CENTRAL:TARGET
#18 #14 OR #15 OR #16 OR #17 AND CENTRAL:TARGET
#19 (angiotensin converting enzyme inhibit*) AND CENTRAL:TARGET
#20 (ace NEAR2 inhibit*) AND CENTRAL:TARGET
#21 acei AND CENTRAL:TARGET
#22 ((alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril* or perindopril* or pivopril or quinapril* or ramipril* or rentiapril or saralasin or s nitrosocaptopril or spirapril* or temocapril* or teprotide or trandolapril* or utibapril* or zabicipril* or zofenopril* or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril)) AND CENTRAL:TARGET
#23 #19 OR #20 OR #21 OR #22 AND CENTRAL:TARGET
#24 (angiotensin NEAR3 (receptor antagon* or receptor block*)) AND CENTRAL:TARGET
#25 (arb or arbs) AND CENTRAL:TARGET
#26 ((abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten)) AND CENTRAL:TARGET
#27 #24 OR #25 OR #26 AND CENTRAL:TARGET
#28 ((amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM)) AND CENTRAL:TARGET
#29 (calcium NEAR2 (antagonist* or block* or inhibit*)) AND CENTRAL:TARGET
#30 #28 OR #29 AND CENTRAL:TARGET
#31 ((methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or "methyl dopa" or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or "alpha methyl dopa")) AND CENTRAL:TARGET
#32 ((reserpine or serpentina or rauwolfia or serpasil)) AND CENTRAL:TARGET
#33 ((clonidine or adesipress or arkamin or caprysin or catapres* or catasan or chlofazolin or chlophazolin or clinidine or clofelin* or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin* or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or "st 155" or "tesno timelets")) AND CENTRAL:TARGET
#34 ((hydralazin* or hydrallazin* or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat)) AND CENTRAL:TARGET
#35 #31 OR #32 OR #33 OR #34 AND CENTRAL:TARGET
#36 ((acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol)) AND CENTRAL:TARGET
#37 (beta NEAR2 (adrenergic or antagonist* or block* or receptor*)) AND CENTRAL:TARGET
#38 #36 OR #37 AND CENTRAL:TARGET
#39 ((alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin)) AND CENTRAL:TARGET
#40 (adrenergic NEAR2 (alpha or antagonist*)) AND CENTRAL:TARGET
#41 ((adrenergic or alpha or receptor*) NEAR2 block*) AND CENTRAL:TARGET
#42 #39 OR #40 OR #41 AND CENTRAL:TARGET
#43 #13 OR #18 OR #23 OR #27 OR #30 OR #35 OR #38 OR #42 AND CENTRAL:TARGET
#44 #11 AND #12 AND #43 (169)
***************************
Database: Ovid MEDLINE(R) 1946 to Present with Daily Update
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp aged/ (2656661)
2 health services for the aged/ or homes for the aged/ or long‐term care/ or nursing care/ or exp nursing homes/ (99860)
3 (advanced years or ageing or aging or elder? or elderly or frail or geriatric? or gerontolog$ or later life or nursing care or nursing home? or old age or oldest old or pensioner? or post‐menopausal or postmenopausal or senior or seniors).tw. (467132)
4 (old$ adj3 (adult? or female? or male? or men or people or person or women)).tw. (223842)
5 ("65 year$" or "over 65" or "over 70" or "over 75" or "over 80" or "over 85" or "85 year$").tw. (87262)
6 (aged or aging or ageing or elder$ or geriatric$ or gerontolog$).jw,nw. (123914)
7 or/1‐6 (3058954)
8 ((goal? or intensive$ or strict$ or target$ or tight$) adj5 (antihypertensive? anti‐hypertensive? or bp or control or dbp or diastolic or pressure? or sbp or systolic or treat$)).tw. (113185)
9 exp antihypertensive agents/ (240187)
10 exp thiazides/ (14950)
11 exp sodium chloride symporter inhibitors/ (13762)
12 exp sodium potassium chloride symporter inhibitors/ (13118)
13 ((ceiling or loop) adj diuretic?).tw. (2368)
14 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide?).tw. (31754)
15 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw. (2185)
16 or/10‐15 [THZ] (46629)
17 exp angiotensin‐converting enzyme inhibitors/ (40812)
18 angiotensin converting enzyme inhibit$.tw. (17081)
19 (ace adj2 inhibit$).tw. (17161)
20 acei.tw. (2685)
21 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw. (24880)
22 or/17‐21 [ACEI] (55316)
23 exp Angiotensin Receptor Antagonists/ (20230)
24 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. (11042)
25 arb?.tw. (4815)
26 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw. (14453)
27 or/23‐26 [ARB] (28524)
28 exp calcium channel blockers/ (77014)
29 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw. (57697)
30 (calcium adj2 (antagonist? or block$ or inhibit$)).tw. (35853)
31 or/28‐30 [CCB] (102777)
32 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp. (14955)
33 (reserpine or serpentina or rauwolfia or serpasil).mp. (19775)
34 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or st 155 or tesno timelets).mp. (18801)
35 exp hydralazine/ (4569)
36 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw. (4222)
37 or/32‐36 [CNS] (56145)
38 exp adrenergic beta‐antagonists/ (79891)
39 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw. (58765)
40 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. (91362)
41 or/38‐40 [BB] (146852)
42 exp adrenergic alpha antagonists/ (48281)
43 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw. (13197)
44 (adrenergic adj2 (alpha or antagonist?)).tw. (18811)
45 ((adrenergic or alpha or receptor?) adj2 block$).tw. (53474)
46 or/42‐45 [AB] (107263)
47 hypertension/ (214045)
48 hypertens$.tw. (338051)
49 ((high or elevat$ or rais$) adj2 blood pressure).tw. (23720)
50 or/47‐49 (398358)
51 randomized controlled trial.pt. (446305)
52 controlled clinical trial.pt. (91768)
53 randomized.ab. (339401)
54 placebo.ab. (167835)
55 clinical trials as topic/ (180932)
56 randomly.ab. (234159)
57 trial.ti. (151570)
58 or/51‐57 (1002859)
59 animals/ not (humans/ and animals/) (4278833)
60 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (844365)
61 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. (13602)
62 58 not (59 or 60 or 61) (884239)
63 7 and 8 and (9 or 16 or 22 or 27 or 31 or 37 or 41 or 46) and 50 and 62 (1012)
64 remove duplicates from 63 (956)
***************************
Database: Embase <1974 to 2017 February 2>
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1 exp aged/ (2583775)
2 exp elderly care/ (71836)
3 home for the aged/ (11287)
4 exp long term care/ (1451228)
5 exp nursing care/ (37779)
6 nursing home/ (50235)
7 (advanced years or ageing or aging or elder? or elderly or frail or geriatric? or gerontolog$ or later life or nursing care or nursing home? or old age or oldest old or pensioner? or post‐menopausal or postmenopausal or senior or seniors).tw. (688198)
8 (old$ adj3 (adult? or female? or male? or men or people or person or women)).tw. (381010)
9 ("65 year$" or "over 65" or "over 70" or "over 75" or "over 80" or "over 85" or "85 year$").tw. (148322)
10 (aged or aging or ageing or elder$ or geriatric$ or gerontolog$).jw. (166512)
11 or/1‐10 (4311485)
12 ((goal? or intensive$ or strict$ or target$ or tight$) adj5 (antihypertensive? anti‐hypertensive? or bp or control or dbp or diastolic or pressure? or sbp or systolic or treat$)).tw. (192761)
13 exp antihypertensive agent/ (646863)
14 exp thiazide diuretic agent/ (51733)
15 exp loop diuretic agent/ (65914)
16 ((loop or ceiling) adj diuretic?).tw. (3860)
17 (amiloride or benzothiadiazine or bendroflumethiazide or bumetanide or chlorothiazide or cyclopenthiazide or furosemide or hydrochlorothiazide or hydroflumethiazide or methyclothiazide or metolazone or polythiazide or trichlormethiazide or veratide or thiazide?).tw. (41553)
18 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or oxodoline or thalitone or hygroton or indapamide or metindamide).tw. (3689)
19 or/14‐18 [THZ] (119990)
20 exp dipeptidyl carboxypeptidase inhibitor/ (157164)
21 angiotensin converting enzyme inhibit$.tw. (22649)
22 (ace adj2 inhibit$).tw. (26678)
23 acei.tw. (5866)
24 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw. (35656)
25 or/20‐24 [ACEI] (164652)
26 exp angiotensin receptor antagonist/ (76543)
27 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. (17451)
28 arb?.tw. (10619)
29 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or Teveten).tw. (24392)
30 or/26‐29 [ARB] (82203)
31 calcium channel blocking agent/ (56975)
32 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or Verelan PM).tw. (78076)
33 (calcium adj2 (antagonist? or block$ or inhibit$)).tw. (46937)
34 or/31‐33 [CCB] (139564)
35 (methyldopa or alphamethyldopa or amodopa or dopamet or dopegyt or dopegit or dopegite or emdopa or hyperpax or hyperpaxa or methylpropionic acid or dopergit or meldopa or methyldopate or medopa or medomet or sembrina or aldomet or aldometil or aldomin or hydopa or methyldihydroxyphenylalanine or methyl dopa or mulfasin or presinol or presolisin or sedometil or sembrina or taquinil or dihydroxyphenylalanine or methylphenylalanine or methylalanine or alpha methyl dopa).mp. (28824)
36 (reserpine or serpentina or rauwolfia or serpasil).mp. (29009)
37 (clonidine or adesipress or arkamin or caprysin or catapres$ or catasan or chlofazolin or chlophazolin or clinidine or clofelin$ or clofenil or clomidine or clondine or clonistada or clonnirit or clophelin$ or dichlorophenylaminoimidazoline or dixarit or duraclon or gemiton or haemiton or hemiton or imidazoline or isoglaucon or klofelin or klofenil or m‐5041t or normopresan or paracefan or st‐155 or st 155 or tesno timelets).mp. (45476)
38 hydralazine/ (18128)
39 (hydralazin$ or hydrallazin$ or hydralizine or hydrazinophtalazine or hydrazinophthalazine or hydrazinophtalizine or dralzine or hydralacin or hydrolazine or hypophthalin or hypoftalin or hydrazinophthalazine or idralazina or 1‐hydrazinophthalazine or apressin or nepresol or apressoline or apresoline or apresolin or alphapress or alazine or idralazina or lopress or plethorit or praeparat).tw. (6289)
40 or/35‐39 [CNS] (106640)
41 exp beta adrenergic receptor blocking agent/ (269491)
42 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw. (79478)
43 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. (116165)
44 or/41‐43 [BB] (323332)
45 exp alpha adrenergic receptor blocking agent/ (130812)
46 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).tw. (16623)
47 (adrenergic adj2 (alpha or antagonist?)).tw. (18188)
48 ((adrenergic or alpha or receptor?) adj2 block$).tw. (71187)
49 or/45‐48 [AB] (197816)
50 exp hypertension/ (631543)
51 (hypertens$ or antihypertens$).tw. (546297)
52 ((high or elevat$ or rais$) adj2 blood pressure).tw. (35424)
53 or/50‐52 (799059)
54 double blind$.mp. (218883)
55 placebo$.tw. (253070)
56 blind$.tw. (340091)
57 or/54‐56 (492194)
58 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5883553)
59 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (700427)
60 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. (19965)
61 57 not (58 or 59 or 60) (457458)
62 11 and 12 and (13 or 19 or 25 or 30 or 34 or 40 or 44 or 49) and 53 and 61 (617)
63 remove duplicates from 62 (601)
***************************
Database: ClinicalTrials.gov
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Search terms: (intensive OR strict OR target OR tight) AND (randomized) AND (aged OR elderly OR geriatric OR older)
Study type: Interventional Studies
Conditions: hypertension
Outcome measure: blood pressure (34)
***************************
Database: WHO International Clinical Trials Registry Platform (ICTRP)
Search Date: 3 February 2017
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
hypertens* AND aged AND intensive
hypertens* AND aged AND strict
hypertens* AND aged AND target*
hypertens* AND aged AND tight
hypertens* AND elderly AND intensive
hypertens* AND elderly AND strict
hypertens* AND elderly AND target*
hypertens* AND elderly AND tight
hypertens* AND older AND intensive
hypertens* AND older AND strict
hypertens* AND older AND target*
hypertens* AND older AND tight
hypertens* AND geriatric AND intensive
hypertens* AND geriatric AND strict
hypertens* AND geriatric AND target*
hypertens* AND geriatric AND tight
Notes
New
Data and analyses
Comparison 1
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 All‐cause mortality | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.99, 1.54] |
| 2 Stroke | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.94, 1.67] |
| 3 Cardiovascular serious adverse events | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.98, 1.45] |
| 4 Cardiovascular mortality | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.52 [1.06, 2.19] |
| 5 Non‐cardiovascular mortality | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.81, 1.46] |
| 6 Unplanned hospitalisation | 1 | 3079 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.55, 2.53] |
| 7 Cardiovascular serious adverse events (by component) | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Cerebrovascular disease | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.93, 1.61] |
| 7.2 Cardiac disease | 3 | 8221 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.82, 1.79] |
| 7.3 Vascular disease | 1 | 4418 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.01 [0.37, 10.94] |
| 7.4 Renal failure | 2 | 7497 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.38, 1.89] |
| 8 Total serious adverse events | 1 | 3079 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.69, 1.24] |
| 9 Total minor adverse events | 2 | 7497 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.91, 1.08] |
| 10 Withdrawals due to adverse effects | 2 | 7497 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.58, 1.19] |
| 11 Mean systolic BP achieved | 3 | 8221 | Mean Difference (IV, Fixed, 95% CI) | 8.88 [8.38, 9.39] |
| 12 Mean diastolic BP achieved | 3 | 8221 | Mean Difference (IV, Fixed, 95% CI) | 3.09 [2.72, 3.47] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Methods | PROBE study. Presumably multi‐centre (not stated) 4418 randomised and analysed 2212 (lower), 2206 (higher) | |
| Participants | Elderly Japanese outpatients 65‐85 years with baseline BP > 160 mmHg Mean 73.6 years, 60% women Baseline BP 170/90, 12% had diabetes mellitus, 55% previous BP treatment, 13.5% smoked Exclusions: current use of efonidipine, diastolic BP > 120 mmHg, secondary hypertension, recent stroke (< 6 months prior) or signs and symptoms of stroke, a recent MI or coronary angioplasty (< 6 months previously), angina pectoris requiring hospitalisation, CHF (NYHA) ≥ class II, persistent arrhythmia such as atrial fibrillation, dissecting aneurysm of the aorta or occlusive arterial disease, hypertensive retinopathy, serum aspartate aminotransferase or serum alanine aminotransferase levels > double the respective upper limits of normal, poorly controlled diabetes mellitus (fasting blood sugar ≥ 200 mg/dL or HbA1c ≥ 8%), renal disease (serum creatinine ≥ 1.5 mg/dl), malignant disease or collagen disease. People considered "unsuitable as subjects" were also excluded | |
| Interventions | 2 years lower BP target (systolic BP < 140 mmHg) versus higher BP target (systolic BP < 160 but ≥ 140 mmHg) Run‐in period (4 weeks in untreated participants and 2–4 weeks in treated participants) to assess baseline BP during which participants were examined on at least two occasions Untreated participants initially received efonidipine 20‐40 mg once daily (a long‐acting dihydropyridine calcium antagonist). In participants who were already receiving antihypertensive medications, a similar dose of efonidipine was added or substituted for one of the drugs being received before study entry without a washout period. Daily dose of efonidipine could be increased to 60 mg (once or twice daily) and antihypertensive drugs other than calcium antagonists were added, if needed Study visits: with physicians every 2 or 4 weeks. During these visits BP drugs were titrated to the allocated target BP with the goal of reaching that achieved BP within 3 months of treatment allocation. Achieved BP at study completion 135.9/74.8 (lower) versus 145.6/78.1 (higher) | |
| Outcomes | The primary endpoint was the combined incidence of cerebrovascular disease (cerebral haemorrhage, cerebral infarction, transient ischaemic attack, and subarachnoid haemorrhage), cardiac and vascular disease (myocardial infarction, angina pectoris requiring hospitalisation, heart failure, sudden death, dissecting aneurysms of the aorta, and occlusive arterial disease), and renal failure (acute or chronic renal failure; doubling of the serum creatinine concentration to a value of 1.5 mg/dL or higher) Cerebrovascular disease was diagnosed based on neurological and radiological examinations. Cardiac and vascular diseases were diagnosed using radiographic, echocardiographic, and biochemical methods in addition to signs and symptoms. Sudden death, defined as death from instantaneous, unanticipated circulatory collapse within 1 h of initial symptoms, was also included in cardiac and vascular disease. Arrhythmias such as atrial fibrillation were not included in the primary endpoint, but were considered adverse events. Secondary endpoints were "deaths from any cause, morbidity other than cardiovascular disease, changes in BP and heart rate, and any problems in regard to safety." All outcomes were assessed at 2 years. Participants who died within 28 days after the onset of any of the primary or secondary endpoints were considered to have died from these diseases. | |
| Notes | Dates: the registration period was from 1 April 2001‐31 December 2002. The treatment period ended on 31 December 2004. All participants followed for two years Funding Source: sponsored by Shionogi & Co Ltd (makers of efonidipine) Declaration of potential conflicts of interest: not reported Other: supported by the Japan Physicians Association and the Japanese Society of Hypertension collaborators, but did not mention how these organisations are funded | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomly assigned the subject to either treatment group using a computer‐generated list |
| Allocation concealment (selection bias) | Low risk | "The investigators sent a registration form describing the clinical characteristics of eligible patients to the registration office by facsimile. Immediately after registration, the registration office randomly assigned the subject to either treatment group using a computer‐generated list and informed the investigators of the treatment assignments." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants and clinicians not blinded |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Endpoint assessment committee was blinded and reasonably objective outcomes were used |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | An ITT analysis was performed on all randomised participants with the exception of the 1.6% and 1.7% of participants that were lost to follow‐up. Unclear how those lost to follow‐up were handled in the analysis |
| Selective reporting (reporting bias) | Low risk | Reporting appears complete |
| Other bias | Low risk | The study was funded by the makers of efonidipine but the study question and design were not product focused |
| Methods | PROBE study. Multicenter 1545 lower, 1534 higher in analysis (after removing loss to follow‐up and those that withdrew) | |
| Participants | Japanese outpatients ≥ 70 and < 85 years with isolated systolic hypertension (systolic BP > 160 mm Hg and diastolic BP < 90 mm Hg) who were either previously untreated or who could be switched from their current medications to valsartan. It is unclear whether only participants that tolerated valsartan were randomised. Exclusions: secondary or malignant hypertension, seated systolic BP ≥ 200 mmHg or diastolic BP ≥ 90 mmHg, cerebrovascular disorder or myocardial infarction in the 6 months prior to enrolment, coronary arterioplasty 6 months prior to enrolment or coronary arteriography planned in the 6 months following enrolment, severe heart failure (≥ NYHA functional classification III), severe aortic stenosis or valvular heart disease, atrial fibrillation/flutter or serious arrhythmia, renal dysfunction with a serum creatinine level of ≥ 2 mg/dL, serious liver disease, history of hypersensitivity to valsartan, and "other patients who are judged to be inappropriate for the study by the investigator or subinvestigator". Mean age: 76.1 years. Baseline BP 170/81. 62.4% women, 13.0% had diabetes, 19.2% smoked | |
| Interventions | Blood pressure targets of < 140 (lower) versus 140 to ≤ 150 mmHg (higher) Staged dose adjustments: valsartan, 40‐80 mg once daily, was the first‐step therapy for all participants. If the target BP in each group was not achieved within 1‐2 months, the dose of valsartan was increased (if < 160 mg) and/or other antihypertensive agents (except angiotensin II type 1 receptor blockers) were added. Participants visited the clinic a minimum of once every 3 months for 2 years. 56.1% of lower participants & 57.6% of higher participants received valsartan only. 43.9% of lower participants and 42.4% of higher participants received additional BP meds (most commonly a CCB). Mean medications n = 1.6 for both groups Achieved BP at study completion: 136.6/74.8 (lower) versus 142/76.5 (higher) | |
| Outcomes | The primary end point of this study was a composite of cardiovascular events: sudden death, fatal or nonfatal stroke, fatal or nonfatal myocardial infarction, death because of heart failure, other cardiovascular death, unplanned hospitalisation for cardiovascular disease, and renal dysfunction (doubling of serum creatinine to a level > 2.0 mg per 100 mL or introduction of dialysis). Secondary end points were each component of the primary end point independently, total mortality, and new onset or exacerbation of angina pectoris. Cardiovascular death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke excluding transient ischaemic attacks were evaluated as hard end points | |
| Notes | Dates: participants were enrolled from February 2004‐August 2005 and followed up until March 2008 (median follow‐up 3.07 years) Funding Source: this study was funded by a grant from the Japan Cardiovascular Research Foundation and supported by the Japanese Society of Hypertension Declarations of potential conflicts of interest: all of the study authors report receiving lecture fees from various pharmaceutical companies in Japan, including Novartis Pharma Japan (maker of valsartan ‐ the first medication introduced) Other: unclear how the funding agencies are themselves funded | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Randomization of target BP levels, i.e., SBP of <140mmHg (L group) or ≥140mmHg and <150 mmHg (M group), will be performed with a minimization method based on the following assignment factors using a computer program: Sex: male or female; Age: younger than 75 years or 75 years or older; Seated SBP: less than 175 mmHg or 175 mmHg or higher; Antihypertensive therapy: not being treated or being treated; and Institution." |
| Allocation concealment (selection bias) | Unclear risk | “the patients were randomly assigned by the VALISH Data Center according to the following factors...” |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants and clinicians were not blinded to treatment group |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | “End points and adverse events were blindly evaluated according to the prospective, randomised, open‐label, blinded end point design by the endpoint committee and the safety committee, respectively.” |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | More participants (181 = 5.9%) withdrew or were lost to follow‐up than experienced the primary outcome. This included 82/1627 assigned to the lower (< 140 mmHg) BP target and 99/1633 assigned to the higher target. No sensitivity analysis was performed |
| Selective reporting (reporting bias) | Low risk | Reporting appears complete |
| Other bias | Unclear risk | How participants were selected for the per‐protocol analysis was neither described in the main publication of findings (VALISH 2010), nor pre‐defined in the preceding Rationale and Design publication which stated that the per‐protocol analysis would exclude participants "...according to judging a criteria drawn up by the Statistical Committee of this study". |
| Methods | PROBE study. Unclear if single site or multicenter 363 lower and 361 higher participants randomised and analysed by ITT | |
| Participants | Chinese general practice outpatients > 70 years with either SBP ≥ 150 mm Hg and/or diastolic BP ≥ 90 mm Hg or a diagnosis of hypertension and current antihypertensive medication Exclusions: secondary hypertension, valvular heart disease, chronic kidney dysfunction (serum creatinine ≥ 3.0 mg/dL), previous myocardial infarction or stroke in the preceding 6 months, NYHA ≥ class III CHF, echocardiography determining left ventricular ejection fraction < 40%, hepatic dysfunction, autoimmune disorders, malignant tumour, Alzheimer's disease, and "other noncardiovascular diseases potentially causing death before the end of the study". Mean age: 76.5 years. Baseline BP 160/84. 66% men, 23% had diabetes, 25% smoked | |
| Interventions | Lower BP target of < 140/90 versus higher BP target of < 150/90. Participants were started with single‐drug treatment of an ACE inhibitor (benzene enalapril 10 mg/d), a beta ‐blocker (bisoprolol 2.5–5 mg or metoprolol 50–100 mg/d), a CCB (amlodipine 5–10 mg/d), or a diuretic (indapamide 1.5–2.5 mg/d). Presumably initial choice of therapeutic was up to the treating physician (not stated). It is unclear whether, or how, participants already treated at baseline were switched to study medications. To achieve the target BP, 1, 2, or 3 additional antihypertensive drugs could be added stepwise. If quadruple antihypertensive therapy (CCB + beta ‐blocker + ACE inhibitor + diuretic) failed to achieve the BP goal increasing the dose of antihypertensive drugs was recommended. BP was measured at 4 weeks, 3 months, 6 months, and every 6 months thereafter. Achieved BP at study completion 135.7/76.2 (lower) versus 149.7/82.1 (higher) | |
| Outcomes | The primary outcome was the combined incidence of fatal/nonfatal stroke, acute myocardial infarction, and other cardiovascular deaths (sudden death and heart failure death). Secondary endpoints were deaths from any causes. | |
| Notes | Dates: not reported. Mean follow‐up 4 years Funding Source: not reported Declarations of Interest: not reported Other: an abstract was published in 2011 (first author Jin, Wei 2013) with a completed analysis and no mention of Wei (the lead author of the final publication) as a co‐investigator. E‐mail queries to co‐authors confirm that first author Wei was a late addition to the project. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | “...randomly assigned to either intensive antihypertensive treatment or standard treatment by using a computer‐generated table of random numbers.” |
| Allocation concealment (selection bias) | Unclear risk | Method of allocation not reported |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Participants and clinicians were not blinded |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | "In order to reduce investigation bias, endpoints were evaluated by the members of the Endpoint Evaluation Committee, who were blinded to the treatment assignments and the time course of BP." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Lower BP target: 2 discontinued treatment, 1 withdrew consent, 1 lost to follow‐up (1.1%) Higher BP target: 7 discontinued treatment, 5 withdrew consent, 2 lost to follow‐up (3.9%) Although an ITT analysis was stated it is unclear how missing data was handled. |
| Selective reporting (reporting bias) | Low risk | Reported adverse events selectively only. Total serious adverse events not provided. |
| Other bias | High risk | An initial analysis of this study was published in abstract form with no mention of Wei (the lead author of the final publication) as a co‐investigator. E‐mail queries to co‐authors confirm that first author Wei was a late addition to the project. |
ACE: angiotensin‐converting enzyme; BP: blood pressure; CCB: calcium channel blocker; CHF: congestive heart failure; ITT: intention‐to‐treat; MI: myocardial infarction; NYHA: New York Heart Association; PROBE: Prospective Randomised Open Blinded End‐point assessment
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Arima 2006 | Participants were not randomised to different BP targets |
| Denardo 2010 | Participants were not randomised to different BP targets |
| Ihle‐Hansen 2015 | Examined the data according to achieved BP but did not randomise to different BP targets (participants were instead randomised to intense treatment of all risk factors including systolic BP < 140 versus usual care by GP) |
| Ogihara 2008 | Participants were not randomised to different BP targets |
| Ogihara 2009 | Participants were not randomised to different BP targets |
| Ogihara 2011 | Participants were not randomised to different BP targets |
| Ogihara 2012 | Participants were not randomised to different BP targets |
| Omboni 2015 | Participants were not randomised to different BP targets |
| Saito 2011 | Participants were not randomised to different BP targets |
| Saxby 2008 | Participants were not randomised to different BP targets |
| SPRINT 2015 | Although an older adult subgroup was reported, subjects in this RCT were randomised to lower BP targets than considered in this review (< 120 vs < 140 mmHg systolic) |
| Steurer 2016 | Compared lower BP targets than considered in this review (< 120 vs < 140 mmHg systolic) |
| Zhang 2011 | Participants were not randomised to different BP targets |
BP: blood pressure; GP: general practitioner; SBP: systolic blood pressure
Characteristics of ongoing studies [ordered by study ID]
| Trial name or title | |
| Methods | |
| Participants | |
| Interventions | |
| Outcomes | |
| Starting date | |
| Contact information | |
| Notes | Trial registry only. Study is recruiting. May qualify for inclusion once complete (compares SBP 110‐130 mmHg to SBP 130‐150 mmHg). Estimated completion Dec 2021 |
| Trial name or title | |
| Methods | |
| Participants | |
| Interventions | |
| Outcomes | |
| Starting date | |
| Contact information | |
| Notes | Published protocol only. Recrutiment completed. Final data collection anticipated Sept 2018. Randomises to 24‐h SBP < 130 versus 24‐h SBP < 145. Does not appear to be examining cardiovascular outcomes (focuses on cognition and mobility) |
Differences between protocol and review
In the original protocol we stated that we would examine outcomes at two years and, if some studies did not extend that far, at one year. Only one of our studies reported two‐year outcomes. Rather than interpolating results from these other studies to the two‐year time frame, we chose instead to report outcomes using the mean period of observation from each analysis (ranging from 2.4 to 2.6 years). We made this revision upon recognizing it to be the standard approach in other Cochrane Reviews.
Contributions of authors
Dr Garrison drafted both the protocol and the full review and is the guarantor of the review. All authors performed critical review and approved the final text. Drs Garrison, McCracken, Korownyk and Allan searched for and identified studies for inclusion. Drs Korownyk and Kolber assessed studies for bias and extracted data. Dr Heran entered data and studies into Review Manager 5 and performed the analyses. Dr Allan verified the data extraction and entry into Review Manager 5.
Sources of support
Internal sources
- University of Alberta, Canada.
Academic salary (SRG, MRK, CSK, GMA)
- Alberta Health Services, Canada.
Clinical practice income (SRG, MRK, CSK, GMA)
- British Columbia Medical Services Plan, Canada.
Clinical practice income (RKM)
External sources
- Clinical Scholar Award, Canada.
Competitive research trainee program offered by the University of British Columbia's Dept of Family Practice (RKM)
- Providence Health Care Research Award, Canada.
Competitive research award from the author's local health authority (RKM)
- British Columbia College of Family Physicians Research Award, Canada.
Competitive research award from professional body (RKM)
Declarations of interest
Scott Garrison: none
Mike Kolber: none
Tina Korownyk: none
Rita McCracken: none
Benji Heran: none
G Michael Allan: none
References
References to studies included in this review
JATOS 2008 {published data only}
- Hayashi K, Saruta T, Goto Y, Ishii M, on behalf of the JATOS Study Group. Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine: renal subset analysis of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertension Research 2010;33:1211‐20. [PubMed] [Google Scholar]
- JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertension Research 2008;31(12):2115‐27. [PubMed] [Google Scholar]
- JATOS Study Group. The Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS): protocol, patient characteristics, and blood pressure during the first 12 months. Hypertension Research 2005;28(6):513‐20. [PubMed] [Google Scholar]
- Kawano Y, Ogihara T, Saruta T, Goto Y, Ishii M. Association of blood pressure control and metabolic syndrome with cardiovascular risk in elderly Japanese: JATOS study. American Journal of Hypertension 2011;24(11):1250‐6. [PubMed] [Google Scholar]
- Rakugi H, Ogihara T, Goto Y, Ishii M, on behalf of the JATOS Study Group. Comparison of strict‐ and mild‐blood pressure control in elderly hypertensive patients: a per‐protocol analysis of JATOS. Hypertension Research 2010;33:1124‐8. [PubMed] [Google Scholar]
VALISH 2010 {published data only}
- Ogihara T, Saruta T, Matsuoka H, Shimamoto K, Fujita T, Shimada K, et al. Valsartan in elderly isolated systolic hypertension (VALISH) study: rationale and design. Hypertension Research 2004;27(9):657‐61. [PubMed] [Google Scholar]
- Ogihara T, Saruta T, Rakugi H, Matsuoka H, Shimamoto K, Shimada K, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension 2010;56(2):196‐202. [PubMed] [Google Scholar]
Wei 2013 {published data only}
- Jin Z, Guoying S, Xiaowei Z, Ye Z, Pingyan F, Junying P, et al. Intensified antihypertensive therapy and blood pressure variability in older than 70 of Chinese hypertensive patients. Heart. 2011; Vol. 97, issue 3:A193.
- Wei Y, Jin Z, Shen G, Zhao X, Yang W, Zhong Y, et al. Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years. Journal of Clinical Hypertension 2013;15(6):420‐7. [PMC free article] [PubMed] [Google Scholar]
References to studies excluded from this review
Arima 2006 {published data only}
- Arima H, Chalmers J, Woodward M, Anderson C, Rodgers A, Davis S, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. Journal of Hypertension 2006;24(6):1201‐8. [PubMed] [Google Scholar]
Denardo 2010 {published data only}
- Denardo SJ, Gong Y, Nichols WW, Messerli FH, Bavry AA, Cooper‐DeHoff RM, et al. Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy. American Journal of Medicine 2010;123(8):719‐26. [PMC free article] [PubMed] [Google Scholar]
Ihle‐Hansen 2015 {published data only}
- Ihle‐Hansen H, Thommessen B, Fagerland MW, Oksengard AR, Wyller TB, Engedal K, et al. Blood pressure control to prevent decline in cognition after stroke. Vascular Health and Risk Management 2015;11:311‐6. [PMC free article] [PubMed] [Google Scholar]
Ogihara 2008 {published data only}
- Ogihara T, Nakao K, Fukui T, Fukiyama K, Fujimoto A, Ueshima K, et al. The optimal target blood pressure for antihypertensive treatment in Japanese elderly patients with high‐risk hypertension: a subanalysis of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE‐J) trial. Hypertension Research 2008;31(8):1595‐601. [PubMed] [Google Scholar]
Ogihara 2009 {published data only}
- Ogihara T, Saruta T, Rakugi H, Fujimoto A, Ueshima K, Yasuno S, et al. Relationship between the achieved blood pressure and the incidence of cardiovascular events in Japanese hypertensive patients with complications: a sub‐analysis of the CASE‐J trial. Hypertension Research 2009;32:248‐54. [PubMed] [Google Scholar]
Ogihara 2011 {published data only}
- Ogihara T, Matsuoka H, Rakugi H. Practitioner’s trial on the efficacy of antihypertensive treatment in elderly patients with hypertension II (PATE‐Hypertension II study) in Japan. Geriatrics & Gerontology International 2011;11:414‐21. [PubMed] [Google Scholar]
Ogihara 2012 {published data only}
- Ogihara T, Fujimoto A, Ueshima K, Nakao K, Saruta T. Optimal blood pressure to prevent cardiovascular events in the elderly high‐risk hypertensive patients: subanalysis of the CASE‐J Ex study. Journal of Hypertension. 2012; Vol. 30, issue e‐Supplement 1:e244‐5.
Omboni 2015 {published data only}
- Omboni S, Malacco E, Mallion JM, Volpe M. Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double‐blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines. Clinical Interventions in Aging 2015;10:1575‐86. [PMC free article] [PubMed] [Google Scholar]
Saito 2011 {published data only}
- Saito I, Suzuki H, Kageyama S, Saruta T. Treatment of hypertension in patients 85 years of age or older: a J‐BRAVE substudy. Clinical and Experimental Hypertension 2011;33(5):275‐80. [PubMed] [Google Scholar]
Saxby 2008 {published data only}
- Saxby BK, Harrington F, Wesnes KA, McKeith IG, Ford GA. Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology 2008;70(19 Pt 2):1858‐66. [PubMed] [Google Scholar]
SPRINT 2015 {published data only}
- SPRINT Research Group. A randomized trial of intensive versus standard blood‐pressure control. New England Journal of Medicine 2015;373(22):2103‐16. [PMC free article] [PubMed] [Google Scholar]
Steurer 2016 {published data only}
- Steurer J. Intensive blood pressure treatment vs. less intensive treatment [Intensive Blutdruckbehandlung vs. weniger intensive Behandlung]. Praxis (Bern 1994) 2016;105(4):225‐6. [10.1024/1661‐8157/a002281] [PubMed] [Google Scholar]
Zhang 2011 {published data only}
- Zhang Y, Zhang X, Liu L, Zanchetti A. Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial. European Heart Journal 2011;32(12):1500‐8. [PubMed] [Google Scholar]
References to ongoing studies
Cai 2017 {unpublished data only}
- Cai J. Strategy of blood pressure intervention in the elderly hypertensive patients (STEP). clinicaltrials.gov/show/NCT03015311. [PubMed]
White 2013 {published data only}
- White WB, Marfatia R, Schmidt J, Wakefield DB, Kaplan RF, Bohannon RW, et al. Intensive versus standard ambulatory blood pressure lowering to prevent functional decline in the elderly (INFINITY). American Heart Journal 2013;165(3):258‐65. [DOI: 10.1016/j.ahj.2012.11.008] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Additional references
Aronow 2011
- Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2011;123(21):2434‐506. [PubMed] [Google Scholar]
Beckett 2008
- Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine 2008;358(18):1887‐98. [PubMed] [Google Scholar]
Cadieux 1989
- Cadieux RJ. Drug interactions in the elderly. How multiple drug use increases risk exponentially. Postgraduate Medicine 1989;86(8):179‐86. [PubMed] [Google Scholar]
Chan 2005
- Chan BT, Schultz SE. Supply and utilization of general practitioner and family physician services in Ontario. ICES investigative report. Toronto, ON: Institute for Clinical Evaluative Sciences www.ices.on.ca/file/FP‐GP_aug08_FINAL.pdf. Toronto, ON, (accessed 12 November 2013).
Chen 2010
- Chen N, Zhou M, Yang M, Guo J, Zhu C, Yang J, et al. Calcium channel blockers versus other classes of drugs for hypertension. Cochrane Database of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/14651858.CD003654.pub4] [PubMed] [CrossRef] [Google Scholar]
Dai 2009
- Dai S, Bancej C, Bienek A, Walsh P, Stewart P, Wielgosz A. 2009 Tracking Heart Disease and Stroke in Canada. Report from the Canadian Chronic Disease Surveillance System. www.phac‐aspc.gc.ca/publicat/2009/cvd‐avc/index‐eng.php (accessed 18 March 2015).
Daskalopoulou 2012
- Daskalopoulou SS, Khan NA, Quinn RR, Ruzicka M, McKay DW, Hackam DG, et al. Canadian Hypertension Education Program. The 2012 Canadian hypertension education program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy. Canadian Journal of Cardiology May 2012;28(3):270‐87. [PubMed] [Google Scholar]
Deeks 2011
- Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Ettehad 2016
- Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta‐analysis. Lancet 2016;387(10022):957‐67. [PubMed] [Google Scholar]
Finegold 2013
- Finegold JA, Asaria P, Francis DP. Mortality from ischaemic heart disease by country, region, and age: statistics from World Health Organisation and United Nations. International Journal of Cardiology 2013;168(2):934‐45. [PMC free article] [PubMed] [Google Scholar]
Higgins 2003
- Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. [PMC free article] [PubMed] [Google Scholar]
Higgins 2011
- Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.
Hilmer 2007
- Hilmer SN, McLachlan AJ, Couteur DG. Clinical pharmacology in the geriatric patient. Fundamental & Clinical Pharmacology 2007;21(3):217‐30. [PubMed] [Google Scholar]
Jamerson 2008
- Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high‐risk patients. New England Journal of Medicine 2008;359(23):2417‐28. [PubMed] [Google Scholar]
Lefebvre 2011
- Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
Lewington 2002
- Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360(9349):1903‐13. [PubMed] [Google Scholar]
Liberati 2009
- Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta‐analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. [DOI: ] [PMC free article] [PubMed] [Google Scholar]
Mancia 2009
- Mancia G, Laurent S, Agabiti‐Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Pressure 2009;18(6):308‐47. [PubMed] [Google Scholar]
Masoudi 2003
- Masoudi FA, Havranek EP, Wolfe P, Gross CP, Rathore SS, Steiner JF, et al. Most hospitalized older persons do not meet the enrolment criteria for clinical trials in heart failure. American Heart Journal 2003;146(2):250‐7. [PubMed] [Google Scholar]
Musini 2009
- Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD000028.pub2] [PubMed] [CrossRef] [Google Scholar]
Odden 2012
- Odden MC, Peralta CA, Haan MN, Covinsky KE. Rethinking the association of high blood pressure with mortality in elderly adults: the impact of frailty. Archives of Internal Medicine 2012;172(15):1162‐8. [PMC free article] [PubMed] [Google Scholar]
RevMan 2014 [Computer program]
- Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Sabayan 2012
- Sabayan B, Oleksik AM, Maier AB, Buchem MA, Poortvliet RK, Ruijter W, et al. High blood pressure and resilience to physical and cognitive decline in the oldest old: the Leiden 85‐plus Study. Journal of the American Geriatric Society 2012;60(11):2014‐9. [PubMed] [Google Scholar]
Van Spall 2007
- Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high‐impact general medical journals: a systematic sampling review. JAMA 2007;297(11):1233‐40. [PubMed] [Google Scholar]
Wiysonge 2017
- Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta‐blockers for hypertension. Cochrane Database of Systematic Reviews 2017, Issue 1. [DOI: 10.1002/14651858.CD002003.pub5] [PMC free article] [PubMed] [CrossRef] [Google Scholar]
Wright 2009
- Wright JM, Musini VM. First‐line drugs for hypertension. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD001841.pub2] [PubMed] [CrossRef] [Google Scholar]
Xue 2015
- Xue H, Lu Z, Tang WL, Pang LW, Wang GM, Wong GWK, et al. First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension. Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD008170.pub2] [PubMed] [CrossRef] [Google Scholar]
