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Objective: Office and ambulatory blood pressure (BP) measurements are the main techniques to detect the effects of antihypertensive treatments in clinical trials, but the treatment-induced changes in these BP values can differ markedly. We performed a meta-analysis of clinical trials to quantify these differences and identified some of the associated factors., Methods: We conducted a MEDLINE search for randomized clinical trials (RCTs) on hypertensive patients treated with at least one antihypertensive drug that reported changes in both office and 24-h BP. Random-effects models were fitted to estimate the summary of the difference between the changes as quantified by either technique. The I and Cochrane's Q statistics were calculated to evaluate the heterogeneity between studies., Results: A total of 52 studies were included in our meta-analysis with about 9500 patients. The summary estimate Δ of SBP and DBP was -6.5 (95% confidence interval: -7.5 to -5.6) and -3.3 (95% confidence interval, -3.9 to -2.7), respectively. The difference was independent on the treatment duration and use of mono or combination treatment but for SBP it varied with the different treatment types in monotherapy, and it was greater in relation to baseline office BP and age. Allowing for the placebo effect also reduced the difference. Absolute on treatment BP values were at target for either pressure and the rate of controlled hypertensive individuals was similar (around one-third) for either measuring approach., Conclusion: Our meta-analysis confirms that overall treatment-induced reduction is markedly greater for office BP than for 24-h BP, but it also shows that the quantitative relationship between these two measuring approaches varies with demographic, clinical and therapeutic conditions as well as in relation to placebo correction.

Introduction: Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM., Methods and Analysis: MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP <140/90 mm Hg, and at least one of the following: daytime ABP ≥135/85 mm Hg; night-time ABP ≥120/70 mm Hg; 24 hour ABP ≥130/80 mm Hg), and will be randomised to a management strategy based on OBPM (group 1) or on ABPM (group 2). Patients in group 1 will have OBP measured at 0, 3, 6, 12, 18, 24, 30, 36, 42 and 48 months and taken as a guide for treatment; ABPM will be performed at randomisation and at 12, 24, 36 and 48 months but will not be used to take treatment decisions. Patients randomised to group 2 will have ABPM performed at randomisation and all scheduled visits as a guide to antihypertensive treatment. The effects of MUCH management strategy based on ABPM or on OBPM on CV and renal intermediate outcomes (changing left ventricular mass and microalbuminuria, coprimary outcomes) at 1 year and on CV events at 4 years and on changes in BP-related variables will be assessed., Ethics and Dissemination: MASTER study protocol has received approval by the ethical review board of Istituto Auxologico Italiano. The procedures set out in this protocol are in accordance with principles of Declaration of Helsinki and Good Clinical Practice guidelines. Results will be published in accordance with the CONSORT statement in a peer-reviewed scientific journal., Trial Registration Number: NCT02804074; Pre-results., Competing Interests: Competing interests: GP: honoraria as lecturer for Pfizer, Daiichi Sankyo, Menarini, Omron Healthcare. EA-R: honoraria and/or support from Menarini, Servier, Recordati,Guidotti,Malesci, Ferrer, DOC gen, Bruno farm. GLB: principal investigator (FIDElio)-Bayer, Steering committee (CREDENCE(Janssen), SONAR (AbbVie)-Consultant for Merck, Relypsa, Vascular Dynamics, Elceyx, Bayer, Janssen, AbbVie. FC: collaboration with Smart Solutions Technologies S.A.; AMICUS; Boston Scientific International S.A . ADS: honoraria as lecturer for Abbott, Daiichi-Sankyo, Lacer, Menarini, and Pfizer. MD: Honoria from Recordati and Servier. TK: Research grants Karolinska Institutet from Amgen, Medtronic, Pfizer, and Record, all outside the presented work. SL: Honoraria for lecturing from Axelife, Daichi-Sankyo, Fukuda-Denshi, Menarini, Novartis, Omron, Servier and Recordati. GM: honoraria aslecturer Actavis, Amgen, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, Sanofi,Servier. RJM: has received BP Monitors forresearch use from Omron. JR: hasbeen paid as lecturer by Daiichi Sankyo, Menarini, BoehringerIngelheim, MSD. MYR: Lecture honoraria from Pfizer,LG Life Sciences, Bayer Korea, Hanmi Pharm. Co., Yuhan Co., Boryung Pharmaceutical Co., Research grant fromBoryung Pharmaceutical Co. and Dong-A Pharmaceutical Co., CJ HealthCare Co. GS: Conductedvalidation studies for various manufacturers; advised manufacturerson device development. JGW: lecture and consulting fees from Bayer, Daiichi-Sankyo, Novartis,Omron, Pfizer, Sanofi, and Servier. AZ: Honoraria from Menarini International., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The five major classes of blood pressure (BP)-lowering drugs have all been shown to significantly reduce the risk of major cardiovascular events when compared with placebo, and when directly (head-to-head) compared, no significant differences in their overall effectiveness have been detected, except for minor differences in cause-specific events. It is unknown, however, whether age-related differences exist and if some classes of drugs are differently effective in older or younger individuals. This clinically relevant question has been the object of a systematic search and meta-analysis of all available data., Methods: Two databases we had previously identified [72 placebo-controlled BP-lowering randomized clinical trials (RCTs) in 260 210 individuals and 50 RCTs head-to-head comparing treatments with BP-lowering drugs of different classes in 247 006 individuals) were searched for separately reported data on patients older or younger than 65 years, and the data were further stratified according to the class of drug [diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers] compared with placebo or with other drug classes. Seven fatal and nonfatal outcomes were considered for benefits. Adverse events were investigated as permanent treatment discontinuations for adverse events. Risk ratios and absolute risk changes were calculated by a random effects model. Effects at older and younger ages were compared by heterogeneity test., Results: We identified 20 placebo-controlled RCTs on 55 645 older individuals and 21 on 99 621 younger individuals, and 21 head-to-head drug comparison RCTs on 94 228 older individuals and 27 on 100 232 younger individuals (for a total of 349 726 individuals). When compared with placebo, all five classes of BP-lowering drugs significantly reduced the risk of major cardiovascular events or stroke, with no significant difference between older and younger patients. However, in head-to-head comparisons, no significant difference was found between older and younger patients in the effects of diuretics, calcium antagonists, ACE inhibitors and angiotensin receptor blockers on all cardiovascular outcomes, whereas beta-blockers revealed an age-dependent effectiveness, being equally effective as the other agents at an age below 65 years, but less effective at an older age., Conclusion: Most BP-lowering classes are equally effective in preventing risk of fatal and nonfatal cardiovascular events both in older and younger patients, whereas beta-blockers, though being equally effective as the other agents in patients younger than 65, loose some of their effectiveness at an older age.

Background: There is overwhelming evidence that blood pressure (BP)-lowering treatment can reduce cardiovascular outcomes also in the elderly, but some important aspects influencing medical practice are controversial as sufficient evidence has not been provided by single randomized controlled trials (RCTs), whereas evidence may result from a systematic search and meta-analysis of all available data., Objectives: The following clinically relevant issues concerning the effects of BP lowering in older and younger individuals have been investigated: differences in benefits; the oldest and the youngest age range for which evidence of BP-lowering effects is available; the SBP level at which BP-lowering treatment should be initiated; the SBP and DBP levels treatment should be aimed at; differences in treatment burdens and harms., Methods: A database we previously identified of 72 BP-lowering RCTs in 260 210 patients was searched for separately reported data on older and younger individuals [cutoffs of 65 (primary analyses), 70, 75, 80, 60 and 55 years). The data were further stratified according to the levels of baseline (untreated) BP, and of on-treatment achieved SBP or DBP. Seven fatal and nonfatal outcomes were considered for benefits. Burdens and harms were investigated as permanent treatment discontinuations for adverse events, and hypotension/syncope. Risk ratios and absolute risk changes were calculated by a random effects model. Effects at older and younger ages were compared by heterogeneity test., Results: Thirty-two RCTs provided data on 96 549 patients older than 65 years, and 31 RCTs on 114 009 patients younger than 65 years. All cardiovascular outcomes were significantly reduced by treatment both in older and younger individuals, without significant age-dependent differences in relative risk reduction but with significantly higher absolute risk reductions in older individuals. The extreme age ranges for which evidence of significant benefits of treatment were available was greater than 80 and less than 55 years. Only one RCT provided data on benefits of BP-lowering at age greater than 65 when treatment was initiated at SBP values in the grade 1 range, but more consistent evidence was provided when age was greater than 60 years. Both in patients older and younger than 65 years, significant reductions of cardiovascular outcomes were found at on-treatment SBP less than 140 mmHg and DBP less than 80 mmHg. There was no evidence that treatment discontinuations for adverse events or hypotension/syncope were more frequent at age greater than 65., Conclusion: Antihypertensive treatment should be recommended to all individuals with elevated BP, independent of age. The prudent recommendation to initiate treatment at SBP values 140-159 mmHg is supported at older age defined as greater than 60 years. SBP and DBP values lower than 140 mmHg and, respectively, 80 mmHg can be aimed at with incremental benefits without disproportionate burdens until age 80 years, above which available evidence is for benefits at on-treatment SBP 140-149 mmHg.

: Whether isolated systolic hypertension in the young (ISHY) implies a worse outcome and needs antihypertensive treatment is still a matter for dispute. ISHY is thought to have different mechanisms than systolic hypertension in the elderly. However, findings from previous studies have provided inconsistent results. From the analysis of the literature, two main lines of research and conceptualization have emerged. Simultaneous assessment of peripheral and central blood pressure led to the identification of a condition called pseudo or spurious hypertension, which was considered an innocent condition. However, an increase in pulse wave velocity has been found by some authors in about 20% of the individuals with ISHY. In addition, obesity and metabolic disturbances have often been documented to be associated with ISHY both in children and young adults. The first aspect to consider whenever evaluating a person with ISHY is the possible presence of white-coat hypertension, which has been frequently found in this condition. In addition, assessment of central blood pressure is useful for identifying ISHY patients whose central blood pressure is normal. ISHY is infrequently mentioned in the guidelines on diagnosis and treatment of hypertension. According to the 2013 European Guidelines on the management of hypertension, people with ISHY should be followed carefully, modifying risk factors by lifestyle changes and avoiding antihypertensive drugs. Only future clinical trials will elucidate if a benefit can be achieved with pharmacological treatment in some subgroups of ISHY patients with associated risk factors and/or high central blood pressure.

Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level., Methods and Findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP ≥ 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP ≥ 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD., Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

: Evidence from randomized trials has shown that effective treatment with blood pressure (BP)-lowering medications reduces the risk of cardiovascular morbidity and mortality in patients with hypertension. Therefore, hypertension control and prevention of subsequent morbidity and mortality should be achievable for all patients worldwide. However, many people in Latin America remain undiagnosed, untreated or have inadequately controlled BP, even where this is access to health systems. Barriers to hypertension control in low-income countries include difficulties in transportation to health services; inappropriate opening hours; difficulties in making clinic appointments; inaccessible healthcare facilities, lack of insurance and high treatment costs. After a review of the best recent available evidence on the efficacy and tolerability of antihypertensive drugs and strategies, the Latin American Society of Hypertension experts conclude that all major classes of BP-lowering drugs be available to hypertensive patients, because all have been shown to reduce major cardiovascular outcomes compared with placebo, and have shown to be associated with a comparable risk of major cardiovascular events and mortality when compared between classes. Within each class, no evidence whatsoever is available to show that one compound is more effective than another in outcome prevention. Therefore, the selection of individual drugs may be based mainly on the capacity of Latin American governments to obtain the lowest prices of the different molecules manufactured by companies with high production quality standards.

Background: In recent meta-analyses of blood pressure (BP)-lowering randomized controlled trials (RCTs), we have shown that in hypertensive patients with diabetes, but not in those without, relative risk reduction of cardiovascular outcomes for a standardized BP reduction is significantly smaller at progressively lower SBP values achieved by treatment., Objectives: Whether this feature is typical of diabetes or is common to all hypertensive patients at high-very high cardiovascular risk is unknown. To clarify these points, we report a new set of meta-analyses, in which BP-lowering RCTs have been stratified in a double way, according to two levels of cardiovascular risk (below and above 5% cardiovascular death in 10 years) and three SBP levels attained by treatment (≥140, 130-139, and <130 mmHg)., Methods: The database consisted of 72 BP-lowering RCTs including 260 210 patients, stratified in two ways (cardiovascular risk and achieved SBP) as indicated above. Risk ratios and 95% confidence intervals of six fatal and nonfatal cardiovascular outcomes and all-cause death were calculated (random effects model) for all patients and, separately, for those with and those without diabetes mellitus. Differences between treatment effects at different achieved SBP levels were evaluated by test of homogeneity or trend analysis., Results: When all patients at higher cardiovascular risk were analyzed (46 RCTs, 182 248 patients), no significant difference could be found in the relative risk reduction of any outcome in response to a standard BP reduction at any level of achieved SBP. On the other hand, in patients at a high level of cardiovascular risk, the presence of diabetes (29 RCTs, 52 350 patients) was associated with a significantly smaller outcome benefit of a standardized BP lowering to SBP less than 130 mmHg, and the opposite was found in absence of diabetes (22 RCTs, 102 792 patients). Similar findings were obtained in lower cardiovascular risk patients, but the smaller number of trials and, particularly, events weakens the evidence they provide, particularly on lower risk patients with diabetes., Conclusion: A high level of cardiovascular risk is not in itself a restraint to target at SBP values less than 130 mmHg, if treatment is well tolerated. Though a high cardiovascular risk associated with diabetes is not an indication for aiming at SBP less than 130 mmHg, current evidence is that SBP values slightly below 130 mmHg are not associated with harm.

Background: It is currently unknown whether individuals with SBP/DBP values in the ranges 120-139/80-89 mmHg, usually defined as with prehypertension or high-normal and normal blood pressure (BP), benefit from BP-lowering treatment and whether benefits in these individuals depend on the level of their cardiovascular risk., Objectives: Meta-analyzing all available data from randomized controlled trials (RCTs) about the effects on cardiovascular outcomes of BP-lowering treatment in individuals with normal or high-normal BP values in absence of baseline antihypertensive drugs and free from a recent myocardial infarction, left ventricular dysfunction and heart failure., Methods: From an available database of BP-lowering RCTs updated to end 2016, RCTs were selected only including normotensive individuals or including both hypertensive and normotensive individuals but providing separate information in normotensive individuals. Risk ratios and 95% confidence intervals, and absolute risk reduction of cardiovascular outcomes and all deaths were calculated by a random-effects model., Results: We identified 24 RCTs providing data on 47 991 high-normal or normal BP individuals. BP-lowering treatment was found to significantly reduce cardiovascular disease risk in these individuals, but risk reduction was limited to stroke. When RCTs were stratified according to total cardiovascular risk, no significant benefits were found in RCTs including individuals at low-moderate risk (13 RCTs, 21 128 individuals), whereas a significant reduction in stroke risk (-60% to a SBP/DBP reduction of 10/5 mmHg) was found in RCTs including individuals at high-very high risk mostly because of symptomatic cardiovascular disease (11 RCTs, 26 863 individuals). In high-very high-risk normotensive individuals, BP-lowering treatment appeared to reduce stroke risk independently of the drug class used., Conclusion: Individuals with very high cardiovascular risk due to symptomatic cardiovascular disease should consider BP-lowering treatment even when their BP is in the high-normal and normal range.

Importance: Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown., Objectives: To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5., Data Sources: Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases., Study Selection: All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016., Data Extraction and Synthesis: Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials., Main Outcome and Measure: All-cause mortality during the active treatment phase of each trial., Results: This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups., Conclusions and Relevance: Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.

Hypertension is a leading risk factor for disease burden globally. An unresolved question is whether grade 1 hypertension (140-159/90-99mmHg) with low (cardiovascular mortality <1% at 10 years) to moderate (cardiovascular mortality ≥1% and <5% at 10 years) absolute total cardiovascular risk (CVR) should be treated with antihypertensive agents. A virtual international consultation process was undertaken to summarize the opinions of select experts. After holistic analysis of all epidemiological, clinical, psychosocial, and public health elements, this consultation process reached the following consensus in hypertensive adults aged <80 years: (1) The question of whether drug treatment in grade 1 should be preceded by a period of some weeks or months during which only lifestyle measures are recommended cannot be evidence based, but the consensus opinion is to have a period of lifestyle alone reserved only to patients with grade 1 "isolated" hypertension (grade 1 uncomplicated hypertension with low absolute total CVR, and without other major CVR factors and risk modifiers). (2) The initiation of antihypertensive drug therapy in grade 1 hypertension with moderate absolute total CVR should not be delayed. (3) Men ≥55 years and women ≥60 years with uncomplicated grade 1 hypertension should automatically be classified within the moderate absolute total CVR category, even in the absence of other major CVR factors and risk modifiers. (4) Statins should be considered along with blood-pressure lowering therapy, irrespective of cholesterol levels, in patients with grade 1 hypertensive with moderate CVR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes mellitus is associated with an increased risk of hypertension, and cardiovascular and renal disease, and it has been recommended that management of hypertension should be more aggressive in presence than in absence of diabetes mellitus, but the matter is controversial at present., Objectives: Meta-analysing all available randomized controlled trials (RCTs) to compare the effects on cardiovascular and renal outcomes of blood pressure BP lowering to different systolic BP (SBP) and diastolic BP (DBP) levels or by different drug classes in patients with and without diabetes mellitus., Methods: The database consisted of 72 BP-lowering RCTs (260 210 patients) and 50 head-to-head drug comparison RCTs (247 006). Among these two sets, RCTs or RCT subgroups separately reporting data from patients with and without diabetes mellitus were identified, and stratified by in-treatment achieved SBP and DBP, by drug class compared with placebo, and drug class compared with all other classes. Risk ratios and 95% confidence intervals, and absolute risk reductions of six fatal and non-fatal cardiovascular outcomes, all-cause death, and end-stage renal disease (ESRD) were calculated (random-effects model) separately for diabetes mellitus and no diabetes mellitus, and compared by interaction analysis., Results: We identified 41 RCTs providing data on 61 772 patients with diabetes mellitus and 40 RCTs providing data on 191 353 patients without diabetes mellitus. For achieved SBP at least 140 mmHg, relative and absolute reductions of most cardiovascular outcomes were significantly greater in diabetes mellitus than no diabetes mellitus, whereas for achieved SBP below 130 mmHg, the difference disappeared or reversed (greater outcome reduction in no diabetes mellitus). Significant ESRD reduction was found only in diabetes mellitus, but it was greatest when achieved SBP was at least 140 mmHg, and no further effect was found at SBP below 140 mmHg. All antihypertensive drug classes reduced cardiovascular risk vs. placebo in diabetes mellitus and no diabetes mellitus, but angiotensin-converting enzyme inhibitors were the only class more effective in diabetes mellitus than in no diabetes mellitus. When compared to other classes, renin-angiotensin system blockers were equally effective in cardiovascular prevention in no diabetes mellitus, but moderately, though significantly, more effective in diabetes mellitus., Conclusion: BP-lowering treatment significantly and importantly reduces cardiovascular risk both in diabetes mellitus and no diabetes mellitus, but evidence for reduced ESRD risk is available only in diabetes. Contrary to past recommendations, in diabetes mellitus there is little or no further benefit in lowering SBP below 130 mmHg, whereas continuing benefit is seen in no diabetes mellitus also at SBP below 130 mmHg. Although all BP-lowering drugs can beneficially be prescribed in hypertensive patients with diabetes mellitus, the current recommendation to initiate or include a renin-angiotensin system blocker is supported by the evidence here presented.

Background: Choice of antihypertensive drugs is also based on the expected burden of adverse events associated with each class of agents, and we have recently identified treatment discontinuation for adverse events as a measure of treatment tolerability frequently reported in randomized controlled trials (RCTs)., Objectives: To investigate whether all classes of blood pressure (BP) lowering drugs increase discontinuations for adverse events when compared with placebo and whether risk of discontinuation is similar for all classes when compared in head-to-head RCTs., Methods: RCTs of BP-lowering treatment were subdivided in groups according to class of drug compared with placebo or with other classes. Risk ratios and 95% confidence intervals of major cardiovascular events and of treatment discontinuations for adverse events were calculated (random-effects model)., Results: Thirty-eight placebo-controlled RCTs (147 788 patients) and 37 head-to-head RCTs (242 481 patients) provided comparative information on discontinuations for adverse events. All classes of drugs significantly increased discontinuations for adverse events over those occurring on placebo: risk ratio diuretics 2.23 (1.32-3.76), beta-blockers 2.88 (1.58-5.28), calcium antagonists 2.03 (1.17-3.56), angiotensin-converting enzyme inhibitors 2.78 (1.37-5.47), central agents 1.74 (1.24-2.45), with the single exception of angiotensin receptor blockers, which did not significantly increase adverse events over placebo [risk ratio 1.13 (0.78-1.62)]. Similarly, in head-to-head comparison RCTs with other classes, angiotensin receptor blockers were the only class associated with a significantly lower risk of adverse events [risk ratio 0.71 (0.58-0.87)] when head-to-head compared with other classes. Regression analysis also shows that incidence of discontinuations for adverse events is proportional to the number of antihypertensive and other cardiovascular drugs, which accounts for the high incidence of this outcome often found in groups randomized to placebo., Conclusion: Reduction of cardiovascular events by all classes of BP-lowering drugs is accompanied by increased treatment discontinuations for adverse events, except when angiotensin receptor blockers are used. Treatment discontinuations are also related to treatment often accompanying antihypertensive agents.

Background: Previous meta-analyses of randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment provided overwhelming evidence that treatment markedly reduces risk of cardiovascular outcomes in hypertensive patients. However, adverse events associated with BP-lowering treatment have never been surveyed systematically., Objectives: Identifying among BP-lowering RCTs those reporting a common and meaningful index of treatment-attributed adverse events, and describing the burden of these adverse events accompanying the benefits of mortality and morbidity reduction induced by treatment., Methods: The database consisted of the BP-lowering RCTs (active vs. placebo or less active treatment) we have described (70 RCTs, 255 970 participants, 1 091 964 patient-years). A common index of relevant adverse events was identified as permanent treatment discontinuation attributed to treatment adverse events. Risk ratios and 95% confidence intervals, standardized to a SBP/DBP reduction of 10/5 mmHg, of seven fatal and nonfatal outcomes and of treatment discontinuations for adverse events were calculated (random-effects model). The relationships of outcome reductions and discontinuation excess to SBP and DBP reductions were investigated by meta-regressions., Results: Forty-four RCTs provided data on treatment discontinuations for adverse events and six more on serious adverse events because of treatment (179 949 patients, 719 796 patient-years). In these 50 RCTs, a significant 24% reduction of major cardiovascular event risk was associated with a significant 89% increase in the risk of discontinuations (33 major cardiovascular effects prevented and 84 excess discontinuations/1000 patients for 5 years). Metaregression analysis indicated that both outcome reductions and treatment discontinuation excess were significantly related to the extent of SBP and DBP reduction, but absolute treatment discontinuation excess disproportionally increased with larger BP reductions than increase in outcome risk reduction. Furthermore, a standard SBP reduction was found associated with a constant relative reduction, but a smaller absolute reduction of cardiovascular events, and a greater relative excess of treatment discontinuations when the achieved SBP was below 130 mmHg rather than in higher ranges., Conclusion: The burden of adverse events associated with BP-lowering treatment should be considered not to deny patients the overwhelming benefits of BP lowering, but whenever the extent of the BP lowering or the BP target to be achieved are discussed.

In June 2015, a panel of experts gathered in a consensus conference to plan updating recommendations on the management of the hypertensive patient with elevated heart rate (HR), previously released in 2006. The issues examined during that meeting and further discussed by the participants during the following months involved the assessment of HR, the relevance of HR as a cardiovascular risk factor, the definition of tachycardia and the treatment of the hypertensive patient with high HR. For the measurement of resting HR the panel experts recommended that scientific investigations focusing on HR should report information on length of resting period before measurement, information about temperature and environment, method of measurement, duration of measurement, number of readings, time interval between measurements, body position and type of observer. According to the panellists there is convincing evidence that HR is an important risk factor for cardiovascular disease and they suggest to routinely include HR measurement in the assessment of the hypertensive patient. Regarding the definition of tachycardia, the panellists acknowledged that in the absence of convincing data any threshold used to define tachycardia is arbitrary. Similarly, as there are no outcome studies of HR lowering in tachycardia hypertension, the panellists could not make practical therapeutic suggestions for the management of such patients. However, the experts remarked that absence of evidence does not mean evidence against the importance of tachycardia as a risk factor for cardiovascular disease and that long-term exposure to a potentially important risk factor may impair the patient's prognosis. The main aims of the present document are to alert researchers and physicians about the importance of measuring HR in hypertensive patients, and to stimulate research to clarify unresolved issues.

Background and Objectives: Previous meta-analyses of our group have investigated the cardiovascular effects of more vs. less intense blood pressure (BP) treatment and the BP levels to be achieved by treatment. A few additional trials have been completed recently, particularly the large SPRINT study. Updating of the previous meta-analyses has been done with the objective of further clarifying the practical question of BP targets of antihypertensive treatment., Methods: Among randomized-controlled trials (RCTs) of BP lowering treatment between 1966 and 2015, 16 (52 235 patients) compared more vs. less intense treatment and fulfilled other preset criteria, and in 34 (138 127 patients) SBP in the active (vs. placebo) or the more (vs. less) intense treatment was below (vs., respectively, above) three predetermined cutoffs. For their meta-analyses risk ratios (RR) and 95% confidence intervals, standardized to -10/-5 mmHg SBP/DBP reduction, and absolute risk reductions of seven fatal and nonfatal outcomes were calculated., Results: More intense BP lowering significantly reduced risk of stroke [RR 0.71 (0.60-0.84)], coronary events [0.80 (0.68-0.95)], major cardiovascular events [0.75 (0.68-0.85)] and cardiovascular mortality [0.79 (0.63-0.97)], but not heart failure and all-cause death. When the 16 RCTs were stratified according to cardiovascular death risk, relative risk reduction did not differ between strata, but absolute risk reduction increased with cardiovascular risk, though the residual risk also increased. Stratification of the 34 RCTs according to the three different SBP cutoffs (150, 140 and 130 mmHg) showed that a SBP/DBP difference of -10/-5 mmHg across each cutoff significantly reduced risk of all outcomes to the same proportion (relative risk reduction), but absolute risk reduction of most outcomes had a significant trend to decrease at lower cutoffs., Conclusion: Updating of previous meta-analyses indicates that more vs. less intense BP lowering can reduce not only stroke and coronary events, but also cardiovascular mortality. Including data from recent RCTs also shows that all major outcomes can be reduced by lowering SBP a few mmHg below vs. above 130 mmHg, but absolute risk reduction becomes smaller, suggesting patients at lower initial SBP were at a lower level of cardiovascular risk.

Aims: Recent hypertension guidelines recommend that also in high cardiovascular (CV) risk, hypertensive patients blood pressure (BP) is lowered to <140/90 mmHg as no evidence is available supporting the lower target of <130/80 mmHg recommended in previous guidelines. Whether this represents the optimal treatment strategy is debated, however., Methods and Results: The high CV risk hypertensive patients of the Valsartan Antihypertensive Long-term use Evaluation (VALUE) trial were divided into subgroups according to (i) the percentage of on-treatment visits in which BP was reduced to <140/90 or <130/80 mmHg or (ii) the mean systolic or diastolic BP (SBP/DBP) values achieved during the entire treatment period or up to the occurrence of an event. A progressive increase from <25 to ≥75% of the visits in which BP was <140/90 mmHg was accompanied by a significant, progressive marked decrease in the covariate adjusted risk of CV morbidity and mortality, cause specific CV events (myocardial infarction, heart failure, and stroke), and all-cause mortality. Except for a persistent progressive decrease in stroke, no significant trend to a risk decrease occurred for a similar progressive increment of the proportion of visits with BP <130/80 mmHg. Increasing the proportion of visits with a BP <140/90 mmHg (but not <130/80 mmHg) was accompanied by a decreased risk of events also when differences in baseline risk were adjusted using a propensity score. Finally, compared with patients remaining at a mean on-treatment SBP ≥140 or DBP ≥90 mmHg, the risk of all events was markedly reduced when on-treatment mean SBP was lowered to a mean SBP of 130-139 mmHg or a mean DBP of 80-89 mmHg, whereas at on-treatment mean SBP <130 mmHg or DBP <80 mmHg, an additional risk reduction was found for stroke but for any other type of event, the risk of which remained similar or only slightly greater than that seen at the higher BP target., Conclusions: In the high CV risk, hypertensives of the VALUE trial reducing BP consistently to <140/90 mmHg had marked beneficial effects both when data were calculated as proportion of visits at BP target or as on-treatment mean BP. Reducing BP to <130/80 mmHg led only to some possible further benefit on stroke, whereas the risk of other outcomes remained substantially similar to or slightly greater than that seen at the higher target. Thus, aggressive BP reductions when CV risk is high may not offer substantial advantages, except perhaps in patients or conditions in which stroke risk is particularly common., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background and Objectives: Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization., Methods: Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions., Results: First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]., Conclusion: BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists.

Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP ≥ 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with ≥ 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J-curve in either group. Systolic BP ≥ 150 but not < 130 mmHg, compared with 130-149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata ≥ 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection.

Background and Objectives: We have recently published an overview and meta-analysis of the effects of the five major classes of blood pressure-lowering drugs on cardiovascular outcomes when compared with placebo. However, possible differences in effectiveness of the various classes can correctly be estimated only by head-to-head comparisons of different classes of agents. This has been the objective of a new survey and meta-analysis., Methods: A database search between 1966 and August 2014 ide ntified 50 eligible randomized controlled trials for 58 two-drug comparisons (247 006 patients for 1 029 768 patient-years). Risk ratios and their 95% confidence intervals of seven outcomes were estimated by a random-effects model., Results: The effects of all drug classes are not significantly different on most outcomes when their blood pressure effect is equivalent. However, there are also significant differences involving almost all classes of drugs. When compared to all other classes together, diuretics are superior in preventing heart failure; beta-blockers less effective in preventing stroke; calcium antagonists superior in preventing stroke and all-cause death, but inferior in preventing heart failure; angiotensin-converting enzyme inhibitors more effective in preventing coronary heart disease and less in preventing stroke; angiotensin receptor blockers inferior in preventing coronary heart disease; and renin-angiotensin system blockers more effective in preventing heart failure. When stratifying randomized controlled trials according to total cardiovascular risk, no drug class was found to change in effectiveness with the level of risk., Conclusions: The results of all available evidence from head-to-head drug class comparisons do not allow the formulation of a fixed paradigm of drug choice valuable for all hypertensive patients, but the differences found may suggest specific choices in specific conditions, or preferable combinations of drugs.

Background and Objectives: Demonstration of antihypertensive beneficial role in population settings is difficult. Relationships of antihypertensive treatment, blood pressure control, risk factors and cardiovascular outcomes were investigated in the Gubbio study., Material and Methods: Among 2248 cardiovascular disease-free men and women aged 35-74 years, individuals were classified as nonhypertensive, controlled hypertensive, uncontrolled hypertensive and untreated hypertensive based on cut-off limits of 140/90  mmHg for SBP/DBP and/or the use of antihypertensive drugs. End-point was the first major coronary, cerebrovascular or peripheral hard event [cardiovascular disease (CVD)] during a 15-year average. Univariate and multivariate analyses were run., Results: Nonhypertensive individuals were about 10 years younger and had lower risk factor levels than the other categories. The relative risk (and 95% confidence interval) for CVD versus nonhypertension was 1.78 (1.02-3.10) for controlled hypertension, 3.76 (2.79-5.06) for uncontrolled hypertension and 3.30 (2.59-4.21) for untreated hypertension (UTH). After adjusting for covariates, such as sex, age, achieved blood pressure and other risk factors, the CVD risk of controlled hypertension was practically equal to that of nonhypertension, and remained unchanged even when blood pressure was excluded from the model (1.03, 0.58-1.82). The higher cardiovascular risk of uncontrolled hypertension and UTH was reduced after adjusting for covariates, but remained significantly higher than in nonhypertension, with no significant differences between uncontrolled hypertension and UTH., Conclusions: A higher level of baseline risk is not due to treatment per se, the risk being similar in uncontrolled hypertension and UTH. Adjustment for risk factors reduces the risk only in controlled hypertension, suggesting that there may be structural alterations scarcely reversible by antihypertensive treatment.

Sixty-eight blood pressure (BP)-lowering randomized controlled trials (defined as randomized controlled trials comparing active treatment with placebo, or less active treatment, achieving a BP difference, performed between 1966 and end 2013 in cohorts with ≥ 40% hypertensive patients, and exclusive of trials in acute myocardial infarction, heart failure, acute stroke, and dialysis) were identified and meta-analyzed grouping the randomized controlled trials on the basis of clinically relevant questions: (1) does BP lowering reduce all types of cardiovascular outcome? (2) Is prevention of all outcomes proportional to the extent of systolic, diastolic, and pulse BP? (3) Have all classes of BP-lowering drugs been shown capable of reducing all types of cardiovascular outcome? (4) Is BP lowering beneficial when intervention is initiated at any grade (or stage) of hypertension? (5) Do BP-lowering randomized controlled trials provide evidence about systolic BP and diastolic BP targets of treatment? (6) Should BP-lowering treatment be preferentially addressed to patients in higher risk categories promising larger absolute treatment benefits? The results of these meta-analyses provide further support to current hypertension treatment guidelines by showing that BP lowering can significantly reduce major cardiovascular outcomes largely independent of the agents used, significant risk reduction is found at all hypertension grades (stages), and when systolic BP is lowered below a cut off of 140 mm Hg with some further reduction limited to stroke at systolic BP values just <130 mm Hg. Absolute risk reduction progressively increases higher is total cardiovascular risk, but this greater benefit is associated with a progressively higher residual risk, ie, higher treatment failures., (© 2015 American Heart Association, Inc.)

Background and Objectives: In 68 randomized controlled trials (RCTs), blood pressure (BP) lowering was obtained by using drugs of different classes. We have investigated whether BP lowering by any of the major drug classes is effective in reducing the cardiovascular outcomes., Methods: A total of 55 RCTs (19,5 267 individuals) were suitable for drug-class meta-analyses. Risk ratios and their 95% confidence intervals of seven fatal and nonfatal outcomes were estimated by a random-effects model., Results: Twelve RCTs (48, 898 patients) compared a diuretic with no treatment. SBP/DBP differences of about -12/-5  mmHg were accompanied by significant reductions of all outcomes, including mortality. The same results were obtained by limiting analyses to eight RCTs using low-dose diuretics. Separate analyses for thiazides, chlorthalidone and indapamide (all low dose) showed each subclass was associated with significant reduction of some major outcome. Five RCTs (18 ,724 patients; SBP/DBP difference -10.5/-7  mmHg) showed beta-blockers significantly reduced stroke, heart failure and major cardiovascular events. In RCTs comparing calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with placebo smaller SBP/DBP differences were achieved, mostly because in the majority of these later RCTs the antihypertensive drug and placebo were added on a background treatment with other antihypertensive agents. Nonetheless, significant reductions of stroke, major cardiovascular events, cardiovascular and all-cause death were obtained with calcium antagonists (10 RCTs, 30, 359 patients); stroke, coronary heart disease, heart failure and major cardiovascular events by ACE inhibitors (12 RCTs, 35, 707 patients); and stroke, heart failure and major cardiovascular events by ARBs (13 RCTs, 65, 256 patients)., Conclusion: BP lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular events. This supports the concept that reduction of these events is because of BP lowering per se rather than specific drug properties. However, evidence of risk reduction of other events and particularly mortality was obtained so far with some drug classes only. As a result of marked differences in the trial design, total cardiovascular risk, SBP/DBP differences and statistical power, comparisons of meta-analyses of different drug-specific placebo-controlled RCTs appear unwarranted.

Background: Randomized controlled trials (RCTs) of blood pressure (BP) lowering lend themselves to be meta-analyzed to help providing evidence-based recommendations for hypertension treatment., Objectives: To investigate whether relative or absolute risk reductions increase at increasing levels of baseline cardiovascular risk and whether BP-lowering treatment should be addressed to patients in risk categories promising larger absolute treatment benefits., Methods: Sixty-eight RCTs of intentional and nonintentional BP lowering were classified in four strata of increasing average 10-year incidence of cardiovascular death in the placebo or less active treatment group: low-to-moderate risk (<5%; 23 RCTs, 81,675 individuals), high risk (5% to <10%; 11 RCTs, 46,162 individuals), very high risk (10% to <20%; 19 RCTs, 91,152 individuals), and very very high risk (≥20%; 16 RCTs, 26,881 individuals). Risk ratios and 95% confidence intervals (CIs; random-effects model) standardized to 10/5 mmHg SBP/DBP reduction, absolute risk reduction, and residual risk of seven major fatal/nonfatal outcomes were calculated. Relative and absolute risk reductions in the cardiovascular risk strata were compared by the trend analysis, residual risk by calculating odds ratio (OR) relative to low-to-moderate risk., Results: Relative reductions of all outcomes did not differ in the risk strata, but absolute reductions significantly increased with increasing cardiovascular risk (P for trend <0.001 except for CHD): a 10/5 mmHg SBP/DBP reduction reduced the incidence of major cardiovascular events by 7 (95% CI 3-10), 30 (9-50), 56 (35-76), and 87 (62-112) events every 1000 patients treated 5 years, with increasing cardiovascular risk. However, also residual risk significantly (P < 0.001) increased with increasing cardiovascular risk [up to an OR 9.43 (8.60-10.35) for cardiovascular death]. The increase in residual risk with increasing level of cardiovascular risk persisted when RCTs with average initial age at least 65 years were excluded, and mean ages at the different cardiovascular risk levels were comparable., Conclusion: BP-lowering treatment induces greater absolute risk reductions the higher the cardiovascular risk level, but a higher risk level is also associated with higher absolute residual risk, independent of age. Whereas reserving antihypertensive treatment to high-risk hypertensive patients maximizes the cost-benefit ratio, only treatment of low-to-moderate risk hypertensive patients may prevent the increasing number of treatment failures when treatment is initiated at higher risk.

Background: Antihypertensive treatment is based on randomized controlled trials (RCTs) started since 1966. Meta-analyses comprehensive of all RCTs but limited to RCTs investigating blood pressure (BP) lowering in hypertensive patients are lacking., Objectives: Two clinical questions were investigated: the extent of different outcome reductions by BP lowering in hypertensive patients, and the proportionality of outcome reductions to SBP, DBP, and pulse pressure (PP) reductions., Methods: PubMed between 1966 and December 2013 (any language), Cochrane Collaboration Library and previous overviews were used as data sources for identifying and selecting all RCTs comparing the antihypertensive drugs with placebo or less intense BP lowering (intentional BP-lowering RCTs); comparing BP-lowering drugs with placebo without BP-lowering intention, but with BP difference (nonintentional BP-lowering RCTs); and enrolling at least 40% hypertensive patients. RCTs on acute myocardial infarction, heart failure, acute stroke, and dialysis were excluded. RCT quality was assessed by scoring. Risk ratios and 95% confidence interval (CI), standardized to 10/5 mmHg SBP/DBP reduction, of seven fatal and nonfatal outcomes were calculated (random-effects model). The relationships of different outcome reductions to SBP, DBP, and PP reductions were investigated by meta-regressions., Results: A total of 68 RCTs (245,885 individuals) were eligible, of which 47 (153,825 individuals) were 'intentional' RCTs. All outcomes were reduced (P < 0.001) by BP lowering, stroke [-36% (-29, -42)], and heart failure [-43% (-28, -54)] to a greater extent, with smaller reductions for coronary events [coronary heart disease (CHD): -16% (-10, -21)], cardiovascular [-18% (-11, -24)], and all-cause mortality [-11% (-5, -16)]. Absolute risk reductions were 17 (14, 20) strokes, 28 (19, 35) cardiovascular events, and 8 (4, 12) deaths prevented every 1000 patients treated for 5 years. Logarithmic risk ratios were related to SBP, DBP, and PP reductions (P = 0.001-0.003) for stroke and composite cardiovascular events, but not for CHD., Conclusion: Meta-analyses of all BP-lowering RCTs involving hypertensive patients provide precise estimates of benefits (larger for stroke and heart failure, but also significant for CHD and mortality). Absolute risk reductions are substantial. Relationships of logarithmic risk ratios with BP reductions imply risk reduction increases progressively to a smaller extent the larger the BP reduction.

Background: Relevant clinical questions not approached by randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment can be explored by meta-analyses stratified by clinical criteria., Objectives: Investigating whether all grades of hypertension benefit from BP-lowering treatment and which are the target BP levels to maximize outcome reduction., Methods: Of the 68 RCTs of intentional and nonintentional BP-lowering, those without baseline antihypertensive drugs were stratified by the average baseline SBP and DBP (hypertension grades 1, 2, and 3). RCTs with or without baseline treatment were considered for investigating the effects of mean achieved SBP/DBP across three SBP cutoffs and two DBP cutoffs. Risk ratios (RR) and 95% confidence interval (CI) (random-effects model), standardized to 10/5 mmHg SBP/DBP reduction, and absolute risk reductions of seven fatal and nonfatal outcomes were calculated. Differences between relative and absolute risk reductions in the different strata of baseline or achieved SBP/DBP were evaluated by trend or heterogeneity analyses., Results: In 32 RCTs (104,359 individuals), significant outcome reductions were found independently of the hypertension grade, with no trend toward risk ratio changes with increasing baseline BP. A secondary analysis limited to RCTs on grade 1 hypertension at low-to-moderate risk showed significant outcome reductions [risk ratio: stroke 0.33 (0.11-0.98), coronary events 0.68 (0.48-0.95), and death 0.53 (0.35-0.80)]. In 32 RCTs (128,232 individuals), relative and absolute outcome reductions were significant for the SBP differences across 150 and 140 mmHg cutoffs. Below 130 mmHg, only stroke and all-cause death were significantly reduced. Absolute outcome reduction showed a significant trend to decrease, the lower the SBP cutoff considered. In 29 RCTs (107,665 individuals), outcomes were significantly reduced across DBP cutoffs of 90 and 80 mmHg. After excluding RCTs with baseline DBP less than 90 mmHg, only stroke reduction was significant at achieved DBP less than 80 mmHg., Conclusion: Meta-analyses favor BP-lowering treatment even in grade 1 hypertension at low-to-moderate risk, and lowering SBP/DBP to less than 140/90 mmHg. Achieving less than 130/80 mmHg appears safe, but only adds further reduction in stroke.

Introduction: The aim of the study was to identify the association of systolic blood pressure (SBP) levels with cardiovascular events, all-cause mortality, and falls among elderly persons taking antihypertensive medication., Methods: US adults ≥ 45 years of age taking antihypertensive medication enrolled in the REGARDS study were categorized into 3 age groups: 55-64, 65-74 and ≥ 75 years old and baseline on-treatment SBP levels. Our primary analyses focused on incident cardiovascular disease (CVD) (n=9787) and all-cause mortality (n=13,948)., Results: During follow-up, 530 (5.4%) participants had CVD events and 2095 (15%) participants died. After multivariable adjustment among participants ≥ 75, the incidence of CVD per 1000 person-years (95% confidence interval) was 16.9 (11.1-25.7), 13.4 (9.2-19.7), 11.6 (7.6-17.7), 17.8 (11.2-27.5) and 36.7 (26.6-50.8) at SBP levels of <120, 120-129, 130-139, 140-149, and ≥ 150 mmHg, respectively. For the same SBP categories, the adjusted CVD incidence rates were 9.3 (7.2-12.0), 10.0 (8.1-12.3), 9.4 (7.5-11.8), 14.0 (11.0-17.8), and 16.4 (12.5-21.4), respectively, among participants 55-64 years, and 16.5 (13.6-21.5), 17.4 (14.8-20.6), 19.2 (16.4-22.5), 22.3 (18.6-26.9), and 27.6 (22.7-33.4), respectively, for participants 65-74 years. Among participants aged 55-64 and 65-74 years, a linear association was present between higher SBP categories and all-cause mortality risk (each p-trend<0.001). In contrast, for participants ≥ 75 years no association was present between SBP and all-cause mortality (p-trend=0.319). No association was observed between SBP and falls among participants in all age groups., Conclusions: Among adults aged ≥ 55 taking antihypertensive medication, SBP between 120 and 139 mmHg was significantly associated with a reduced risk for cardiovascular and all-cause mortality outcomes., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the study. The original target cohort consists of individuals aged ≥5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the city were also included. Three active screenings (exams) were conducted. A total of 5376 individuals (response rate 92%) participated in Exam 1 which was performed in 1983-86. Follow-up exams were completed between 1989-92 and 2001-2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-h ambulatory blood pressure and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality and causes of death were collected starting from completion of Exam 1. The study shared the data with other studies., (Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2013; all rights reserved.)

Background and Objective: Guidelines for management of cardiovascular diseases stratify absolute cardiovascular risk into categories with a high-risk threshold defined at a 20% cardiovascular events risk in 10 years, but it is unclear whether only major events or the Framingham-extended definition should be considered. The 2013 ESH-ESC hypertension guidelines, instead, define cardiovascular risk as a risk of cardiovascular death in 10 years, as in the SCORE model, setting the threshold for high risk at the 5% level. It would be therefore convenient to know the quantitative relationship between the risks of the different outcomes adopted by the different guidelines, especially because some outcome definitions include serious nonfatal cardiovascular events relevant in cardiovascular prevention. We have therefore analysed these relationships in trials of antihypertensive therapy as an aid to defining total cardiovascular risk in hypertensive patients., Design and Methods: Sixty-one trials were identified, and 51 retained for analysis of the relationship of cardiovascular death to the incidence of all-cause death, major cardiovascular events and inclusive (Framingham) cardiovascular events. The relationship between cardiovascular death rates and each type of event rates was explored by fitting flexible regression models., Results: The included trials provided 15164 cardiovascular deaths and 1674427 patient-years. The relation of each event rate to cardiovascular death rate was best explained by a model considering the logarithm of each event rate as a dependent variable and the logarithm of cardiovascular death rate as a predictor. Mean patients' age and treatment were also predictors, but to a minor extent. The increase of the incidence rates of all types of events was less steep the higher the CV death rate: the rate ratios of all-cause death to cardiovascular death were 2.2, 1.9 and 1.8 at low-moderate (cardiovascular death <5% in 10 years), high (cardiovascular death 5% to <10%) and very high risk (cardiovascular death ≥ 10%), respectively; the rate ratios of major cardiovascular events to cardiovascular death were 3.9, 2.7, 2.3 and the rate ratios of extended cardiovascular events to cardiovascular death were 8.4, 5.6 and 4.6, respectively. Ratios only slightly changed when 12 trials of secondary prevention were excluded., Conclusion: Ratios of various event rates to cardiovascular death rate vary with cardiovascular disease severity, cardiovascular mortality representing an increasing proportion of total cardiovascular risk when the former is higher. From the models, a total risk can be estimated in groups of hypertensive patients whose cardiovascular death risk is calculated by the SCORE model.

In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure established a definition of a new category of BP levels called 'prehypertension' (preHT) that included individuals with a systolic BP of 120-139 mm Hg or a diastolic BP of 80-89 mm Hg. Patients with preHT were considered to be at increased risk for progression to hypertension and in individuals with BP in the range 130/80 to 139/89 mmHg the risk of developing hypertension was twice as high as in subjects with lower values. Still then there has been a large debate whether the introduction of preHT was based on evidence and as a consequence, it was fully justified. It has been suggested that the term prehypertension may in many subjects create anxiety and a need for unnecessary medical visits and examinations. This group of patients is also very heterogeneous and it has been pointed out that subdividing preHT group into individuals with normal BP and high normal BP would much better correspond to the continuum of BP risk for CV disease. Finally, despite some data suggesting the potential benefits of antihypertensive therapy in patients with preHT (high normal BP), there are still no hard evidences on the outcome reduction by giving antihypertensive drugs in these individuals.

Background: In antihypertensive treatment trials, when randomized therapies do not reach target, additional drugs are administered. However, patients requiring (add-on) or not requiring add-on therapy (no-add-on) may be at different cardiovascular risk and differently susceptible to benefits of antihypertensive treatment., Methods and Results: The Felodipine Event Reduction study included 9711 Chinese hypertensive patients receiving 12.5  mg/day hydrochlorothiazide and randomized to associating either felodipine (5  mg/day) or placebo. Within 6 months, add-on therapy (further diuretic and other drugs) was required by 2185 patients, whereas 7243 did not require it. Despite significant SBP/DBP reductions by add-on therapy, outcome incidence remained much lower in no-add-on than in add-on patients: hazard ratios for various outcomes, after adjusting for baseline variables and blood pressure (BP) at time of add-on decision, were 0.22-0.368 (P always <0.001) and remained substantially unchanged when further adjusted for the small SBP/DBP difference persisting during follow-up treatment (-2.4/-1.1  mmHg in no-add-on). When felodipine was compared to placebo, the benefit of a lower SBP/DBP caused by felodipine was evident in the no-add-on patients (hazard ratio 0.45-0.68, P always <0.001), but it was lost in the add-on group (hazard ratio 0.91-1.17)., Conclusion: Comparing patients more or less easily responding to antihypertensive treatment may identify patients at high risk of outcomes and less susceptible to benefits of a lower BP. It remains to be more directly investigated to what extent adding drugs to drugs is effective in reducing outcomes of patients in whom simple antihypertensive therapy does not achieve goal BP.

Objectives: To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy., Background: Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy., Methods: We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90  mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made., Results: The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]., Conclusion: Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

Objective: To assess the antihypertensive efficacy of olmesartan medoxomil and ramipril on 24-h ambulatory blood pressure (ABP) in elderly hypertensive patients by pooled data analysis of two studies with identical designs (one Italian, one European)., Methods: After a 2-week placebo wash-out 1453 elderly hypertensive patients (65-89 years; sitting office DBP 90-109 mmHg and/or sitting office SBP 140-179 mmHg) were randomized to a 12-week double-blind treatment with olmesartan medoxomil 10 mg or ramipril 2.5 mg once-daily, up-titrated (20 and 40 mg olmesartan medoxomil; 5 and 10 mg ramipril) after 2 and 6 weeks in patients without normalized office BP. 24-h ABP was recorded at randomization and after 12 weeks., Results: In 715 patients with valid baseline and end-of-treatment recordings baseline-adjusted 24-h SBP and DBP reductions were greater with olmesartan medoxomil (n = 356) than with ramipril (n = 359) [between-treatment differences and 95% confidence interval (CI), SBP: 2.2 (3.8, 0.6), P = 0.006; DBP: 1.3 (2.2, 0.3), P = 0.009]. Olmesartan medoxomil showed larger BP reductions in the last 6 h from the dosing interval and higher smoothness indices than ramipril. Olmesartan medoxomil reduced the SBP morning rise [-2.8 (-4.9, -0.8) mmHg], whereas ramipril did not [+1.5 (-0.6, +3.6) mmHg; P = 0.004 between-treatments]. Five hundred and eighty-two patients with sustained hypertension (office and 24-h ambulatory hypertension) showed the largest antihypertensive effect, with between-treatment differences still in favor of olmesartan medoxomil [SBP: 2.1 (3.9, 0.4), P = 0.019; DBP: 1.2 (2.3, 0.1), P = 0.032]., Conclusions: Olmesartan medoxomil provides a more effective and sustained 24-h BP control than ramipril in elderly hypertensive patients, particularly in the hours farthest from last intake.

Background: Recent studies have reported that in patients under antihypertensive treatment visit-to-visit (or long-term) variability of clinic BP within a given patient has an independent prognostic significance. Partly based on between-patient dispersion of BP values during treatment (interindividual variability) it has also been reported that long-term clinic BP variability is greater for β-blocker than for calcium antagonist and other types of treatment., Goals: To measure visit-to-visit intraindividual variations of both clinic and 24-h mean BP in the hypertensive patients of the European Lacidipine Study on Atherosclerosis (ELSA) trial treated for 4 years with either atenolol or lacidipine, and to check whether interindividual clinic and 24-h BP variabilities during treatment can really be considered a surrogate of intraindividual variabilities in exploring differences between β-blocker and calcium antagonist treatments., Methods: Long-term intraindividual BP variability was defined as the coefficient of variation of the average systolic or diastolic values of clinic and 24-h BP measured at each visit throughout the treatment period. Patients in whom at least seven clinic (6-month intervals) or at least three (yearly intervals) 24-h values were available from the end of the drug titration phase to the end of the study were considered., Results: Visit-to-visit 24-h SBP/DBP variabilities were 20-25% smaller than, and loosely correlated with clinic BP variability (r(2) < 0.022). There was also a very limited relationship (r (2)< 0.026) between visit-to-visit and within 24-h ambulatory BP variabilities, the latter being two to three times greater than the former. Visit-to-visit intraindividual clinic SBP variability was only slightly lower on calcium antagonist than on β-blocker treatment but little or no between-treatment difference was found for visit-to-visit clinic DBP and ambulatory SBP/DBP particularly in patients under monotherapy throughout the study. Interindividual BP variability was markedly greater than the intra-individiual one of which it did not precisely reflect the treatment-induced changes., Conclusion: In mild-to-moderate hypertensive patients, visit-to-visit BP variability does not differ substantially between β-blocker and calcium antagonist treatment. Major discrepancies exist between visit-to-visit BP variability as quantified by 24-h vs. clinic BP, making investigation of which of these indices is clinically more relevant important. Interindividual BP variability during treatment shows marked quantitative differences with intraindividual BP variability questioning whether its use can accurately reflect individual BP variations from one visit to another.

Aims: Major guidelines recommend lowering systolic blood pressure (SBP) to <140 mmHg in all hypertensives, but evidence is missing whether this is beneficial in (i) uncomplicated hypertensives, (ii) grade 1 hypertensives, and (iii) elderly hypertensives. Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives., Methods and Results: Felodipine Event Reduction (FEVER) was a double-blind, randomized trial on 9711 Chinese hypertensives, in whom cardiovascular outcomes were significantly reduced by more intense therapy (low-dose hydrochlorothiazide and low-dose felodipine) achieving a mean of 138 mmHg SBP compared with less-intense therapy (low-dose hydrochlorothiazide and placebo) achieving a mean of 142 mmHg. FEVER included older and younger patients, and patients with and without diabetes or cardiovascular disease. In the analyses here reported, Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics. Significant reductions in stroke were found in uncomplicated hypertensives (-39%, P = 0.002), in hypertensives with randomization SBP <153 mmHg (-29%, P = 0.03), and in elderly hypertensives (-44%, P < 0.001), when their SBP was lowered by more intense treatment. Significant reductions (between -29 and -47%, P = 0.02 to <0.001) were also found in all cardiovascular events and all deaths. Achieving mean SBP values <140 mmHg by adding a small dose of a generic drug prevented 2.1 (uncomplicated hypertensives) and 5.2 (elderly) cardiovascular events every 100 patients treated for 3.3 years., Conclusions: These analyses provide strong support, missing so far, to guidelines recommending goal SBP <140 mmHg in uncomplicated hypertensives, individuals with moderately elevated BP and elderly hypertensives.

Background: The benefits of reducing blood pressure are well established, but there remains uncertainty about whether the magnitude of the effect varies with the initial blood pressure level. The objective was to compare the risk reductions achieved by different blood pressure-lowering regimens among individuals with different baseline blood pressures., Methods: Thirty-two randomized controlled trials were included and seven comparisons between different types of treatments were made. For each comparison, the primary prespecified analysis included calculation of summary estimates of effect using random-effects meta-analysis for major cardiovascular events in four groups defined by baseline SBP (<140, 140-159, 160-179, and ≥ 180 mmHg)., Results: There were 201 566 participants among whom 20 079 primary outcome events were observed. There was no evidence of differences in the proportionate risk reductions achieved with different blood pressure-lowering regimens across groups defined according to higher or lower levels of baseline SBP (all P for trend > 0.17). This finding was broadly consistent for comparisons of different regimens, for DBP categories, and for commonly used blood pressure cut-points., Conclusion: It appears unlikely that the effectiveness of blood pressure-lowering treatments depends substantively upon starting blood pressure level. As the majority of patients in the trials contributing to these overviews had a history of hypertension or were receiving background blood pressure-lowering therapy, the findings suggest that additional blood pressure reduction in hypertensive patients meeting initial blood pressure targets will produce further benefits. More broadly, the data are supportive of the utilization of blood pressure-lowering regimens in high-risk patients with and without hypertension.