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International surveys are consistent in showing that only a minority of hypertensive people get their blood pressure (BP) controlled to recommended targets. National and international surveys are consistent in showing that only a minority of hypertensive people get their blood pressure (BP) controlled to the currently recommended targets.1 Survey data from around the world show a wide range in awareness, treatment, and control of raised BP,2 and, with the exception of the USA, that only a minority of patients with a prior diagnosis of hypertension are receiving antihypertensive medication. Guidelines around the world vary considerably in their recommendations for first-line antihypertensive agents.
JNC 7—as shown in Figure 2—is not specific regarding which drug combinations to use, but does suggest that “thiazidetype” diuretics should usually be one of the components.9 This reflects the fact that all the RCT data supporting the use of diuretics have been based on either high-dose thiazides (usually with a potassium-sparing component), chlorthalidone, or indapamide. However, by 2006, the BHS along with NICE decided that β-blockers should be demoted to fourth-line therapy. Evidence from BPLTTC (Blood Pressure Lowering Treatment Trialists Collaboration) suggests that, with the exception of heart failure, the CV benefits associated with BP lowering are directly related to the degree of BP reduction.22 This implies that, for the same level of BP reduction, all drug classes are equally effective at preventing CV events.
It is also clear that different antihypertensive agents exert different effects on other non-BP determinants of CV outcomes, including glucose, lipids, potassium, pulse rate, body weight, left ventricular hypertrophy, etc. Very few trials other than ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial] have compared the CV effects of completely different pairs of antihypertensive agents. This trial included over 19 000 patients with hypertension and three or more other common CV risk factors, but without established CHD.
Subsequent analyses suggested that the CV benefits associated with the newer regimen were unlikely to be the result of superior BP reduction alone.25 Other possible contributors to the superior effects of the newer regimen included body weight, glucose, high-density lipoprotein cholesterol, triglycerides, creatinine, and potassium. After the main publication of the ASCOT-BPLA results,11,25 the findings of the CAFE (Conduit Artery Function Evaluation) substudy of ASCOT were published.29 This substudy, which measured central and brachial BP in a subgroup of trial participants, suggested that those receiving the amlodipine ± perindopril regimen had significantly lower central BPs compared with the atenolol ± perindopril group, while brachial BP differences were negligible. The relative benefits of ACE inhibitors and ARBs have been controversial since the launch of the first ARB, losartan. Only the first event in an individual patient was counted in the analysis of the primary end point. Importantly, and in stark contrast with the expectations of some, the combination of ARB and ACE inhibitor induced a significant increase in hard renal end points despite significant improvement in proteinuria.
The ACCOMPLISH trial set out to compare the CV effects of an “A + C” combination with an “A + D” combination (where “A” stands for an ACE inhibitor or an ARB, “C” stands for a CCB and “D” stands for a diuretic).12 This trial included 11 506 hypertensive patients at high risk for CV events, the majority of whom were diabetic.
The VALUE trial compared the effects of an ARB-based regimen with a CCB-based regimen (adding a thiazide to both groups as second-line therapy) among 15 245 hypertensive patients at high CV risk.14 Unfortunately, the results were at least in part confounded by superior BP lowering achieved in the CCB-based group, particularly in the first 6 months of the trial.
It has to be admitted that, once the second agent has been selected, there are no robust RCT data to inform best drug sequencing.
This evidence-based encounter form will assist you in providing care consistent with the latest hypertension guidelines.Mark H.
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Did you know that las 1000 palabras mas usadas en ingles has become the hottest topics in this category? Trial data show that most hypertensive patients require at least two agents to reach BP targets. Dashed horizontal lines refer to goal blood pressure values indicated by International Guidelines to be achieved during treatment. In representative samples of the English population, BP control rates rose from 6% to 28% between 1994 and 2006. While these two sets of guidelines are not consistent in terms of the specific population for which two-drug combinations are recommended, in both guidelines the recommendations apply to a significant proportion of the hypertensive population despite no RCT data being currently available to support the preferential use of this approach.
Thus, it is not surprising that the same guidelines also differ regarding optimal pairs of agents!
It is therefore not too difficult to believe that for the same level of clinic BP reduction, different agents may generate different effects on CV protection. Most early trials compared single agents (± an unstructured assortment of addon drugs) with placebo or with another single agent (± an unstructured assortment of add-on drugs). The authors concluded that these differential effects on central BP of the two antihypertensive regimens may be, in part at least, responsible for the differential effects on CV outcomes. Interestingly, breakdown of this end point into its component parts revealed that the benefits were actually all due to superior stroke prevention with, if anything, marginally less effective CHD prevention.
The results of the ONTARGET trial (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) were eagerly awaited because this trial of 25 588 high-risk people compared the effects of an ACE inhibitor (ramipril) with an ARB (telmisartan) and the combination of both drugs.32 Overall, neither agent was superior to the other, nor to the combination.
For the subsequent analysis of the component end points, if a patient had events in more than one category, one event per category was counted. As a result of early closure of the trial, the primary end point of stroke was not significantly improved. The CCB-based regimen tended to be better than, or at least as good as, the ARB-based regimen in terms of preventing most CV events. Although not mentioned hitherto, improved diets and lifestyle are a critical component of preventing raised BP and associated CV events, and should be encouraged in all populations, hypertensive or not. Ideally one should start with the agent most likely to produce the most effective BP lowering and which has proven benefits on CV morbidity and mortality in one or more RCTs.
The ACCOMPLISH trial12 supports the ASCOTBPLA trial11 and currently provides the best evidence for “A + C” as the most effective drug combination for CV prevention.
Patients who are insufficiently responsive to two antihypertensive agents are increasingly likely to be “water-retainers” and therefore the use of a diuretic is recommended.


However, the data from ASCOT-BPLA described above—albeit observational—are the best available data to support the use of any third- or fourth-line agents.41,42 In clinical practice these five steps will control the BP of the vast majority of hypertensive patients. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference.
The latest European and American guidelines recommend that a large proportion of hypertensive patients should start treatment with two antihypertensive agents. In 2006, 61% were receiving two or more drugs to treat raised BP, compared with only 40% in 1994. More recently, trials have usually specified the add-on agents, and the second second- line agent has often been common to both arms of the trial (eg, a thiazide was the second-line add-on agent used in both arms of both the VALUE14 and LIFE [Losartan Intervention For Endpoint reduction in hypertension]24 trials). The newer regimen was clearly superior in terms of preventing CV events overall and significantly so for most of the end points considered in the trial. These ASCOT results highlight the potential importance of differences between BP-lowering regimens other than those attributable to clinic BP differences. More recently, two sets of analyses includingASCOT data have shown that long-term BP variability is a strong predictor of CV outcomes and that the amlodipine ± perindopril regimen generated much less BP variability than the atenolol ± thiazide regimen.30,31 Furthermore, these analyses suggested that the differential effects of the two regimens on BP variability were the likely mechanisms whereby differential effects on CV events were generated. These results highlight the fact that beneficial effects on proteinuria are not necessarily mirrored (at least within the confines of a trial of up to 5 years’ duration) by benefits in hard renal or CV events.
However, the merit of active intervention is compelling in light of the significant all-cause mortality effects, the large benefits in all CV events, and improved well-being. The effects on the primary outcome of the trial—a composite of CV events—and the individual CV end points, were in favor of the “A + C” combination (Figure 6).
Various post hoc analyses implied that these differences in CV prevention were induced by the dif-ferential BP effects.
For those who also need antihypertensive medication, enhanced efforts to lower BP must be made.
For the reasons outlined above, “A” drugs for younger patients and CCBs for older patients are evidence-based choices. In light of the RCT evidence discussed, nonthiazide diuretics are chosen and the more metabolically friendly profile of indapamide compared with chlorthalidone, makes the former drug my personal preference.
Of importance, and in contrast to the results of the ALLHAT trial, there was no sign of any increase in heart failure associated with the use of doxazosin. Hypertension treatment and control in five European countries, Canada, and the United States. Continued improvement in hypertension management in England: results from the Health Survey for England 2006.
Blood pressure screening, management and control in England; results from the Health Survey for England 1994. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
Major outcomes in high-risk hypertensive patients randomized to angiotensin- converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT).
Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.
Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society 2004-BHS IV. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the ASCOT-BPLA trial and the relative influence of antihypertensive medication. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.
Effects of betablockers and calcium-channel blockers on within individual variability in blood pressure and risk of stroke. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting enzyme inhibitors: the CHARM-Added trial. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome.


Effects of a fixed combination of perindopril and indapamide on macrovascular outcomes in patients with type 2 diabetes mellitus: results of the blood pressure lowering arm of the ADVANCE trial.
Compliance, safety and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
See FPM CME Quiz.Evidence-based clinical guidelines can help synthesize the vast research on a clinical topic and summarize care recommendations. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. We got this image from the web that we think would be one of the most representative photos for jimmy somerville wikipedia. We took this picture from the web we consider would be one of the most representative photos for potluck breakfast recipes. We had taken this image from the web we believe would be one of the most representative photos for las 1000 palabras mas usadas en ingles. In 2006, British guidance prioritized two combinations of therapy – “A + C” or “A + D” where “A” is an angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), “C” is a calcium channel blocker and “D” is a diuretic.
Nevertheless, low-dose thiazides are recommended in several sets of guidelines around the world and are commonly used as monotherapy and in combination therapy. The trial was stopped early because of significant beneficial effects on allcause mortality associated with allocation to the amlodipine ± perindopril regimen. These nonsignificant trends supported previous hypotheses of differential effects on specific end points,33,34 but perhaps most importantly from a practical viewpoint, the overall CV effects were not different. The beneficial effects of the “A + C” combination were almost identical among those with and without type 2 diabetes and in all other subgroups.
Furthermore given that ‘A + C’ is apparently the best 2-drug combination, it is logical to start with “A” and “C” as first-line agents. There were, however, small, but significant, beneficial effects on lipid profiles and the drug was well tolerated.
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Class specific differences on coronary outcomes with ACE-inhibitors and ARBs: insight from meta-analysis and The Blood Pressure Lowering Treatment Trialists’ Collaboration. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial.
However, guidelines alone are often insufficient to change physician behavior at the point of care.
Physicians may photocopy or adapt for use in their own practices; all other rights reserved.
These combinations represent four of the five combinations recommended in the 2009 reappraisal of the European guidelines. Such an effect on total mortality is a relatively unique finding in hypertension trials (see Table II page 68 to put these findings in perspective). One of the equally interesting findings of the ONTARGET trial was that although the combination of the ACE inhibitor and the ARB induced significant additional BP reduction compared with the ACE inhibitor alone, no additional CV benefits were attributable to the combination of drugs compared with either single drug.
Consequently, it seems reasonable to conclude that, pending any further contradictory data, “A + D” is an inferior combination compared with “A + C” in terms of preventing CV events. These unusual benefits on mortality were independent of baseline BP with the implication that additional BP lowering with the type of regimen used in ADVANCE may be appropriate add-on therapy for all patients with type 2 diabetes, irrespective of BP level. Should a patient complain of gynecomastia, eplerenone can be used instead, but larger doses (on a mg for mg basis) are required to achieve the same BP-lowering effect.
In ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), amlodipine plus perindopril (“A + C”) was shown to be superior to a β-blocker and a diuretic (“B + D”) in terms of preventing major cardiovascular events. However, it had the effect of generating insufficient power to allow evaluation of the primary end point effectively.
More recently, the ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) trial compared benazepril and amlodipine (“A + C”) with benazepril and thiazide (“A + D”). Despite very similar BP lowering, the “A + C” combination was significantly superior to the “A + D” combination in terms of the primary composite cardiovascular end point.
Based on current trial evidence, it seems reasonable to conclude that the best evidence-based combination of antihypertensive medication is “A + C.” Consequently in 2011, the NICE guidelines from the UK recommend only “A + C” as the best drug combination. Then, if further BP-lowering is needed, a thiazide-like diuretic, such as indapamide or chlorthalidone, is recommended as step 3 therapy.
This article takes that card one step further by presenting a two-page evidence-based encounter form for the initial evaluation of a patient with hypertension. It begins with an assessment of cardiovascular risk factors and a survey to remind the physician to look for target organ damage. Note that JNC 7 recommends more invasive testing for secondary causes of hypertension only if the patient’s hypertension is difficult to control.




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