Combination therapy in the management of hypertension: which one for which patient?




Neil POULTER,MB, MSc, FRCP, FMed Sci
International Centre for Circulatory Health (ICCH)
Imperial College London – London, UK

Combination therapy in theanagement of hypertension: which one for which patient?

by N. R. Poulter, United Kingdom

International surveys are consistent in showing that only a minority of hypertensive people get their blood pressure (BP) controlled to recommended targets. Trial data show that most hypertensive patients require at least two agents to reach BP targets. The latest European and American guidelines recommend that a large proportion of hypertensive patients should start treatment with two antihypertensive agents. 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. These combinations represent four of the five combinations recommended in the 2009 reappraisal of the European guidelines. 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. 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.

Medicographia. 2012;34:63-72 (see French abstract on page 72)





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. Furthermore, in most countries, it is clear that only a minority of treated patients achieve BP control.2

Figure 1
Figure 1. Blood pressure
reductions achieved in
recent randomized controlled
trials.

Effects of antihypertensive drug treatment on systolic blood pressure (SBP) and
diastolic blood pressure (DBP) in trials on essential hypertensive patients. Blood pressure values at trial entry
and values achieved during treatment are shown for each trial. Dashed horizontal lines refer to goal blood pressure values indicated by International Guidelines to be achieved during treatment.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
Modified from reference 5: Mancia et al. J Hypertens. 2002;20:1461-1464. © 2002,
Lippincott Williams & Wilkins.






However, large improvements in BP management have been reported over relatively short time periods in several parts of the world.3 Reasons for these improvements are not definitively established, but include effective guideline dissemination, better patient/doctor education, increased use of nondrug treatments, a pay-for-performance approach to management, and increased antihypertensive drug use. In representative samples of the English population, BP control rates rose from 6% to 28% between 1994 and 2006. In 2006, 61% were receiving two or more drugs to treat raised BP, compared with only 40% in 1994. Due to this improvement in management, more than half of treated patients had their BP under control in 2006, compared with 35% in 1994.4 The mean BP reductions achieved in randomized controlled trials (RCTs) serve to demonstrate that even in a context where patients and doctors are more likely to be motivated to achieve better BP control, systolic targets are achieved only by a minority of participants while, on average, diastolic targets are almost always achieved (Figure 1).5





Figure 2
Figure 2. JNC 7: algorithm for hypertension
management.

Abbreviations: ACE, angiotensin-converting enzyme;
ARB, angiotensin receptor blocker; BP,
blood pressure; CCB, calcium channel blocker.
After reference 9: Chobanian et al. JAMA.
2003;289:2560-2572. © 2003, American Medical
Association.



Among patients with type 2 diabetes and those with chronic renal failure, the lower BP targets that pertain to these groups (<130/80 mm Hg) are even less frequently achieved in RCTs.5 Indeed, the systolic target of <130 mm Hg had never been achieved in a morbidity/mortality hypertension trial in diabetic patients until the ACCORD trial (Action to Control CardiOvascular Risk in Diabetes) was published in 2010.6

Guideline recommendations

Both the latest European guidelines (European Society of Hypertension [ESH]-EuropeanSociety ofCardiology [ESC] 2007),7 which were reappraised in 2009,8 and American guidelines (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC 7])9 recommend that, for some hypertensive patients, therapy should be initiated with two drugs. 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.

Which antihypertensive drug combinations should be used?

Guidelines around the world vary considerably in their recommendations for first-line antihypertensive agents. Thus, it is not surprising that the same guidelines also differ regarding optimal pairs of 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. Contrary to popular belief, these last two agents are not thiazides. In the three trials in which lowdose thiazides have been used alone or as part of a combination and compared with another agent (ANBP2 [Second Australian National Blood Pressure Study],10 ASCOT-BPLA [Anglo- Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm],11 and ACCOMPLISH [Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension]12), the thiazide was inferior to its comparator in terms of preventing major cardiovascular (CV) events. Nevertheless, low-dose thiazides are recommended in several sets of guidelines around the world and are commonly used as monotherapy and in combination therapy. This practice reflects cost issues rather than RCT-based evidence. Figure 3 shows the ESH-ESC (2007) recommendations for optimal drug combinations.7 Unfortunately, it recommends combinations that have not been formally tried and tested in RCTs (eg, calcium channel blockers [CCB] plus β-blockers) and others that seem illogical due to some mechanistic overlap (eg, CCB plus thiazide diuretic). However, the combination of CCBs and β-blockers was used by a significant number of those in the ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) trial who were randomized to the CCB (amlodipine) group.13 The combination of a CCB and a diuretic was used in the VALUE trial (Valsartan Antihypertensive Long-term Use Evaluation) in comparison with an angiotensin receptor blocker (ARB) (valsartan) plus a thiazide diuretic.14 However, although both drugs promote natriuresis—which presumably is responsible for at least part of the BP-lowering efficacy of these agents—this combination of drugs is quite commonly used in contemporary practice (at least in England!).3 This may, in part, reflect the fact that both classes of drugs have been shown to be effective as monotherapy in the elderly in trials such as Syst-Eur (Systolic Hypertension in Europe)15 and SHEP (Systolic Hypertension in the Elderly Program),16 and/or because diuretics (albeit ill-advisedly from a theoretical view point) are often used to try to offset the ankle edema induced by dihydropyridine CCBs! One glaring error in Figure 3 is the use of “thiazide diuretics” as part of the hexagon. As described above, the RCT evidence for the benefits of true thiazides (at least at a low dose) on CV events is nonexistent and thus, this point on the hexagon should be labeled “diuretics” or “thiazide- like diuretics.”

Figure 3
Figure 3. 2007 ESH/ESC guidelines: combination between some
classes of antihypertensive drugs.

Possible combinations between some classes of antihypertensive drugs. The
preferred combinations in the general hypertensive population are represented
as thick lines. The frames indicate classes of agents proven to be beneficial in
controlled intervention trials.
Abbreviations: ACE, angiotensin-converting enzyme; AT1, angiotensin II type 1;
ESC, European Society of Cardiology; ESH, European Society of Hypertension.
After reference 7: Mancia et al. J Hypertens. 2007;25:1105-1187. © 2007,
European Society of Cardiology and European Society of Hypertension/Lippincott
Williams & Wilkins.



In the 2009 reappraisal of the ESH-ESC guidelines, five combinations are recommended for priority use (Table I); the use of β-blockers plus CCBs is cited later on.8 In essence, there seems to be very little progress in the European recommendations between 20077 and 2009.8 Figure 4 summarizes the British Hypertension Society (BHS)/National Institute for Health and Clinical Excellence (NICE) recommendations of 2006.17 This simple “A/CD” algorithm is based on the fact that, on average, younger people (excluding black people of African origin) have higher renin levels and respond better (in terms of BP reduction) to “A” drugs (angiotensin-converting enzyme [ACE] inhibitors or ARBs), whereas older people or black people of African origin tend to have lower renin levels and respond better in terms of BP reduction to “C” or “D” drugs (CCBs or diuretics, respectively). The “A/CD” algorithm published in 2006 began life as the “AB/CD” algorithm that was included in the BHS guidelines of 2004, and in which β-blockers were recommended as first-line agents for younger patients.18


Table I
Table I. Priority antihypertensive drug combinations (European
guidance 2009).

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor
blocker; CCB, calcium channel blocker.



Figure 4
Figure 4. NICE/BHS 2006 recommendations.

Abbreviations: BHS, British Hypertension Society; NICE, National Institute for
Health and Clinical Excellence. A = ACE inhibitor (consider angiotensin-II receptor
antagonist if ACE inhibitor–intolerant); C = calcium channel blocker; D = thiazide
or thiazide-type diuretic.
After reference 17: National Collaborating Centre for Chronic Conditions. NICE
Clinical Guideline. London, UK: Royal College of Physicians; 2006. © 2006, National
Institute for Health and Clinical Excellence.



However, by 2006, the BHS along with NICE decided that β-blockers should be demoted to fourth-line therapy. The rationale for making that decision was based on four issues:
_ Meta-analyses, including one from the Cochrane Collaboration, showed that β-blockers are less effective in preventing major CV events than the other major drug classes.19
_ Increasing data confirmed that β-blockers exert an adverse effect on the incidence of new-onset diabetes.20
_ The ASCOT-BPLA trial showed that the combination of a β-blocker and a thiazide was inferior to the combination of a CCB and an ACE inhibitor in terms of preventing CV events.11
_ Cost-effectiveness analyses showed β-blockers to be the least cost-effective drug class.17

In 2011, following the usual rigorous systematic review approach, NICE modified its recommendations on drug sequencing as shown in Figure 5.21 The key changes are:
_ Diuretics are demoted to 3rd-line agents except where there is intolerance to CCBs or when there is a high risk of heart failure.
_ “A+C” is the only combination recommended in light of the results of the ACCOMPLISH trial) (see below).12
_ The “Ds” recommended are either indapamide or chlorthalidone. Thiazides are specifically no longer recommended.

Figure 5
Figure 5. NICE/BHS 2011 recommendations.

Abbreviations: BHS, British Hypertension Society; NICE, National Institute for
Health and Clinical Excellence. A = ACE inhibitor or angiotensin-II receptor antagonist;
C = calcium channel blocker; D = thiazide-type diuretic.
After reference 21: NICE Clinical Guideline 127; August 2011. Available from:
http://www.nice.org.uk/nicemedia/live/13561/56008/56008.pdf. © 2011, National
Institute for Health and Clinical Excellence.


Supportive trial evidence

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. However, this implication precludes the possibility that certain agents may exert “benefits beyond BP reduction.” A meta-analysis of the effects of ACE inhibitors on coronary heart disease (CHD) events in several RCTs suggests that the use of ACE inhibitors may be associated with CHD benefits beyond BP lowering.23 Similarly, an analysis of the impact of CCBs on stroke appears to suggest that CCBs generate benefits in terms of stroke prevention beyond BP effects.23

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. 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.

Very few trials other than ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial] have compared the CV effects of completely different pairs of antihypertensive agents. 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). 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 ASCOT trial

This trial included over 19 000 patients with hypertension and three or more other common CV risk factors, but without established CHD. It compared the effect of a standard antihypertensive regimen (β-blocker plus low-dose thiazide) versus a newer regimen (CCB plus ACE inhibitor).11 The newer regimen induced significantly lower average BPs than the standard regimen throughout the trial—although particularly in the first few months. 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. The trial was stopped early because of significant beneficial effects on allcause mortality associated with allocation to the amlodipine ± perindopril regimen. 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). However, it had the effect of generating insufficient power to allow evaluation of the primary end point effectively.

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. Indeed, only changes in pulse rate did not favor the newer regimen. These ASCOT results highlight the potential importance of differences between BP-lowering regimens other than those attributable to clinic BP differences. The 34% reduction in the rate of new-onset diabetes associated with the amlodipine ± perindopril regimen compared with atenolol ± thiazide is a very good example of what is probably a BP-independent difference between two pairs of antihypertensive agents.26 These ASCOT findings are compatible with several previous trials that showed diuretics and β-blockers to have adverse effects on the incidence of new-onset diabetes, whereas other more recent trials have suggested a modest protective effect associated with reninangiotensin system (RAS) blockade.27,28

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 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. 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. Based on those findings, the NICE 2011 guidelines recognized BP variability as an independent risk factor for CV events and recommended the best-available treatment for suppressing BP variability.21

Other trials of combinations of antihypertensive agents

The LIFE trial essentially compared β-blocker plus thiazide vs ARB plus thiazide.24 While achieving very similar effects on BP, the ARB-based regimen produced significantly better reductions in the composite CV primary end point. 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 relative benefits of ACE inhibitors and ARBs have been controversial since the launch of the first ARB, losartan. 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. The ARB was nonsignificantly inferior to the ACE inhibitor in terms of preventing CHD events (hazard ratio [HR], 1.07 [0.94- 1.22]) and the ARB was nonsignificantly superior to the ACE inhibitor in terms of stroke events (HR, 0.91 [0.79-1.05]). 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. 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.

Table II
Table II. Effects of primary end point and mortality in the main clinical trials from the last decade, conducted among hypertensive and/or
at-risk patients.

Abbreviation: ARB, angiotensin receptor blocker; CV, cardiovascular; HCTZ, hydrochlorothiazide, NS, nonsignificant; RRR, relative risk ratio; SR, sustained release.
After: Poulter N. Combination Therapy in Hypertension. © Nova Professional Media, UK, 2010.



Figure 6
Figure 6. ACCOMPLISH:
Effects on primary and
other end points.

Only the first event in an individual patient was counted in the analysis of the primary end point. 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.
Abbreviations: ACCOMPLISH, Avoiding Cardiovascular events through COMbination therapy
in Patients LIving with Systolic Hypertension; ACE, angiotensin-converting enzyme; CCB, calcium channel blocker; CI, confidence interval; HCTZ, hydrochlorothiazide; HR, hazard ratio.
After reference 12: Jamerson, et al. NEJM. 359:2417-2428. © 2008, Massachusetts
Medical Society.



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 obvious conclusion is that the combination of an ACE inhibitor and an ARB should not be used, except perhaps under exceptional circumstances such as those that prevailed in the CHARM trial (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (ie, heart failure).35 The idea that reducing proteinuria is of paramount importance is seriously challenged by the results of the ONTARGET trial. 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.

The HYVET trial (HYpertension in the Very Elderly Trial) investigated the effect of placebo-controlled BP lowering using indapamide and perindopril, in those ≥80 years of age.36 The trial was stopped early due to the benefits on all-cause mortality associated with active treatment. As a result of early closure of the trial, the primary end point of stroke was not significantly improved. 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 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 trial was particularly relevant to the 2006 BHS/NICE guidance because the two combinations of drugs being compared were those recommended in these guidelines.17 BP was reduced very effectively in both treatment arms and to a similar extent, but not at the cost of serious postural hypotension. 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). The beneficial effects of the “A + C” combination were almost identical among those with and without type 2 diabetes and in all other subgroups. 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 data supported by the metabolic data from the STAR trial (Study of Trandolapril/ verapamil SR And insulin Resistance)37 provide compelling support for the selection of the “A + C” combination in preference to any other.

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. 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. Various post hoc analyses implied that these differences in CV prevention were induced by the dif-ferential BP effects. In the largest trial of patients with type 2 diabetes—ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation)— over 11 000 patients who did not necessarily have raised BP at baseline, but had a high CV risk were randomized to receive either a combination of perindopril/indapamide or placebo.38 The resultant differential effect on BP of 5.6/2.2 mm Hg was associated with improved effects on CV mortality and thereby on all-cause mortality and on the primary end points of combined macro- and microvascular 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.

Summary and conclusions

The worsening threat of raised BP to global health,39,40 demands more assertive action. 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. For those who also need antihypertensive medication, enhanced efforts to lower BP must be made. Currently, while not being completely based on definitive RCT evidence, the 2011 NICE recommendations for drug sequencing are based on the best currently available evidence (Figure 5).21 The simplified rationale for why I use these drug choices is as follows:
_ Step 1. 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. For the reasons outlined above, “A” drugs for younger patients and CCBs for older patients are evidence-based choices. 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.
_ Step 2. 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.
_ Step 3. 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. 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.
_ Step 4. In ASCOT-BPLA, doxazosin gastrointestinal therapeutic system was used as the common third-line add-on agent for both of the BP-lowering treatment regimens.41 Based on data from over 11 000 patient-years of follow up, doxazosin was shown to lower BP by 12/7 mm Hg on average. 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. There were, however, small, but significant, beneficial effects on lipid profiles and the drug was well tolerated. Hence, doxazosin is a logical choice as a fourthline agent.

Table III
Table III. A summary comparison of the relative benefits of
monotherapy and combination therapy provided as two pills or a
single pill for the management of hypertension.

Abbreviation: BP, blood pressure.
After: Poulter N. Combination Therapy in Hypertension. © Nova Professional
Media, UK, 2010.



_ Step 5. In the ASCOT-BPLA trial, spironolactone was used as a fourth-line add-on agent by over 1400 patients.42 Among this large cohort of users—who by definition could be considered to have “resistant” hypertension—BP was reduced by 22/ 10 mm Hg on average. At the low doses used (average 42 mg/ day) the drug was well tolerated with only 6% stopping the drug due to side effects. I therefore use spironolactone as a fifth agent. 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.

It has to be admitted that, once the second agent has been selected, there are no robust RCT data to inform best drug sequencing. 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. Meanwhile, for those who do require two or more agents to control their BP to current targets, the increased use of single-pill combinations of drugs (often inaccurately called “fixed-dose combinations”) seems a logical step for the reasons summarized in Table III.43 _

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Keywords: cardiovascular end point; combination therapy; guideline; hypertension; management