Faster blood pressure control for earlier cardiovascular protection

by A. H. Gradman, USA

Temple University School of
Medicine, Philadelphia
Pennsylvania, USA

Initial combination therapy facilitates the achievement and maintenance of target blood pressure (BP). It accelerates the time-to-goal, increases mean BP reduction, and improves responder rates even in patients with stage 1 hypertension. It does so by blocking multiple pressor pathways, interfering with counter regulatory responses, and influencing the behavior of patients and physicians in ways which improve BP management. By reducing pill burden, patient adherence is improved when single-pill combinations are used. Three community-based studies involving ethnically diverse populations have evaluated end point reduction with initial combination versus initial monotherapy in patients with hypertension; all have reported better outcomes. In the one study that evaluated the interrelationship between BP reduction, goal attainment, and cardiovascular events, cardiovascular risk was reduced by 34%. Most of the risk reduction was attributable to earlier achievement of goal BP. It is noteworthy that 54% of patients in this study had stage 1 hypertension and would not generally be considered candidates for initial combination treatment according to current treatment guidelines. Selection of drugs for initial combination therapy is focused preferentially on agents with evidence of cardiovascular protection in long-term clinical trials. Development of simplified dosing regimens adapted for use in a general population of patients promotes the other primary goal of antihypertensive therapy today: the practical application of proven treatment strategies to the broad worldwide population of patients placed at elevated cardiovascular risk by treatable BP elevation.

The association between blood pressure (BP) elevation and cardiovascular risk is robust and consistent across disparate populations.1,2 In clinical trials evaluating antihypertensive agents, cardiovascular protection occurs primarily in response to BP reduction, and less in response to the specific pharmacologic properties of individual drugs or drug classes.3 Although the effectiveness of antihypertensive therapy is well-established, prophylactic treatment, as currently practiced, prevents only about a third of clinical events, including stroke and myocardial infarction, which are statistically related to BP elevation.4 This modest and incomplete degree of cardiovascular protection highlights the enormous potential offered by more effective methods of BP management and control. Combination therapy has been used since the early days of antihypertensive drug treatment,5 and ≈75% of hypertensive patients require more than one drug to achieve target BP.6

In general, combining drugs from pharmacologically complimentary classes is approximately five times more effective in lowering BP than increasing the dose of one drug.7 Although the need to use multiple drugs in many patients has always been recognized, “stepped-care” therapy became and remains the recommended paradigm for initiating treatment in Europe and the United States. Using this approach, treatment of patients is begun with a single drug and its dosage titrated upward in an attempt to achieve target BP. Only if goal BP cannot be achieved with monotherapy is a second drug added. In 2003, the seventh Joint National Committee (JNC 7) recommended the use of initial combination therapy in patients with baseline BP ≥20/10 mm Hg above goal.8 The current European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines suggest that initial combination therapy be considered “in patients at high risk or with markedly high baseline BP”.9 At present, however, ≈75% of stage 1 and 2 patients in the US begin treatment with monotherapy.10

There is accumulating evidence that routine initiation of a drug combination rather than a single agent may prove to be a surprisingly effective strategy for improving the long-term results of antihypertensive therapy. In this paper, the rationale and evidence supporting this evolution in the treatment of hypertension will be discussed.

The importance of early blood pressure control

The stepped-care paradigm is predicated on a measured approach to the management of hypertension. The underlying assumption is that hypertension is a chronic condition which develops over many years, poses little immediate risk to health, and can be treated by the gradual reduction of BP into the normal range. Depending upon baseline cardiovascular risk, the 2013 ESC/ESH guidelines recommend variably effective programs of “lifestyle modification”—weight loss, salt restriction, and increased exercise—which are continued for up to “several months” in patients with stage 1 hypertension and up to “several weeks” in those with stage 2 hypertension.9 This strategy usually delays the initiation of more effective drug treatment. Once drug therapy is begun, the time frame for achievement of BP control is not clearly specified, and it was not thought, until recently, to exert a major influence on the long-term results of therapy.

Recent studies call these assumptions into question. While the optimal time frame for achieving target BP has not been defined, there is evidence that prompt BP control confers advantages in terms of end point reduction. In the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial, which compared initial treatment with valsartan versus amlodipine, amlodipine- treated patients demonstrated 3-4 mm Hg greater BP reduction during the first 6 months of treatment and suffered fewer cardiovascular end points concurrently.11 BP response after only 1 month of treatment predicted events and survival, and achievement of BP ≤140/90 mm Hg during the first 6 months of treatment predicted fewer cardiovascular events over the 5-year duration of the study, regardless of treatment assignment. No difference was seen in end point occurrence after the first 6 months when BP differences between treatment groups narrowed, indicating it was the BP—not the drugs—which determined the early study results. These results suggest both short- and long-term benefits of early BP control.

Initial combination therapy

Effects on early BP reduction
An example of the effects of initial combination therapy on early BP control was shown in the ACCELERATE (Aliskiren and the Calcium ChannEL blockER amlodipine combination as an initial treatment strATEgy for hypertension control) study.12 Patients, the majority of whom were stage 2 (mean baseline BP ≈161/92 mm Hg), were randomized to begin treatment with amlodipine 5 mg, aliskiren 150 mg, or the combination of amlodipine 5 mg/aliskiren 150 mg. These doses were doubled after 8 weeks. At 16 weeks, the group assigned to the initial combination showed a clear advantage in terms of BP reduction (Figure 1, page 98).12 At this juncture, all patients were placed on the high-dose combination of amlodipine 10 mg/aliskiren 300 mg. Within 8 weeks, BP differences between treatment groups were reduced to 2/1 mm Hg. However, integrated over the first 6 months of therapy (by visual inspection), average BPs were considerably higher in the monotherapy groups. There was no significant difference in treatment-related adverse events.

More rapid BP control has also been observed in patients with stage 1 hypertension. Weir et al compared the time-to-goal in 4278 patients treated initially with several doses of valsartan, alone or in combination with hydrochlorothiazide (HCTZ) (12.5 mg or 25 mg), in a meta-analysis of 9 randomized trials including both stage 1 and 2 patients.13 Overall, the median time-to-goal was 8.1 weeks with valsartan 160 mg, 6.1 weeks with valsartan 320 mg, 2.6 weeks with valsartan 160 mg/HCTZ, and 2.1 weeks with valsartan 320 mg/HCTZ. In terms of time-specific prevalence of goal BP achievement, the magnitude of effect was actually greater in stage 1 patients (mean baseline BP 142-145/97 mm Hg) compared to the stage 2 subgroup. Whereas 72.0% and 74.7% of stage 1 patients receiving valsartan 160 mg and 320 mg, respectively, achieved their JNC-7 goal by week 8, these figures increased to 92% and 94% in those randomized to the valsartan 160 mg/HCTZ and 320 mg/HCTZ combinations (Figure 2).13 Median time-to-goal was reduced from 3.4 weeks in subjects receiving valsartan 320 mg to 1.6 weeks in those receiving valsartan 320 mg/HCTZ.

Figure 1. ACCELERATE: blood pressure
reduction in randomized treatment groups.
Patients had a doubling of their doses at 8 weeks.
At 16 weeks, patients on monotherapy advanced to
combination treatment.
*At 24 weeks, HCTZ was added if systolic blood pressure
>140 mm Hg or diastolic blood pressure >90 mm Hg.
Abbreviations: ACCELERATE, Aliskiren and the Calcium
ChannEL blockER amlodipine combination as an initial
treatment strATEgy for hypertension control;
HCTZ, hydrochlorothiazide.
Copied from reference 12: Brown et al. Lancet.
2011;377: 312-320. © 2011, Elsevier Ltd.

In a community practice setting, the STITCH (Simplified Treatment Intervention To Control Hypertension) study compared the effectiveness of a simple treatment algorithm using an initial fixed-dose combination (either angiotensin-converting enzyme [ACE] inhibitor/HCTZ or angiotensin receptor blocker [ARB]/HCTZ) to direct application of the Canadian Hypertension Education Program guidelines by practicing physicians.14 The proportion of patients who achieved BP target within 6 months was 65% in those initiated on the combination and 53% in patients who received guideline-based therapy.

Effects on long-term BP control
Egan et al examined the effects of initial combination therapy on BP control after ≈1 year in a cohort of >100 000 subjects participating in the US National Health and Nutrition Examination Survey.10 Patients receiving initial combinations were divided into those receiving single-pill combinations and “free” combinations, ie, two pills from different pharmacologic classes. During follow-up, 32% of patients started on monotherapy had additional agents added. Among all patients, 59% initiated on free combinations and monotherapy, and 68% begun on single-pill combinations were controlled after 396 days of treatment. The median time to 50% BP control for the single- pill combination was 195 days, compared to 269 days for the free-dose combinations and 280 days for monotherapy. Among the factors independently associated with worse BP control were the number of BP pills prescribed and evidence of therapeutic inertia (ie, failure to intensify treatment when indicated) on the part of the treating practicing physician.

Figure 2. Timeto-
goal blood
(<140/90 mm
Hg) in patients
with stage 1
Abbreviations: BP,
blood pressure;
HCTZ, hydrochlorothiazide;
Val, valsartan.
Copied from reference
13: Weir et al.
Am J Hypertens.
© 2007, American
Journal of Hypertension,

The results of this large study illustrate the importance of examining real-world practice data in addition to the results of clinical trials. “Free” drug combinations are no less effective than fixed-dose combinations, provided the drugs and doses selected are those which produce additive BP reduction. In patients initiated on monotherapy, treating physicians had the option of adding additional drugs as needed and did so in 32% of patients. As illustrated in ACCELERATE, where all patients begun on monotherapy were uptitrated to combination treatment, little long-term difference in achieved BP would be expected if the principles of stepped-care treatment were followed consistently. What then accounts for the superior long term BP control in patients initiated on single-pill combinations?

Although pharmacologic factors may be important, the causes of superior BP control relate to the human aspects of medical care. BP reduction requires patient adherence, which is inversely related to the number of pills prescribed.15-17 In this study, the use of “free” combinations, with a higher pill burden, predicted worse BP control. Therapeutic decisions, in the community practice setting, represent the judgment of individual physicians, who differ in their knowledge base and time available to follow optimal treatment patterns. Single-pill combinations simplify treatment for patients. Their use also takes much of the uncertainty out of decision-making for practitioners by providing marketed combinations that have undergone rigorous testing and have been found to be safe and effective.

The BP data are consistent that initial combination therapy facilitates both the achievement and maintenance of BP control. Since BP reduction is the primary determinant of end point reduction, it would be predicted on the basis of these data that initial combination therapy would improve long-term outcomes.

Effects on cardiovascular end points
Three community-based studies involving ethnically diverse populations have evaluated initial combination versus initial monotherapy on cardiovascular events; all have reported improved outcomes. Corrao et al conducted a population-based case-control study involving >40 000 patients comparing newly treated Italian patients who did and did not experience a subsequent cardiovascular event.18 Patients initiated on a combination had an 11% risk reduction, including both cardiac and cerebrovascular events, compared to those initiated on monotherapy. When patients maintained on either monotherapy or combination treatment for the entire treatment period were compared, initial combination therapy was associated with a 26% risk reduction. Patients begun on monotherapy and later switched to a combination had outcomes indistinguishable from the monotherapy cohort. The authors reasoned that the protective effects associated with initial combination treatment might reflect better BP reduction and/or direct pharmacologic effects resulting from the simultaneous use of agents that block multiple pharmacologic pathways.

Gradman et al assessed the impact of initial versus delayed combination therapy on the risk of cardiovascular events, and evaluated the interrelationship between BP reduction, goal attainment, and cardiovascular risk.19 Using electronic medical records from a large integrated health-care delivery network in the United States, 1762 adult patients initiating combination therapy (either single-pill or “free” combinations) were identified and compared to a similar population matched 1:1 according to baseline clinical characteristics. Mean baseline BP was 150/84 mm Hg and 54% had stage 1 hypertension. Initial treatment with a drug combination was associated with a 34% risk reduction for cardiovascular events (myocardial infarction, stroke/transient ischemic attack, hospitalization for heart failure) or death, relative to patients initiated on monotherapy and subsequently switched to a combination by their physician (P=0.0008) (Figure 3, page 100).19

The cumulative effect of initial versus delayed combination therapy on target BP achievement is shown in Figure 4 (page 100).19 There was early separation of the Kaplan-Meier curves and, after 6 months, 40.3% and 32.6% of patients with initial versus delayed combination treatment reached target BP. During follow-up, the overall proportion of patients achieving target BP was consistently higher in the combination therapy cohort, resulting in a shorter median time-to-goal BP achievement (9.7 versus 11.9 months; log-rank P=0.004). After ≈30 months, control rates in the two treatment groups converged, reaching ≈80%. These findings are consistent with ACCELERATE and other studies, which document a lag time in BP goal attainment when patients initiated on monotherapy and later uptitrated to combination treatment are compared to those begun on a combination. The length of this lag time is variable and highly dependent upon the time course of drug titration. In this study, uptitration at the discretion of the individual practicing physicians occurred an average of 13.5 months after treatment initiation.

Achieving target BP at any time was associated with a significant risk reduction of 23% in cardiovascular events or death. Using a second statistical model in which each BP assessment was used to update the systolic BP stage, the results showed that systolic BP >160 mm Hg at the last reading was associated with a 2.2-fold increased risk of developing a cardiovascular event or death compared to a systolic BP reading of 120-139 mm Hg (P<0.0001). In this study, which documented improved BP control for >2 years in the initial combination therapy cohort, most of the end point reduction was attributable to BP reduction. The residual risk reduction of 16% associated with initial combination therapy approached, but did not reach, statistical significance (P=0.09). It is unclear whether this effect is due to the pharmacologic effects of drug combinations or to unmeasured effects on BP, which would be clarified through the use of more sophisticated methods of BP measurement, such as 24-hour ambulatory BP monitoring.

Figure 3. Initial
combination versus
add-on therapy: incidence
of cardiovascular
end points.
*Number of patients
with an event per
100-person years.
Abbreviations: CV, cardiovascular;
HF, heart failure;
MI, myocardial infarction;
TIA, transient ischemic
Adapted from reference
19: Gradman et al. Hypertension.
© 2013, American Heart
Association, Inc.

This study directly compared patients who received initial combination therapy to those receiving delayed combination therapy, not permanent monotherapy. It therefore mimics a comparison of initial combination therapy to stepped-care treatment in individuals who will require >1 drug to control BP. It documents an advantage of initial usage of combination therapy as opposed to its eventual usage in a population the majority of whom had stage 1 hypertension. It also documents the value of reaching BP targets earlier rather than later, although it does not clarify the optimal time frame for achieving BP control. The results are consistent with Corrao’s study, in that outcomes were superior in patients initiating combination therapy compared to those begun on monotherapy and switched to combination treatment. The study also documented a 9% reduction in the use of health-care resources, including urgent care and outpatient services, associated with initial combination treatment.

Figure 4. Estimates of patients achieving
target BP: initial combination versus add-on
Abbreviation: BP, blood pressure.
Modifie from reference 19: Gradman et al. Hypertension.
2013;61:309-318. © 2013, American Heart
Association, Inc.

In a community-based Chinese study, Yu reported reduction in short-term stroke incidence when 4926 hypertensive patients initiating treatment with a drug combination were compared to 32 682 patients initiating treatment with monotherapy.20 Mean baseline BP was 148/90 mm Hg in the initial combination therapy cohort and statistically greater than the 146/89 mm Hg seen in those who received initial monotherapy. Although there were no differences in BP control rates at 6 months or at subsequent time intervals reported in the manuscript, the authors state that “the target BP control rate was significantly higher in the combination group than in the monotherapy group before the 6th follow-up month” (data not included). Additionally, the mean reduction in systolic BP at 6 months was greater in the combination therapy group (13.8 mm Hg versus 12.5 mm Hg; P=0.0003). The 6-month incidence of stroke in the combination therapy cohort was 36% lower than in patients who received monotherapy. No significant group differences were observed at 12, 24, or 42 months. The authors interpreted the results of the study as unrelated to BP control. A more likely explanation is that, as in the VALUE trial, a transient early advantage in BP reduction translated into an early reduction in stroke incidence.

Choice of drugs
Although a thorough discussion of this complex topic is beyond the scope of this paper, several points can be made regarding agents to be included in combinations targeted for first-line use. It is important to choose drugs which: (i) produce additive BP reduction; (ii) improve outcomes in long-term clinical trials; and (iii) possess a favorable safety and tolerability profile when combined. After consideration of these factors, combinations of ACE inhibitors and ARBs with diuretics or calcium channel blockers (CCBs) were designated as preferred combinations in the 2010 American Society of Hypertension position paper on combination therapy.6 Some authorities recommend ACE inhibitors in preference to ARBs, particularly in patients at high risk for coronary events, because of evidence of non-BP–related cardioprotection with these agents.21 Single-pill combinations are preferred as they reduce pill burden and improve adherence.16,17

The ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) study was the only major hypertension trial to utilize first-line combination therapy.22 The study tested whether initial therapy with a fixed-dose combination of an ACE inhibitor and a CCB differs from that with a fixed-dose combination of an ACE inhibitor and a diuretic with regard to clinical outcomes in high-risk hypertensive patients. Despite comparable BP reduction, the ACE inhibitor/CCB (benazepril/amlodipine) combination reduced the combined end point of cardiovascular death, myocardial infarction, and stroke by 20% compared to the ACE inhibitor/diuretic combination. Of note, 60% of patients were diabetic, and a large percentage had evidence of ischemic heart disease. There are few data from other sources to distinguish between preferred combinations. In the community- based end point studies discussed above, the long term effects of the various combinations used as initial treatment were not compared.

Selection of doses for first-line administration in individual patients involves a careful evaluation of efficacy, safety, and tolerability. Baseline BP is of particular importance. In stage 2 patients, for whom initial combination therapy is most often recommended, higher initial doses are well-tolerated and appropriate as the primary goal is earlier BP control. In the ACCELERATE study, patients in the initial combination therapy arm received both of the component drugs at the same dose given to patients in the monotherapy arms. After 8 weeks of treatment, BP reduction was a robust 21.5/10 mm Hg. This dosing strategy and a similar magnitude of BP reduction has been observed in other studies with combinations of renin angiotensin- aldosterone system blockers and CCBs.23 This dosing strategy is not optimal for all patients. Some stage 2 patients are frail, elderly, or suffer from other conditions that predispose to complications associated with marked short term BP reduction. In these patients and in those with stage 1 hypertension in whom baseline BP is not markedly elevated, there is a need for less potent initial treatment. Uptitration of low initial combination doses of perindopril (2 mg) and indapamide (0.625 mg) was used in the STRATHE (STRAtegies of Treatment in Hypertension: Evaluation) study.24 This treatment strategy resulted in higher rates of goal BP attainment compared to patients treated with the stepped-care approach or “sequential monotherapy,” in which up to three drugs were administered sequentially in an attempt to achieve BP control.

The need to develop simple, effective strategies for rapidly achieving target BP has led to new formulations of perindopril and amlodipine, two drugs that have reported excellent cardiovascular end point reduction in previous studies.11,22,25 The new treatment strategy is based upon a range of doses, which have been specifically adapted for use as first-line combination therapy and which permit combination therapy to be initiated in all or almost all newly diagnosed hypertensive patients.26 Three perindopril/amlodipine formulations will be available: 3.5/2.5 mg, 7.0/5.0 mg, and 14/10 mg. The starting dose has been shown to be more potent than monotherapy with valsartan (80 mg), irbesartan (150 mg), or perindopril (5 mg), with a comparable safety profile.27 Dosing involves doubling the previous dose of both agents with each titration. Use of this strategy with the addition of indapamide 1.5 mg SR if needed as an additional step resulted in goal BP (<140/90 mm Hg) achievement in 86% of 881 patients, 80% of whom had stage 2 and 20% stage 1 hypertension. This was higher than goal BP attainment using valsartan and amlodipine administered via a stepped-care approach.


The challenge in antihypertensive therapy today is to realize its potential, to apply proven therapeutic approaches to a much greater fraction of the worldwide hypertensive population. This requires the prompt achievement and maintenance of target BP in individual patients. It is apparent that that time-to-goal matters and should be reduced to the shortest time compatible with optimal safety and tolerability. It is clear that long-term BP control is necessary to provide continuing cardiovascular protection, and that the simplicity and tolerability of the treatment regimen are critical considerations in achieving these goals. Using appropriate agents and dosing regimens, the default use of initial combination therapy advances these objectives and represents an important evolutionary development in the treatment of hypertension.■

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Keywords: hypertension; drug treatment; combination therapy; cardiovascular protection; time to goal