Analysis of Recent Papers in Hypertension Initial Combination Therapy Provides More Prompt Blood Pressure Control and Reduces Cardiovascular Events But Remains Underutilized

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), initial combination therapy, using either 2 separate pills or fixed‐dose combinations, is indicated in patients whose blood pressure (BP) is at least 20/10 mm Hg above goal.1 The International Society on Hypertension in Blacks (ISHIB) recommends initial combination therapy in black patients whose BP is at least 15/10 mm Hg above goal.2 Yet, despite these and other guideline recommendations, most patients with elevated BP continue to be started on single‐agent therapy with plans to increase treatment if BP is not controlled. One reason clinicians may be reluctant to initiate combination therapy is a lack of clinical trial and/or real‐world evidence demonstrating improved outcomes with initial combination therapy.

Summary of Results and Implications

Using electronic medical records and retrospective case‐control methodology, Gradman and colleagues3 evaluated the effects of initial vs delayed use of combination therapy on BP control and the incidence of cardiovascular (CV) events. In all, 1762 adult patients who were started on combination therapy were retrospectively matched 1:1 utilizing a propensity score with a similar number of patients who were started on single‐agent therapy and later switched to combination therapy. All decisions concerning initial strategy and choice of medications were at the discretion of the treating clinician.

In this analysis, use of initial combination therapy was associated with better BP control at 6 months (40.3% vs 32.6%) and a statistically significant 34% reduction in the risk of CV events or death over the next 2 years. Achieving target BP was associated with a statistically significant 23% reduction in the risk of CV events or death and appeared to be responsible for the improved outcomes seen with initial combination therapy.

The control group for this study was made up of patients who started with monotherapy and subsequently switched to combination therapy. The median time until combination therapy was started in these patients was 13.5 months. JNC 7 and other guidelines and scientific statements suggest that pharmacologic therapy be uptitrated every 2 to 4 weeks, depending on the stage of hypertension, until BP control is achieved. Accordingly, whether initial single‐agent therapy, followed by prompt uptitration to combination therapy, is equally effective as initial combination therapy cannot be ascertained from this analysis. In this study, use of the ‘sequential monotherapy’ approach, apparently utilized in at least 40% of the cohort, may have accounted for much of the delay in uptitrating to combination antihypertensive therapy. Furthermore, this study implies that the main reason for using initial combination therapy is to avoid therapeutic inertia, which was the most likely reason for the delay in adding on additional drug therapy in the monotherapy group.

The primary findings of this paper are consistent with a growing literature in support of initiating combination therapy in the treatment of hypertension. Retrospective analysis of the Valsartan Antihypertensive Long‐Term Use Evaluation (VALUE) trial4 demonstrated that early BP control at 6 months translated into a significant reduction in long‐term CV risk regardless of drug assignment. Additionally, in another analysis of electronic medical records, Egan and colleagues5 found that uncontrolled hypertensive patients initiated on combination antihypertensive therapy, particularly single‐pill fixed‐dose combinations, were more likely to obtain BP control after 1 year compared with patients initiated on monotherapy. Moreover, the median time for 50% of patients to achieve BP control occurred 85 days sooner in the initial combination strategy. Finally, in an Italian population‐based, nested case‐control study from Corrao and colleagues,6 patients started on combination therapy showed an 11% reduction in CV events when followed‐up compared with those started on monotherapy.

In each of these studies, utilization of initial combination therapy was low, even in patients who met criteria established by JNC 7. One reason clinicians have been slow to adopt initial combination therapy is a lack of clear evidence demonstrating its favorable tolerability compared with initial monotherapy. In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) study,7 11,506 patients were started on initial combination therapy (either benazepril‐HCTZ or benazepril‐amlodipine). Initial combination therapy was well tolerated, with only 8.8% of patients discontinuing active treatment during the first 90 days of treatment. However, as more than 97% of patients had a history of taking antihypertensive therapy before the study began, this may not represent a good assessment of initial combination therapy in drug‐naive patients.

The evidence to date certainly supports the concept that initial combination therapy is well tolerated, decreases the risk of therapeutic inertia, and is associated with better BP control and a favorable reduction in CV events. While the currently available reports are consistent with these ideals, it is critically important to remember that the entirety of the data are retrospective, nonrandomized, and subject to bias. Additionally, there are very few data on the use of initial combination therapy in older individuals, those with significant CV disease, or those with advanced renal disease, all of whom may be more susceptible to the potential adverse effects of this strategy. As such, while it seems reasonable to recommend that clinicians use initial combination therapy in nonelderly hypertensive patients without CV or renal disease who most often require >1 antihypertensive medication to reach goal, a stronger endorsement for this recommendation awaits the evidence required from a prospective randomized clinical trial.

Study Details and Further Commentary

Methods

This study utilized electronic medical record data from a large integrated delivery network from the years 2005 to 2009. Adult patients with uncontrolled BP and newly initiated antihypertensive therapy were identified and stratified into the following mutually exclusive groups: (1) patients initiating combination therapy for at least 60 days (combination group) and those initiating monotherapy with the subsequent addition of a second agent after at least 60 days (add‐on group). Combination therapy included patients taking either single pill fixed‐dose combinations or free combinations of ≥2 pills. Patients with a history of CV events were excluded.

The study endpoints were incidence of CV event or death, time to BP goal attainment, and rates of healthcare resource utilization. Time to BP goal attainment was defined as the time from treatment initiation to the first of 2 consecutive target BP readings of <140/90 mm Hg or <130/80 mm Hg for those with chronic kidney disease or diabetes, consistent with JNC 7. CV events were considered as a composite of acute myocardial infarction (MI), stroke/transient ischemic attack (TIA), hospitalization for heart failure, and all‐cause death, all extracted from the medical record based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes. The additional inclusion of healthcare resource utilization is a novel and important aspect of this analysis. It was ascertained by chart review and stratified into 3 mutually exclusive components: urgent or emergent care visits, outpatients services, and other services. Whether a complete picture of healthcare utilization can be determined in this type of retrospective analysis is uncertain.

In order to minimize the potential impact of confounding factors in this retrospective, nonrandomized analysis, propensity score matching was used to assemble a population in which the combination and add‐on therapy groups would be demographically and clinically similar. While the investigators took great pains to account for as many seemingly important demographic and clinical factors as possible, the fact remains that unknown confounding factors may have influenced the clinicians' choice as to why they chose to use initial combination therapy or monotherapy.

Results

Overall, nearly 10,000 patients with uncontrolled hypertension who initiated antihypertensive drug therapy were identified in the database. Of these, the 4696 patients who started on monotherapy but never changed to combination therapy were not included in the analysis. Of the remaining patients, 1808 treated with initial combination therapy and 3309 treated with initial monotherapy and later switched to combination therapy were identified. From this group, 1762 patients from the combination cohort were matched based on propensity scoring with an equal number of patients from the add‐on cohort to form the study population.

The groups appeared to be well matched in terms of age, sex, baseline BP, concomitant medications, and other health conditions. Sixty‐seven percent of patients in each cohort had stage 1 hypertension and 33% had stage 2 hypertension. The mean age was about 60 years and only 9% of patients had a baseline estimated glomerular filtration rate <60 mL/min. In the add‐on cohort, the second medication was not prescribed until a median of 13.5 months after treatment initiation with monotherapy.

BP Control

During the course of follow‐up, the proportion of patients achieving target BP was consistently higher in the initial combination therapy group as compared with the add‐on group (27.9% vs 19.6% at 3 months, 40.3% vs 32.6% at 6 months, and 56.1% vs 50.6% at 12 months). Median time to achieve BP control was 9.7 months in the combination group and 11.9 months in the add‐on group. While the low control rates and extended time to BP control may be evident of a cohort exhibiting a significant amount of therapeutic inertia, it may also be the result of the relatively rigorous definition of BP control that required 2 consecutive office readings at goal.

Incidence of CV Events or Death

The incidence rate for CV events or death was lower in the initial combination therapy group. The effect was more prominent in patients without diabetes or CKD at baseline (all patients: incidence rate ratio [IRR], 0.66 [95% confidence interval (CI), 0.52–0.84]; P=.0008; excluding patients with diabetes or CKD: IRR, 0.45 [95% CI, 0.29–0.69]). Each component of the primary endpoint (MI, stroke/TIA, heart failure hospitalization, and death) was lower with initial combination therapy, although the effect on stroke/TIA did not reach statistical significance.

Relationship Between BP Control and CV Events/Death

Further analysis demonstrated that BP goal attainment was associated with a reduced risk for CV events or death regardless of initial therapy. This finding was consistent in the cohort as a whole as well as in patients with a history of diabetes or CKD on entry. Cox proportional hazard models suggested that the majority of the CV benefit demonstrated with initial combination therapy was driven by improved BP control, a not surprising result. However, this analysis also suggested that 16% of the effect on CV events/death may be independent of BP. Explanation of this non‐BP effect of initial combination therapy is purely speculative, but does suggest the possibility of an unmeasured confounding variable.

Interestingly, an achieved diastolic BP <80 mm Hg was independently associated with an increased risk for CV events or death when compared with a DBP of 80 to 89 mm Hg (hazard ratio, 1.88 [95% CI, 1.48–2.4]; P<.0001). While this finding demonstrates association rather than causation, it supports previous studies suggesting a J‐shaped curve exists (achieving lower diastolic BP in treated hypertensive patients is associated with an increase in CV risk).

Healthcare Resource Utilization

Patients in the combination therapy cohort had a significant overall reduction of 9% in the utilization of all medical services compared with the add‐on cohort (IRR, 0.91 [95% CI, 0.90–0.92]; P<.001). In addition, each individual component of healthcare utilization, including emergency department/urgent care visits, outpatient services, and other services, was significantly reduced in the initial combination therapy group. While this finding suggests that initial combination therapy may be cost‐effective, medication costs were not taken into account and no formal analysis of cost was performed. Additionally, these particular endpoints may be particularly prone to unrecognized confounding variables, whereby patients who would be more likely to be prescribed initial combination therapy may be less likely to utilize many of these services.

Perspective and Final Thoughts

Despite recommendations from JNC 7 and other organizations, use of initial combination therapy in the treatment of hypertension remains relatively uncommon, even in patients who have stage 2 hypertension. In this real‐world retrospective, propensity score–matched analysis, initial combination antihypertensive therapy was associated with a 34% reduction in the risk of CV events and death compared with those started on monotherapy. The reduction in CV events and death was driven mostly by more prompt and effective BP control.

Certainly, results derived from this type of study design cannot be considered definitive. In a perfect world, we would call for an immediate large‐scale, CV endpoint‐driven, prospective, randomized trial that compared initial combination therapy with initial monotherapy (and more prompt) uptitration to combination therapy in the setting of poorly controlled BP. However, it is unlikely that we will see such a trial initiated in the near future, and even if it were, it would be many years before results were available. In the absence of prospective clinical trials, we do not advise therapeutic nihilism, rather a careful consideration of the available data. When looked at in total, the available data suggest that initial combination therapy should be more frequently utilized, at least in nonelderly patients without advanced CV or renal disease, who are likely to require >1 antihypertensive medication to reach BP goal. For clinicians who continue to use initial single‐agent therapy, every effort should be made to avoid therapeutic inertia and more promptly add another drug or switch to fixed‐dose combination therapy for the majority of patients whose BP will not be controlled with just one drug.