Initial Combination Therapy Reduces the Risk of Cardiovascular Events in Hypertensive PatientsNovelty and Significance
A Matched Cohort Study
This study evaluated the effects of initial versus delayed treatment with a drug combination on blood pressure (BP) control and the risk of cardiovascular (CV) events in hypertensive patients. Clinical trials suggest that the time to BP control is an important determinant of long-term outcomes, but real-world evidence is scarce. Using electronic medical charts (2005–2009), we retrospectively analyzed 1762 adult patients with BP elevation initiating combination therapy matched 1:1 with similar patients initiating monotherapy and later switched to combination therapy. Incidence rate ratios of CV events (myocardial infarction, stroke/transient ischemic attack, or hospitalization for heart failure) or all-cause death and Kaplan-Meier analyses of time to BP control were compared between cohorts. Hazard ratios indicating the effects of initial treatment on CV events and BP control were estimated using time-varying Cox proportional hazard models. Initial combination therapy was associated with a significant reduction in the risk of CV events or death (incidence rate ratio, 0.66 [95% confidence interval, 0.52–0.84]; P=0.0008). After 6 months of therapy, 40.3% and 32.6% of patients with initial versus delayed combination treatment reached BP control, respectively. Achieving target BP was associated with a statistically significant risk reduction of 23% for CV events or death (hazard ratio, 0.77 [95% confidence interval, 0.61–0.96]; P=0.0223); the residual effect of initial combination therapy did not reach statistical significance (hazard ratio, 0.84 [95% confidence interval, 0.68–1.03]; P=0.0935). Initial combination therapy was associated with a significant risk reduction of cardiovascular events. More rapid achievement of target BP was found to be the main contributor to the estimated risk reduction.
- combination therapy
- blood pressure goal attainment
- cardiovascular events
- matched cohort study
- healthcare resource utilization
Cardiovascular (CV) disease is the leading cause of mortality in the United States, accounting for 1.0 of every 2.9 deaths in 2007.1 Hypertension is one of the most important risk factors for CV disease,2 with ≈54% of stroke and 47% of ischemic heart disease worldwide attributable to high blood pressure (BP) according to a 2008 International Society of Hypertension report.3 It has been estimated that each increase of 20 mm Hg in systolic BP (SBP) or 10 mm Hg in diastolic BP (DBP) doubles the risk of CV death in individuals aged 40 to 69 years.4
Hypertension treatment guidelines recommend lowering BP to <140/90 mm Hg or <130/80 mm Hg for patients with diabetes mellitus, chronic kidney disease (CKD), or other high risk conditions.5 In the United States, only ≈50% of patients with hypertension achieve BP <140/90 mm Hg.6 Among patients requiring BP reduction of ≥20/10 mm Hg, initial combination therapy is recommended.5 Individual physician practice varies, however, and the majority of patients including those with stage 2 hypertension receive initial monotherapy.7,8
Clinical trials and observational studies indicate that initiating treatment with a 2-drug combination results in more rapid achievement of target BP compared with initial monotherapy.9–12 Retrospective analysis of data from the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial comparing valsartan- and amlodipine-based antihypertensive treatment reported that early BP control translated into a significant reduction in 5-year CV risk regardless of drug assignment.13 Definitive studies have not been conducted, however, and the most advantageous time frame for achieving target BP in clinical practice has never been defined. In this study, a retrospective analysis of electronic medical charts was performed to evaluate the impact of initial combination therapy on CV event rates and its relationship to BP reduction and goal attainment, as well as the impact on healthcare resource use in a real-world, practice-based setting.
Electronic medical chart data between January 2005 and November 2009 from a large integrated delivery network of physicians and hospitals, all sharing a single laboratory, were used to conduct the analysis. The database is de-identified and is in compliance with the Health Insurance Portability and Accountability Act of 1996 to preserve patient anonymity and confidentiality. Data elements used in the present analysis included patient demographics, inpatient and outpatient medical services, prescriptions, laboratory results, and clinical measures such as BP, height and weight, and smoking status.
Adult patients with uncontrolled BP, newly initiated on antihypertensive therapy including angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor blockers, or diuretics, given as a single agent (monotherapy) or a drug combination, were identified. The study population was stratified into the following mutually exclusive exposure groups: patients initiating combination therapy for ≥60 days (combination therapy cohort) and patients initiating monotherapy for ≥60 days with the subsequent addition of a second agent (add-on cohort). Combination therapy included a single-pill (fixed-dose) combination or dual free combination of angiotensin-converting enzyme inhibitor and calcium channel blocker, angiotensin-converting enzyme inhibitor and diuretic, angiotensin II receptor blocker and calcium channel blocker, or angiotensin II receptor blocker and diuretic. A baseline period of 90 days before treatment initiation was imposed to evaluate baseline characteristics and to ascertain that patients had uncontrolled BP, defined as ≥1 BP reading ≥140/90 mm Hg or ≥130/80 mm Hg for patients with diabetes mellitus or CKD.
We excluded from the analysis patients with history of CV event at baseline (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes: 402.9x, 410.xx, 411.0x, 411.1x, 411.81, 411.89, 413.xx, 414.0x, 414.1x, 414.8x, 414.9x, 427.0x, 427.1x, 427.3x, 427.4x, 427.5x, 427.8x, 428.xx, 429.3x, and 430.xx-437.xx) to focus results on incident cases of CV events. Each patient’s follow-up period spanned from their first antihypertensive medication through the earliest of either treatment discontinuation or end of data availability.
Study End Points
The study end points were risk of CV events or all-cause death, time to BP goal attainment, and rates of healthcare resource use. Time to BP goal attainment was defined as the time from treatment initiation to the first of 2 consecutive target BP readings <140/90 mm Hg or <130/80 mm Hg for patients with diabetes mellitus or CKD. The risk of CV events or death was evaluated using the composite end point of acute myocardial infarction (ICD-9-CM code: 410.xx), stroke/transient ischemic attack (TIA) (ICD-9-CM codes: 430.xx-435.xx), hospitalization for heart failure (ICD-9-CM code: 428.xx), and all-cause death. Results were also reported for each CV end point separately. Healthcare resource use was also calculated for both cohorts over the follow-up period and stratified into 3 mutually exclusive components: (1) urgent care services, which included hospitalizations and emergency room visits; (2) outpatient services; and (3) other services.
To minimize the potential impact of confounding factors, we used propensity score matching to assemble a population in which those with initial and delayed treatment with a drug combination would be demographically and clinically similar. The propensity score for the receipt of combination therapy at treatment initiation is defined as the conditional probability of initiating treatment with a drug combination given a patient’s measured characteristics. Propensity scores were calculated separately for each patient using a nonparsimonious multivariate logistic regression model, incorporating the following baseline characteristics: age, sex, race, year of treatment initiation, smoking status, concomitant medications (eg, antihyperlipidemics, antidiabetics, and nonsteroidal anti-inflammatory drugs), comorbidities (eg, Charlson comorbidity index, anemia, CKD, diabetes, and obesity), clinical measures (ie, body mass index, BP, triglyceride, fasting plasma glucose, and cholesterol level), and healthcare resource use. Patients initiating combination therapy were matched 1:1 with add-on patients based on their propensity score using a caliper of 5% and their BP stage.
Descriptive statistics were generated to summarize the baseline characteristics of the studied population. Frequency counts and percentages were used to summarize categorical variables, whereas means and SDs were used for continuous variables. Statistical differences between matched cohorts were assessed using the McNemar test (categorical variables) and paired 2-sided Student t test (continuous variables). Kaplan-Meier analyses and log-rank tests were performed to compare the time to BP goal attainment among the 2 exposure groups and patients who developed a CV event during the follow-up period versus those who did not, irrespective of exposure groups.
To assess the impact of initiating combination therapy on CV end points and healthcare resource use, incidence rates of events were calculated and compared between cohorts using incidence rate ratios (IRRs). Incidence rate for each CV end point was calculated as the number of patients with an event divided by the number of patient-years of observation, censored at the time of the first event, whereas incidence rate for each resource use component was calculated as the number of events divided by the number of patient-years of observation. Statistical differences between matched cohorts, as well as 95% confidence intervals (CIs), were evaluated using conditional Poisson regression models accounting for matched pairs. A sensitivity analysis excluding patients with diabetes mellitus or CKD at baseline was also conducted.
In addition to univariate analyses, time-dependent multivariate Cox proportional hazard models were estimated to assess the interrelationship between exposure groups, BP reduction and goal attainment, and the risk of developing a CV event. Three models were fitted to assess the risk of CV events or all-cause death in which a binary variable controlling for the exposure group was included and patient BP status was inserted as a time-varying explanatory variable. The time-dependent BP covariate was defined as follows: (1; model 1) a binary variable indicating whether or not a patient reached target BP during follow-up; (2; model 2) a categorical variable indicating the SBP and DBP stage at each BP reading; and (3; model 3) a continuous variable indicating the value of the SBP and DBP at each BP reading.
Statistical significance was assessed with a 2-sided test at α-level ≤0.05. All of the statistical analyses were conducted using SAS 9.2 (SAS Institute, Inc, Cary, NC).
Baseline Characteristics of the Matched Cohorts
A total of 1808 patients initiating combination therapy and 3309 initiating monotherapy and subsequently switched to combination therapy were identified. Among them, 1762 patients from the combination therapy cohort (97.5%) were matched to an equal number of patients from the add-on cohort to form the study population. Table 1 presents the baseline characteristics of the matched cohorts. Overall, both exposure groups were well matched in terms of age, sex, baseline BP level and BP stage, concomitant medications, comorbidities, and other health risk factors. Sixty-seven percent of patients in each cohort had stage 1 and 33% stage 2 hypertension at baseline. In the add-on cohort, the combination therapy was prescribed at a median of 13.5 months after treatment initiation.
Relationship Between Exposure Group and Risk of CV Events
Incidence rates for CV events are presented in Figure 1. Initiating combination therapy was associated with a significant risk reduction for CV events or all-cause death compared with delayed treatment with a drug combination (all patients: IRR, 0.66 [95% CI, 0.52–0.84], P=0.0008; excluding patients with diabetes mellitus or CKD: IRR, 0.45 [95% CI, 0.29–0.69], P=0.0002). Of note, when evaluating each CV end point separately, the risk of developing myocardial infarction, stroke/TIA, or hospitalization for heart failure was consistently lower for the combination therapy cohort compared with the add-on cohort (not reaching statistical significance for stroke/TIA when analyzing all of the patients and hospitalization for heart failure when analyzing the subset of patients without diabetes mellitus or CKD.
Relationship Between Exposure Group and BP Goal Attainment
Kaplan-Meier estimates of target BP achievement for each exposure group are shown in Figure 2. During follow-up, the overall proportion of patients achieving target BP was consistently higher in the combination therapy cohort compared with the add-on cohort (3 months, 27.9% versus 19.6%; 6 months, 40.3% versus 32.6%; 12 months, 56.1% versus 50.6%), resulting in significantly shorter median time to achievement of target BP (9.7 versus 11.9 months; log-rank P=0.0040; Figure 2A).
Similarly, when excluding patients with diabetes mellitus or CKD at baseline, initial versus delayed treatment with combination therapy was associated with significantly higher rates of BP goal achievement (3 months, 38.2% versus 23.7%; 6 months, 49.7% versus 39.6%; 12 months, 66.5% versus 60.3%). Half of the patients in the combination therapy group reached BP goal attainment by 6.0 months, whereas patients in the add-on group required 8.3 months to achieve the same result (log-rank P=0.0047; Figure 2B).
Relationship Between BP Goal Attainment and Risk of CV Events
Figure 3 presents the Kaplan-Meier estimates of target BP achievement for patients who developed a CV event during the study versus those who did not among all of the patients and the subset of patients without diabetes mellitus or CKD at baseline. The results of this analysis demonstrated that BP goal attainment was associated with reduced risk of CV events regardless of the diabetes mellitus/CKD status at baseline. More specifically, a larger proportion of patients achieving target BP was found among patients without a CV event relative to patients with a CV event during the follow-up period (all patients: 3 months, 24.1% versus 20.8%; 6 months, 37.0% versus 30.7%; 12 months, 54.0% versus 46.0%; excluding patients with diabetes mellitus or CKD: 3 months, 31.5% versus 24.8%; 6 months, 45.1% versus 39.1%; 12 months, 64.2% versus 52.2%). Median time to target BP achievement was shorter in event-free patients (all patients, 10.6 versus 15.8 months, log-rank P=0.0011; excluding patients with diabetes mellitus or CKD, 7.0 versus 10.7 months, log-rank P=0.0067).
Interrelationship Among Exposure Group, BP Goal Attainment, and CV Events
The results of the time-dependent multivariate Cox models are presented in Table 2 on the overall study population. According to model 1, achieving target BP after treatment initiation was associated with a statistically significant risk reduction of 23% for CV events or all-cause death (hazard ratio [HR], 0.77 [95% CI, 0.61–0.96]; P=0.0223). In model 2, where each BP assessment was used to update the SBP and DBP stage during the follow-up, the results indicated that an SBP >160 mm Hg at the last reading was associated with a 2.2-fold increased risk of developing a CV event or death compared with an SBP reading of 120 to 139 mm Hg (HR, 2.19 [95% CI, 1.55–3.09]; P<0.0001). Furthermore, in model 3, where each BP reading was used to update the SBP and DBP levels during the follow-up, we estimated that each increase of 1 mm Hg in SBP was associated with a 2% increased risk of having an event (HR, 1.02 [95% CI, 1.01–1.03]; P<0.0001). Of note, as illustrated by model 2, a DBP <80 mm Hg was independently associated with an ≈2-fold increased risk of CV event or death relative to a DBP of 80 to 89 mm Hg (HR, 1.88 [95% CI, 1.48–2.40] P<0.0001).
Finally, after controlling for the time-varying BP goal attainment, initial treatment with a drug combination was associated with a residual risk reduction of 16% which approached but did not reach statistical significance at the 5% level (model 1: HR, 0.84 [95% CI, 0.68–1.03]; P=0.0935).
Relationship Between Exposure Group and Healthcare Resource Use
The impact of initial relative to delayed treatment with combination therapy on the rates of healthcare resource use is illustrated in Figure 4. Overall, patients of the combination therapy cohort had a significant reduction of 9% in all services compared with patients in the add-on cohort (IRR, 0.91 [95% CI, 0.90–0.92]; P<0.001). Each individual component reached statistical significance in favor of the combination therapy group (urgent care services: IRR, 0.88 [95% CI, 0.81–0.96], P=0.0022; outpatient services: IRR, 0.93 [95% CI, 0.91–0.94], P<0.001; other services: IRR, 0.91 [95% CI, 0.90–0.91], P<0.001). Similar findings were obtained when excluding patients with diabetes mellitus or CKD at baseline (all services: IRR, 0.90 [95% CI, 0.89–0.91]; P<0.001).
Based on real-world data, this large, retrospective, matched cohort study was specifically designed to assess the impact of initial versus delayed combination therapy on the risk of developing a CV event and to evaluate the interrelationship among BP reduction, goal attainment, and CV risk. The underlying questions are critical for physicians treating patients with hypertension. Although initial combination therapy accelerates the time course over which BP control is achieved, the clinical value of this approach in terms of CV outcomes has not been established. Although the VALUE data suggest that BP control within 6 months of treatment initiation improves long-term outcomes, the use of initial combination treatment was not addressed in this study in which all of the patients were initially treated with a single agent.13
Our results indicate that initial treatment with a drug combination was associated with a 34% risk reduction for CV events or death relative to patients initiated on monotherapy and subsequently switched to combination treatment by their treating physician. Significant risk reductions were found for 2 individual components of the primary end point, myocardial infarction and hospitalization for heart failure. The estimated risk reduction of 21% for stroke/TIA did not reach statistical significance as an individual end point. This result might be considered surprising given the evidence that stroke/TIA is more BP sensitive than are coronary events. It could perhaps be explained by our strict definition of stroke/TIA (ICD-9-CM codes: 430.xx-435.xx), which excluded individuals with poorly characterized neurologic events and, hence, may not have captured all of the events.
As anticipated, initial combination therapy was associated with more rapid and more effective BP control. During follow-up, the proportion of patients achieving target BP was consistently higher in the combination therapy cohort, and the median time to achievement of target BP was significantly reduced (9.7 versus 11.9 months; log-rank P =0.0040). These findings are consistent with previous studies that document a lag time in BP goal attainment in patients who are initiated on monotherapy and later up-titrated to combination treatment.9,12,14–16 The length of this lag time is variable and is highly dependent on the time course of drug titration. In this study, in which treatment decisions were made by individual physicians rather than a research protocol, up-titration occurred at an average of 13.5 months after treatment initiation. In part, this lag time may reflect therapeutic inertia, although our results also suggest that the use of a sequential monotherapy strategy was common among treating physicians. In the add-on cohort, ≈40% of patients received ≥2 classes of antihypertensive monotherapy before being switched to a drug combination.
To assess the extent to which the observed difference in BP goal attainment explained the CV risk reduction associated with initial combination therapy, we fitted 3 time-dependent Cox models to control for both the treatment exposure and time-varying BP level. The results of this analysis indicate that BP goal achievement after treatment initiation was associated with a statistically significant risk reduction of 23% for CV events or all-cause death. After controlling for the time-varying target BP achievement status, initial treatment with a combination was associated with a residual risk reduction of 16%, a finding that approached but did not reach statistical significance (P=0.0935).
The explanation for the residual risk reduction, apparently unrelated to BP control, is, to a large extent, speculative. Indeed, it is possible that the entire benefit of initial combination therapy is, in fact, related to its effects on BP. The BP data used in this study consisted only of recorded clinic BP measurements obtained at variable times, including days of office visits scheduled after an adjustment of treatment regimens. More sophisticated analyses of BP treatment effects including rigorous ascertainment of trough BP, 24-hour ambulatory BP monitoring, or home BP measurement might have provided a more comprehensive and hence more accurate depiction of on-treatment differences in BP parameters. Alternatively, simultaneous administration of 2 agents with complimentary pharmacological mechanisms could, theoretically, result in synergistic effects through unknown mechanisms. Because this study did not look independently at the different antihypertensive classes, it was not possible to determine whether any drug class or combination of drug classes conferred benefits above and beyond BP reduction. Such potential drug-specific effects could serve as an explanation regarding the reduced risk of hospitalization for heart failure observed in the cohort receiving initial combination treatment. Additional research is warranted to address these questions.
This study fills an important gap in the literature by examining the interrelationship among initial treatment with combination therapy, BP control, and CV events. A study assessing whether, compared with antihypertensive monotherapy, a combination of antihypertensive drugs provides greater CV protection in a community practice setting has been published recently by Corrao et al.7 In their case–control study, hypertensive patients who did and did not experience CV end points were compared. Patients initiated on combination therapy had an 11% CV risk reduction compared with those begun on a single agent. In patients maintained on either monotherapy or combination treatment for the entire follow-up period, combination therapy was associated with a 26% reduction of CV risk. Patients who were initiated on monotherapy and subsequently switched to a combination were statistically indistinguishable from those who received long-term monotherapy with regard to CV event rates.
Our study confirms these findings while addressing several important limitations. Although the authors performed some statistical adjustments, their results were based on data obtained from 2 very distinct patient populations, those who did and did not experience CV events. In the present study, we were able to directly control for potential confounding factors affecting these 2 cohorts through propensity score matching. Also, in the study by Corrao et al,7 no BP data were reported, making it impossible for the authors to explore the factors, including differences in on-treatment BP, which may have accounted for the observed CV risk reduction in patients receiving combination therapy. In the present study, 3 statistical models were used to assess the interrelationship among exposure groups, BP goal attainment, and the risk of developing a CV event. As noted above, the results indicate that most, but not all, of the beneficial effects of combination therapy are related to more rapid BP control.
Another important finding of our study is the independent increased CV risk associated with a low DBP. Thus, a DBP <80 mm Hg was associated with an ≈2-fold increased risk of a CV event or death relative to a DBP between 80 and 89 mm Hg (P<0.0001) after controlling for the SBP level. This finding supports previous studies that have reported a J-shaped relationship between DBP and CV disease risk, with DBP <70 mm Hg being acknowledged as a contributor to an increased CV disease risk.17–19 However, it is important to note that the current study did not assess the numerical value below which a J-curve is evident and, therefore, cannot determine whether values substantially below a DBP of 80 mm Hg are primarily responsible for the observed increase in CV risk.
In addition, in this study, initiating combination therapy also appeared to be effective in reducing healthcare resource use. Patients whose physicians delayed the use of combination treatment required more healthcare resource use per year in all of the individual service components (emergency room visits and hospitalizations, outpatient visits, and other services).
Although recent studies have questioned the use of lower BP targets in patients with diabetes mellitus or CKD, the current study used 130/80 mm Hg as the target BP for these patients. A sensitivity analysis excluding patients with diabetes mellitus or CKD demonstrated that initial relative to delayed combination therapy resulted in a greater reduction in overall CV events compared with the entire cohort. These results suggest that the use of a lower BP target for patients with CKD or diabetes mellitus may have underestimated the impact of initial combination treatment and expedited BP lowering.
Lastly, this study compared patients who initiated combination therapy versus those who initiated monotherapy but later required combination treatment. As a group, the monotherapy cohort exhibited the same clinical characteristics that had prompted other physicians to initiate combination treatment. In these patients, initial combination treatment was associated with more rapid BP goal achievement and fewer CV end points. Patients who initiated monotherapy but never required combination therapy were not studied (n=4696). Our results, therefore, do not provide evidence that initial combination therapy is preferable for all of the patients. Rather, the data indicate that combination therapy should be initiated in all of the patients likely to require multiple agents to reach goal BP. Although physicians cannot know for certain which patients will require combination therapy, it can be predicted with reasonable certainty. Overall, ≈75% of patients require multiple drugs using current treatment guidelines. Patients with stage 2 hypertension and those with hypertension in the clinical setting of diabetes mellitus, obesity, or chronic renal disease, who constituted the bulk of our study population, have a very high likelihood of requiring multiple agents. The results of the current study support the routine use of initial combination treatment in patients with these characteristics. It is noteworthy that the mean baseline BP in the study population was ≈150/85 mm Hg and two thirds had stage 1 hypertension.
Limitations of this study include the use of electronic medical charts that may contain inaccuracies in coding or omissions, and patient visits that might have occurred outside of the data vendor delivery network are not captured. Also, physician prescriptions may not reflect a patient’s actual compliance. To assess BP control, the study required that patients had ≥ 1 visit before and after treatment initiation. This requirement may have resulted in the inclusion of patients who sought health services more intensively and were potentially more closely managed for their hypertension.
In addition, the identification of hypertensive patients relied on a single elevated BP reading measured during the 3-month baseline period, which is not a definitive standard for diagnosing hypertension. However, patients were also required to initiate antihypertensive therapy, reducing the likelihood of including nonhypertensive patients in the study population. Another limitation of this study is the fact that patients who remained on monotherapy throughout the follow-up period were not analyzed. Therefore, as stated above, it is not possible to determine from this study whether initial combination therapy is beneficial for all patients.
Finally, despite efforts made to control for a comprehensive selection of baseline demographics and clinical characteristics in the matching algorithm, there may have been residual confounding effects from factors that could not be observed in the database and may have explained the physician’s choice of initial treatment. Nevertheless, large observational studies, well designed and with appropriate statistical techniques adjusting for potential confounding factors through matching techniques, can provide valuable information with real-life scenarios and high generalizability.
Results of the current real-world study suggest that early versus delayed combination treatment is advantageous in decreasing the risk of CV events in most patients with hypertension and that this effect occurs primarily through greater BP reduction and more rapid achievement of goal BP. Initial relative to subsequent treatment with combination therapy was also associated with a significant reduction in healthcare resource use. It is noteworthy that these results were obtained in a patient population consisting largely of patients with stage 1 hypertension in whom initial combination therapy is not routinely recommended. Although these retrospective data cannot be a sufficient basis for changing treatment guidelines, they strongly suggest that the routine use of initial combination therapy is a superior treatment strategy for a large segment of the hypertensive population, including many patients with relatively mild hypertension. The only apparent downside relates to patients with low diastolic BP in whom overly aggressive BP reduction may be deleterious.
Source of Funding
This research was funded by Novartis Pharma AG, Basel, Switzerland.
Four of the authors (Ms Parise, Ms Lafeuille, Mr Lefebvre, and Dr Duh) are employees of Analysis Group, Inc, a consulting company that has received research grants from Novartis Pharma AG. Ms Falvey is an employee of Novartis Pharma AG. Dr Gradman has received research grants from Novartis Pharma AG, Basel, Switzerland.
Parts of the work were presented as posters at the American Society of Hypertension 26th Annual Scientific Meeting and Exposition, New York, NY, May 21–24, 2011.
- Received July 6, 2012.
- Revision received August 2, 2012.
- Accepted October 27, 2012.
- © 2013 American Heart Association, Inc.
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Novelty and Significance
What Is New?
This was the first study evaluating the comparative effectiveness of initial versus delayed combination therapy on CV event rates and its relationship to BP reduction and goal attainment and healthcare resource use using real-world data.
Matched design ensured balanced characteristics between study cohorts.
What Is Relevant?
Initial combination therapy significantly increased the magnitude of BP reduction and reduced the median time required to achieve BP targets.
Initial combination therapy significantly decreased the risk of CV events and the rates of healthcare resource use.
Initial versus delayed treatment with combination therapy was associated with a decreased risk of CV events, and this effect occurs primarily through better and more rapid BP control.
Initial relative to subsequent treatment with combination therapy was also associated with a significant reduction in healthcare resource use.