The optimal blood pressure (BP) to prevent major adverse outcomes (death, myocardial infarction, and stroke) for patients with hypertension and coronary artery disease who have undergone previous revascularization is unknown but might be influenced by the type of revascularization procedure. We analyzed data from the INternational VErapamil SR-Trandolapril STudy, focusing on the relation between BP and the outcomes of 6,166 previously revascularized patients, using the 16,410 nonrevascularized patients as a reference group. The previous revascularization strategy consisted of coronary artery bypass grafting (CABG, 45.2%), percutaneous coronary intervention (PCI, 42.1%), or both (CABG+PCI, 12.8%). Patients who had undergone both CABG+PCI and CABG-only had a greater adverse outcome risk (adjusted hazard ratio 1.27% and 1.20%, 95% confidence interval 1.06 to 1.53 and 1.07 to 1.35, respectively). The risk was similar for PCI-only patients (adjusted hazard ratio 1.04, 95% confidence interval 0.92 to 1.19). The relations between the adjusted hazard ratio and on-treatment BP appeared J -shaped for each revascularization strategy, accentuated for PCI and diastolic BP (DBP), but excepting CABG only and DBP for which the relation was linear and positive. In conclusion, major adverse outcomes were more frequent in patients with coronary artery disease who had undergone previous CABG, with or without PCI, compared to those with previous PCI only. This likely reflected more severe vascular disease. The relation to systolic BP was J -shaped for each strategy. Among those patients with previous CABG only, the linear relation with DBP suggested that more complete revascularization might attenuate hypoperfusion at a low DBP. The management of BP might, therefore, require modification of targets according to the revascularization strategy to improve outcomes.
The number of patients with coronary artery disease and previous revascularization is increasing, and most of these patients have hypertension. Major adverse outcomes (death, myocardial infarction, and stroke) occur more frequently in this group than in similar patients without previous revascularization, in part because of more adverse risk conditions, leading to more severe vascular disease. Additionally, major adverse outcomes have been reported to be related to blood pressure (BP) in a quadratic orJ -shape. However, the relation between adverse outcomes and BP as a function of a specific previous revascularization strategy (coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI], or both [CABG+PCI]) in hypertensive patients is unknown. The INternational VErapamil SR-Trandolapril STudy (INVEST) provides an opportunity to initiate an understanding of this relation. We report the results of a substudy analysis focusing on the 6,166 of 22,576 INVEST patients who had undergone previous revascularization, stratified by the revascularization strategy: CABG-only, PCI-only, or CABG+PCI.
Methods
The INVEST design, methods, and principal results have been previously described in detail (registration site www.clinicaltrials.gov/ct2/show/NCT00133692 ; registration number NCT00133692 ). The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committees, and all patients provided informed consent. In brief, patients with clinically stable coronary artery disease aged ≥50 years with hypertension were randomized to either a verapamil sustained release (SR)- or an atenolol-based antihypertensive treatment strategy. The addition of trandolapril with or without hydrochlorothiazide was recommended if needed for BP control. Trandolapril was also recommended for patients with heart failure, diabetes, or renal insufficiency. The BP treatment goal was <140/90 mm Hg (or <130/85 mm Hg for patients with diabetes or renal insufficiency). The primary adverse outcome was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. The secondary outcomes were death, fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and revascularization. The main results of the INVEST were that both strategies provided excellent BP control (>70% patients achieved <140/90 mm Hg) and were equivalent for reducing mortality and major morbidity.
The original analysis focusing on patients with previous coronary revascularization was prespecified ; however, the present subgroup analysis was not. Patients undergoing revascularization <1 month immediately before enrollment were excluded from the present study. The data on any revascularization procedures ≥1 month before enrollment were collected at baseline, including the specific strategy (CABG, PCI, and CABG+PCI).
The baseline data for each revascularization strategy have been summarized as the mean ± SD for continuous variables and the number and percentage for categorical variables. The pulse pressure was calculated as the difference between the systolic blood pressure (SBP) and diastolic blood pressure (DBP). In the present exploratory analysis, the patients were grouped by 10-mm Hg strata of the average follow-up SBP. The distribution of the primary outcome rate stratified by follow-up BP was evaluated to determine whether the relation was linear. Because the frequency distributions were most commonly consistent with a quadratic function, a quadratic stepwise Cox proportional hazard model was formed for the time interval to the primary outcome for each BP variable (factors for BP and BP ). A similar analysis was conducted for DBP. A SBP of 140 mm Hg and a DBP of 90 mm Hg were used as the reference (hazard ratio [HR] 1.0) within each subgroup.
Kaplan-Meier analysis was used to assess the time interval to the first event for the primary outcome. A stepwise Cox proportional hazard model was used to identify the factors associated with the primary outcome among the 3 revascularization strategy groups and the nonrevascularized reference group (n = 16,410). The following covariates were forced into the model: medical treatment strategy (verapamil SR vs atenolol), age (in decades), gender, race, previous myocardial infarction, and previous congestive heart failure. Other factors were retained in the final model if p ≤0.10 was achieved.
To estimate the risk of the primary outcome for the different revascularization strategies, 3 separate Cox proportional hazard models with factors for CABG, PCI, and CABG+PCI were conducted for the whole population (using the nonrevascularized population as the reference): (1) unadjusted model; (2) stepwise model; and (3) stepwise model with the addition of the average follow-up SBP and DBP (linear and quadratic terms).
To control for the nonrandom assignment of patients to each of the 3 specific revascularization strategies (or to no revascularization), we calculated the propensity score for each patient to be in one group or another, adjusting for all demographic and clinical characteristics available for each patient at the baseline as explanatory variables. The propensity score was then used as a variable in the Cox proportional hazard model to adjust for any group membership differences attributable to the variables used to create the propensity score. This analysis was performed as a sensitivity analysis to assess whether the difference in baseline characteristics for each group explained the difference in the risk of the primary outcome.
Data management and statistical analyses were performed using Statistical Analysis System statistical software, version 8.2 (SAS Institute, Cary, North Carolina). Statistical significance was assumed when p <0.05 (2-tailed).
Results
Of the 22,576 patients enrolled in INVEST, 6,166 (27.3%) had undergone previous coronary revascularization: CABG, 2,784 (45.2%); PCI, 2,594 (42.1%); and CABG+PCI, 788 (12.8%). Those with CABG+PCI had the greatest prevalence of adverse conditions associated with a high risk of adverse outcomes, including a history of myocardial infarction, congestive heart failure, stroke/transient ischemic attack, diabetes, dyslipidemia, and cigarette smoking ( Table 1 ). Those who had undergone CABG only had the second greatest prevalence of adverse conditions, and those who had undergone PCI only had the lowest. However, those who had undergone CABG only had the lowest prevalence of angina. The revascularized patients, as a group, compared to the nonrevascularized patients tended to be older, more frequently men, white, and United States residents, with a greater prevalence of characteristics associated with a high risk of adverse outcomes.
| Characteristic | CABG (n = 2,784) | PCI (n = 2,594) | CABG+PCI (n = 788) | No Previous Revascularization (n = 16,410) | p Value † |
|---|---|---|---|---|---|
| Age (years) | 68.3 ± 8.8 | 66.2 ± 9.4 | 67.2 ± 9.2 | 65.6 ± 9.9 | <0.001 |
| Age >70 years | 42.7% | 33.3% | 37.1% | 31.6% | <0.001 |
| Body mass index (kg/m 2 ) | 28.7 ± 5.0 | 29.2 ± 8.1 | 30.0 ± 14.7 | 29.2 ± 6.7 | <0.001 |
| Men | 71.3% | 60.8% | 68.4% | 40.8% | <0.001 |
| United States residency | 82.1% | 78.5% | 90.9% | 73.7% | <0.001 |
| Race/ethnicity | <0.001 | ||||
| White | 74.8% | 70.2% | 78.0% | 39.0% | |
| Black | 8.8% | 9.5% | 8.0% | 15.1% | |
| Hispanic | 14.2% | 18.4% | 11.8% | 43.1% | |
| Asian | 0.9% | 0.8% | 1.5% | 0.6% | |
| Other/multiracial | 1.3% | 1.1% | 0.6% | 2.2% | |
| Myocardial infarction | 47.8% | 51.5% | 55.6% | 25.1% | <0.001 |
| Angina pectoris | 31.7% | 38.3% | 42.4% | 78.2% | <0.001 |
| Unstable angina (≥1 month before enrollment) | 18.8% | 22.5% | 31.5% | 7.5% | <0.001 |
| Stroke/transient ischemic attack | 9.3% | 8.0% | 11.0% | 6.6% | 0.023 |
| Left ventricular hypertrophy | 19.5% | 17.9% | 18.3% | 23.1% | <0.001 |
| Arrhythmia | 8.7% | 7.1% | 10.0% | 6.7% | 0.012 |
| Heart failure class I–III | 7.5% | 4.4% | 9.5% | 5.2% | <0.001 |
| Peripheral vascular disease | 15.9% | 11.0% | 15.6% | 11.3% | <0.001 |
| Cigarette smoking (any history) | 58.7% | 58.4% | 60.2% | 41.6% | <0.001 |
| Diabetes | 34.1% | 27.8% | 35.0% | 27.1% | <0.001 |
| Renal impairment | 3.6% | 1.9% | 3.6% | 1.5% | <0.001 |
| Dyslipidemia | 74.0% | 75.4% | 79.1% | 48.5% | 0.013 |
| Antiplatelet drug therapy | 82.7% | 85.9% | 83.5% | 46.4% | 0.004 |
| Lipid-lowering drug therapy | 60.8% | 61.5% | 66.1% | 27.3% | 0.025 |
At baseline, the SBP and DBP were similar, regardless of the revascularization strategy used and were lower compared to the SBP and DBP of the nonrevascularized patients (p <0.001 for each revascularization strategy vs no previous revascularization; Figure 1 ). The pulse pressure was greater for CABG-only patients (p <0.001) but not for the CABG+PCI and PCI-only patients (p >0.05) compared to nonrevascularized patients. The greatest decrease in SBP, DBP, and pulse pressure for all patients occurred during the first 6 weeks of treatment (p <0.001), followed by smaller changes out to 24 months. However, by 24 months, the SBP was uniformly greater and the DBP was uniformly lower for the CABG-only and CABG+PCI patients compared to the PCI-only and nonrevascularized patients (p <0.001). Thus, by 24 months, the pulse pressure was greater for the CABG-only and CABG+PCI patients compared to the PCI-only patients, whose pulse pressure, in turn, was greater than that of the nonrevascularized patients (p <0.001). Among the revascularized patients, the verapamil SR- and atenolol-based treatment strategies resulted in similar control of BP, regardless of the revascularization strategy used (data not shown).
