Clinical Outcomes in the Diabetes Cohort of the International Verapamil SR-Trandolapril Study
The INternational VErapamil SR-Trandolapril study (INVEST) had 6400 of 22 576 (28.3%) participants with diabetes at entry. The objectives of this prespecified analysis were to compare antihypertensive treatment strategies in the diabetes cohort (verapamil SR-based [n=3169] versus atenolol-based [n=3231]) and identify predictors for the primary outcome (a composite of first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke). During a mean follow-up of 2.7 years, 913 participants with diabetes experienced a primary outcome event, with no significant difference between treatment strategies (14.6%, verapamil SR versus 13.9%; atenolol hazard ratio, 1.05; 95% confidence interval, 0.92 to 1.19). Risk for the primary outcome increased with presence of baseline heart failure, renal impairment, US residency, age, previous stroke/transient ischemic attack, previous myocardial infarction, peripheral vascular disease, or smoking. High systolic and diastolic pressures during follow-up also were associated with increased risk, as were low diastolic pressures. Antihypertensive treatment with a verapamil SR or atenolol strategy resulted in similar rates of cardiovascular outcomes in coronary artery disease (CAD) patients with diabetes. Thus, a verapamil SR-based antihypertensive treatment strategy is an alternative to a β-blocker–based strategy in adults with CAD and diabetes.
Adults with diabetes are 2 to 4× more likely to die from heart disease and stroke than those without diabetes. This risk increases for adults with hypertension (HT) and diabetes.1 To reduce cardiovascular risk in those with diabetes, more aggressive blood pressure (BP) control is needed compared with the general population. The sixth report of the Joint National Committee (JNC VI) recommended a target BP of <130/85 mm Hg for persons with diabetes, and the seventh report (JNC 7) recommends a target of <130/80 mm Hg.2,3
Postmyocardial infarction studies demonstrate that β-blockers and diuretics, alone or in combination, reduce cardiovascular mortality in coronary artery disease (CAD), with β-blockers being preferred.2,4 However, use of β-blockers or diuretics is associated with metabolic abnormalities, including impaired glucose tolerance, insulin resistance and hypokalemia, and increased risk for new-onset diabetes.5–9
Nondihydropyridine calcium antagonists (non-DHPCAs) such as verapamil SR are recommended as an alternative to β-blockers for angina relief in persons with CAD-HT.2,3 Verapamil SR effectively reduces BP10 and clinical outcomes in patients with CAD.11 Moreover, non-DHPCAs are generally considered metabolically neutral.7,10
Previous outcome studies evaluated the effect of BP reduction with different antihypertensive medications in a cohort of established CAD and HT but without concomitant use of renin-angiotensin system (RAS) blockers (ie, angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptors blockers [ARBs]) and lower BP goals. The INternational VErapamil SR-Trandolapril study (INVEST) evaluated 2 recommended antihypertensive regimens in a CAD-HT population,2 with the option of adding an ACE inhibitor or hydrochlorothiazide (HCTZ), to achieve JNC VI BP targets.12 This prespecified analysis reports outcomes in the cohort with diabetes.
INVEST was a prospective, randomized, open trial with blinded end point design comparing clinical outcomes in 22 576 participants with CAD-HT randomized to a verapamil SR-based or atenolol-based antihypertensive treatment strategy. Results from the main trial were reported previously.12
Of these participants, 6400 (28.3%) had diabetes at baseline (defined by a history of diabetes mellitus and/or use of oral hypoglycemic medication or insulin) and were followed for a mean duration of 2.7 years (Figure 1). The objectives of this prespecified cohort analysis were to compare risk for adverse outcomes between strategies and to identify predictors of risk.
Participants were randomized to 240 mg per day of verapamil SR or 50 mg per day of atenolol and titrated to maximal doses to achieve JNC VI2 target BP of <130/85 mm Hg.12 If BP goal was not achieved, trandolapril (0.5 to 8 mg per day) and HCTZ (12.5 to 100 mg per day) were recommended as primary and secondary add-on agents in the verapamil SR strategy, and the sequence was reversed in the atenolol strategy. Trandolapril also was recommended for participants with diabetes, heart failure, or renal impairment.2,13
The primary outcome was a composite of first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke.12 Secondary outcomes included all-cause death, nonfatal MI and nonfatal stroke, BP control (<130/85 mm Hg), cardiovascular hospitalizations, and cardiovascular death.
Outcomes were assessed with Cox proportional hazards models and Kaplan–Meier plots. Unless otherwise specified, a P value <0.05 was considered statistically significant. A stepwise Cox proportional hazards model identified baseline factors associated with the primary outcome. Five prespecified covariates (age, race/ethnicity [white, Asian, black, Hispanic, multiracial/other], gender, previous MI, and heart failure [class I–III]) and a factor for strategy were forced entries in the model. Additional covariates were selected if significant at the 10% level.
The association of follow-up BP with the primary outcome was explored with a Cox model that included factors for average systolic BP (SBP) and average SBP squared. Average SBP and diastolic BP (DBP) were derived from postbaseline BP measurements before primary outcome or censoring, or baseline SBP and DBP for participants without postbaseline measurements were used.
Data were captured and stored in Oracle database tables version 7.1. Statistical analyses were performed using SAS version 8.2 (SAS Institute).
Baseline characteristics were comparable between strategies (Table 1), except that a higher proportion of women reported use of hormone replacement therapy in the atenolol strategy.
Table 2 details medication use at 24 months. The majority of participants required add-on therapy with differences in use of trandolapril and HCTZ by strategy. More than half the participants (59.3%) were taking aspirin or antiplatelet agents throughout the trial. This did not differ between groups, nor were there differences in antidiabetic medications. However, among those taking oral hypoglycemic agents at baseline, initiation of insulin treatment was greater in the atenolol group (5.2% verapamil SR versus 7.9% atenolol; P=0.01). Increases in insulin use were not related to sex, age, or body mass index (BMI).
BP and Heart Rate
Similar reductions in BP were present in both strategies (Figure 2). Greatest BP reductions occurred within 6 months of randomization and were maintained to trial end. BP goal (<130/85 mm Hg) was achieved in >40% of all participants annually throughout the 4-year follow-up, with the highest prevalence at 2 years (44.0% and 43.9% for verapamil SR and atenolol strategies, respectively; P=0.94). Mean resting heart rate was 3.4 bpm less at 24 months in the atenolol group (P<0.001).
Primary and Secondary Outcomes
The primary outcome occurred in 913 (14.3%) of diabetes participants; this compared with 1356 (8.4%) of participants without diabetes (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.63 to 1.93). Time to primary outcome demonstrated no difference between strategies (Figure 3). Risk for primary and secondary outcomes did not differ by strategy (Table 3). Presence of prior heart failure, US residency, increas-ing age, and previous MI significantly increased risk for the primary outcome in the diabetes cohort. In addition, presence of prior renal impairment (HR, 1.76; 95% CI, 1.39 to 2.25), previous stroke/transient ischemic attack (HR, 1.42; 95% CI, 1.19 to 1.71), peripheral vascular disease (HR, 1.34; 95% CI, 1.15 to 1.56), and smoking (HR, 1.23; 95% CI, 1.07 to 1.41) also significantly increased risk in the diabetes cohort.
BPs of ≤140/90 mm Hg were associated with reduced risk of the primary outcome, an effect that extends to a BP of 110/60 mm Hg (Figure 4). Risk appears to increase at levels <110/60 mm Hg, but this is limited by the very small sample size.
Finally, an on-treatment analysis of randomized drugs, using 50 mg per day of atenolol as a reference group, indicates a trend for reduced risk of the primary outcome with the addition of 2 mg per day of trandolapril to the verapamil SR–based strategy or 12.5 mg per day of HCTZ to atenolol-based strategy. Increasing doses of trandolapril or HCTZ to a maximum of 8 mg per day or 50 mg per day, respectively, did not change this benefit.
Both strategies were well tolerated with no differences in adverse events, except for constipation (1.6% verapamil SR versus 0.2% atenolol; P=0.001) and wheezing (0.2% verapamil SR versus 0.4% atenolol; P=0.04).
Although a large body of trial data supports the recommended use of β-blockers to reduce mortality in adults with diabetes after MI or heart failure,3,14 this is the first large outcome study in CAD participants to document a similar cardiovascular outcome benefit between β-blocker–based and non-DHPCA–based strategies. Moreover, many of the β-blocker trials in CAD occurred before use of RAS blockers, which have been shown to reduce mortality in persons with CAD and diabetes.15 The observed benefits of β-blockers in earlier studies may have been less dramatic if RAS blockers were the comparator agent, or more dramatic if these different classes were used in combination. The data reported here are important additions to the spectrum of antihypertensive treatment data in the diabetes population, particularly because so many adults with diabetes develop CAD.
There are important similarities and differences between INVEST and recent antihypertensive trials that included cohorts with diabetes regardless of CAD.5,16,17Although a diuretic was more effective than a dihydropyridine calcium antagonist or an ACE inhibitor for reducing risk of heart failure in the diabetes cohort of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),5 there were no differences between regimens in this cohort for the primary outcome. In the CAptopril Prevention Project (CAPPP), an ACE inhibitor was superior to a diuretic/β-blocker combination in preventing cardiovascular events in hypertensive participants with diabetes.16 The Controlled Onset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial used antihypertensive agents similar to INVEST. The primary outcome of the diabetes subgroup in the main report were similar between verapamil-based and β-blocker–based treatments.17 Thus, BP lowering with agents other than β-blockers reduced cardiovascular events in people with diabetes, many of whom had documented CAD.
INVEST is one of the few trials to document that almost half of the participants with diabetes achieved the JNC VI (<130/85 mm Hg) BP goal.2 This control rate is much higher than that observed in the general diabetes population (25%),18 in the practice-based setting (22%),19 or in other trials.8 The results reported here, in addition to the primary results,12 reinforce the effectiveness of non-DHPCAs and β-blockers in controlling BP and demonstrate that although BP control is difficult to achieve in the patient with diabetes, it is attainable.
Participants with diabetes in INVEST had almost twice the risk for cardiovascular events compared with those without diabetes, similar to previous reports.1,16,20 Hypercholesterolemia and higher BMI were not associated with increased risk of the primary outcome in this trial. However, >67% of patients reporting hypercholesterolemia at baseline also reported use of lipid-lowering agents, which likely affected risk; and studies suggest that waist circumference more accurately defines risk than BMI,21,22 which was not assessed in INVEST.
Risk analyses in 2 trials in which BP levels were randomized supports the concept of lower BP levels for CAD patients with diabetes.23,24 However, in small observational studies, an excessively low DBP was associated with increased cardiovascular risk in angina patients.25 In INVEST, <1% (62 of 6400) of diabetes participants achieved a BP <110/60 mm Hg; of these, only 28% had a primary outcome. Given the small number of participants who achieved these pressures, no firm statements can be made for this subgroup. However, guidelines are clear about avoiding such BP levels in such a subgroup.
Results from the on-treatment analysis suggest that combination therapy is more effective for reducing adverse outcomes. These data complement previous studies that demonstrated improved outcomes for combination versus monotherapy26 and provide novel information on the effectiveness of a non-DHPCA and ACE inhibitor used in combination. It is clear that combination therapy is needed to achieve BP goal in those with diabetes and CAD.3 Events related to stroke and, to a lesser extent, CAD, are related to BP level;4,27 this would explain why a similar benefit in cardiovascular outcome was seen in both INVEST groups.
This subanalysis does have some limitations. Although this was a prespecified analysis, it represents a subgroup of participants from the overall study. Participants with diabetes were not specifically randomized but were part of a larger randomized population. Also, diabetes status was based on history of diabetes and/or use of antidiabetic agents at baseline and was not confirmed by laboratory testing; however, others have verified the accuracy of using self-reports.28
We conclude that use of a verapamil SR–based strategy effectively achieves BP goal in adults with diabetes, HT, and CAD, similar to that of an atenolol-based strategy with no difference in cardiovascular mortality and morbidity outcomes.
It is clear that multiple BP-lowering agents are needed to achieve BP goals in the CAD population12 and that achievement of such goals translates into reduced cardiovascular outcomes, especially in those with diabetes. Current guidelines of the American Diabetes Association state that any approved antihypertensive agent can be used, although ACE inhibitors, ARBs, β-blockers, and diuretics are preferred agents.1 Data from INVEST, together with other studies, support the use of a non-DHPCA combined with an ACE inhibitor as an alternative initial therapy to a β-blocker–based strategy for patients with diabetes and CAD.
INVEST was funded by grants from Abbott Laboratories and the University of Florida Research Foundation and Opportunity Fund. Investigators conceived the study and designed and conducted it independently of all sponsors. G.L.B. had full access to all data.
The following conflicts of interest have been disclosed: G.B. has consultant agreements with and serves on speakers’ bureaus for AstraZenaca, Abbott Laboratories, Amersham, Alteon, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Merck, Novartis, Sanofi-Synthelabo, Sankyo, and Solvay and has received grant support from AstraZenaca, Abbott Laboratories, Amersham, Alteon, Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Sankyo, and Solvay. Dr Messerli has received honoraria from Merck, Pfizer, Abbott Laboratories, Forest, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Biovail, Solvay, Reliant, and Pharmacia. R.C.-D. has received grant support from Abbott Laboratories and Pfizer. C.J.P. has received grant support from Abbott Laboratories, AstraZeneca, Aventis Pharmaceuticals, Inc., Berlex Laboratories, Inc., Bristol-Myers Squibb, Sanofi Company, CV Therapeutics, Monarch Pharmaceuticals, Novartis, Pfizer, and Wyeth-Ayerst Laboratories and has been a consultant for Abbott Laboratories. C.J.P. and R.C.-D. are coinventors of the online prescribing system used in INVEST, which is licensed to the University of Florida.
- Received June 19, 2004.
- Revision received July 8, 2004.
- Accepted August 24, 2004.
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