INVEST Revisited: Review of Findings from the International Verapamil SR–Trandolapril Study

Rhonda M Cooper-DeHoff; Eileen M Handberg; Giuseppe Mancia; Qian Zhou; Annette Champion; Udo F Legler; Carl J Pepine


Expert Rev Cardiovasc Ther. 2009;7(11):1329-1340. 

In This Article


Primary Outcome

After 61,835 patient-years of follow-up, the PO rate was not statistically significantly different between the two treatment strategies (verapamil SR strategy: 9.4%, atenolol strategy: 10.2%; relative risk [RR]: 0.98; 95% CI: 0.90–1.06) in the overall population or any of the subpopulations. The PO rate was highest in subgroups of patients with heart failure, age over 70 years old, diabetes, coronary revascularization and prior MI. Also within these subgroups there was no difference in PO by treatment strategy.[25]

In the overall population, baseline predictors of the PO in descending order of risk increase were heart failure, diabetes, increasing age, US residency, renal impairment, stroke/transient ischemic attack (TIA), smoking, prior MI, peripheral arterial disease and coronary revascularization.[32]

Overall, higher baseline BMI was not a risk factor for the PO. In a stepwise model with normal BMI (20 to <25 kg/m2) as the reference point, the relationship between BMI and the PO was found to be quadratic rather than linear. The risk of the PO was highest for thin patients (BMI < 20 kg/m2; adjusted hazard ratio [HR]: 1.52; 95% CI: 1.24–1.86) and lowest for class I obesity patients (BMI: 30 to <35: adjusted HR: 0.68; 95% CI: 0.59–0.77).[31]

In a model adjusted for baseline covariates, multi-drug therapy was associated with reduced risk for the PO in both strategies compared with monotherapy, and with similar results when the model was adjusted for average follow-up systolic BP (SBP) and diastolic BP (DBP).[24]

Outcomes and predictors of outcomes are summarized in Table 2 for the randomized population and clinically important subgroups.

New-onset Diabetes

Among the 16,176 nondiabetics at baseline, new-onset diabetes, a prespecified outcome, occurred in 1234 patients during follow-up. The rate of new diabetes was lower in the verapamil SR strategy than in the atenolol strategy (7.03 vs 8.23%; RR: 0.85; 95% CI: 0.76–0.95).[25,33]

Baseline characteristics associated with increased risk of new-onset diabetes included US residency, prior stroke/TIA, coronary revascularization, Hispanic ethnicity, other race (including multiple races), left ventricular hypertrophy, hypercholesterolemia and increasing BMI. While the risk of new-onset diabetes decreased with increasing age above 50 years old, elevated follow-up SBP was associated with an increased risk of new-onset diabetes. From a stepwise time-dependent model, risk of new diabetes was 53% higher with an SBP of 150 mmHg than with an SBP of 120 mmHg.[33]

Using drug dose modeling[24] with atenolol 50 mg/day as reference, atenolol 50 mg/day plus HCTZ 50 mg/day increased the risk of new diabetes (HR: 1.38; 95% CI: 1.06–1.80), which was not reduced when trandolapril was added. Verapamil SR 240 mg/day plus trandolapril 4 mg/day reduced the risk of new diabetes (HR: 0.58; 95% CI: 0.44–0.78), which was not increased when HCTZ was added.[33]

Preliminary data show that while the death rate during INVEST in those who developed diabetes was low, after extended follow-up (5 years after the end of INVEST), the rate of all-cause death in those who develop diabetes surpasses those without diabetes and is similar to those who had diabetes at baseline.[34]

Angina Episodes

While the prevalence of angina at baseline in this CAD population was high, as BP was controlled during follow-up, the percentage of patients reporting angina declined by more than 50% in both strategies, with fewer angina episodes per week reported in the verapamil SR strategy (24 months, mean [SD]: verapamil SR 0.77 [1.31], atenolol 0.88 [1.62]; p = 0.02).[25] Mean resting heart rate (RHR), which was 75.5 ± 9.6 beats per minutes (bpm) at baseline, was reduced more at 24 months in the atenolol strategy (69.2 bpm) than in the verapamil SR strategy (72.8 bpm), as was expected. Despite this difference in RHR, both strategies had equivalent outcomes. An analysis using a stepwise Cox proportional hazards model determined that the relationship between follow-up RHR and PO was quadratic. The RHR nadir was 59 bpm for the overall INVEST population and was lower for the atenolol strategy (51 bpm) than for the verapamil SR strategy (62 bpm), consistent with the differences in mean RHR between the two strategies.[35]

Blood Pressure

As expected, baseline BP was lower in treated patients; however, at entry, fewer than 20% of patients had BP under control. During follow-up, BP reductions were equivalent comparing the strategies (24 months, verapamil SR 18.7/10.0 mmHg, atenolol 19.0/10.2 mmHg, p-values not significant), with most of the BP reduction occurring in the first 6 months.[25] BP control was similar in both treatment groups (24 months, <140/90 mmHg: verapamil SR 72%, atenolol 71%).

Most INVEST patients required multiple drugs for BP control. At 24 months in both strategies, 30% of patients were taking two antihypertensive medications and approximately half of the patients were taking three or more antihypertensive medications. At 24 months, only 2% of patients in each strategy were not taking any antihypertensive medication,[25] and patients with diabetes were taking an average of 2.9 antihypertensive medications, compared with 2.8 for patients with and 2.0 for patients without new diabetes.[29,33]

Table 3 summarizes baseline and follow-up BP in the overall population and multiple subgroups. Regardless of the subgroup evaluated, similar to the overall population there was no difference in BP reduction when comparing the treatment strategies. At the completion of the trial, the level of BP control achieved in INVEST compares favorably to many other large BP treatment trials undertaken in recent years (Figure 2).

Figure 2.

Percentage of patients in contemporary blood pressure treatment trials achieving blood pressure control defined as <140/<90 mmHg.
ACCOMPLISH: Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension;[46] ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial;[7] Aml: Amlodipine; ASCOT: Anglo–Scandinavian Cardiac Outcomes Trial;[45] COER: Controlled-onset, extended-release; CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular End Points;[51] INVEST: International Verapamil SR–Trandolapril Study;[25] LIFE: Losartan Intervention For Endpoint reduction in hypertension;[44] SR: Sustained release; VALUE: Valsartan Antihypertensive Long-term Use Evaluation.[52]

Baseline BP was not predictive, while follow-up BP was predictive of the PO. Patients with mean follow-up SBP lower than 140 mmHg or DBP lower than 90 mmHg had a lower risk of PO (adjusted HR: 0.82 and 0.70, respectively; p < 0.001 for both comparisons).[32] Lower on-treatment SBP was associated with significant risk reduction for the PO, in the overall population as well as in multiple high-risk subgroups (Figure 3).[32]

Figure 3.

Risk (adjusted HR and 95% CI) for primary outcome associated with high-risk subgroups by time-dependent systolic blood pressure category. In general, risk was lower when SBP was lower than 140 mmHg.
HR: Hazard ratio; MI: Myocardial infarction; SBP: Systolic blood pressure; TIA: Transient ischemic attack.
Redrawn with permission from [32]

Patients with mean follow-up SBP lower than 140 mmHg or DBP lower than 90 mmHg had a lower risk of stroke (adjusted HR: 0.63 and 0.50, respectively; p = 0.001 for both comparisons).[36] Follow-up SBP lower than 140 mmHg was associated with a significant reduction in risk of stroke in subgroups with prior coronary artery bypass graft, prior stroke/TIA, age over 70 years, US residency, diabetes and a history of smoking.[36]

The relationship between PO and follow-up BP followed a J-shaped curve, which when adjusted for baseline differences was flatter for SBP than for DBP and had a nadir of 129.5/73.8 mmHg. Patients with follow-up DBP of 70 mmHg or less accounted for 10.7% of patients (2415 out of 22,576) and 19.6% of the PO events (445 out of 2268). A similar relationship was found for DBP and all-cause death (the main component of the PO), MI (fatal and nonfatal) and, to a lesser extent, stroke (fatal and nonfatal).[37]

To investigate the impact of consistency of BP control on outcomes, INVEST patients were divided into four groups based on the proportion of visits with BP in control (<25%, ≥25% to <50%, ≥50% to <75%, ≥75%). All four groups experienced reductions in BP during the study, with the size of the reduction increasing for all but the group with 75% or more of the visits in control (6.4/4.1, 13.9/7.4, 19.0/9.9, 17.3/9.3 mmHg, respectively). Risk for PO, MI (fatal and nonfatal) and stroke (fatal and nonfatal) decreased as the proportion of office visits with BP in control increased and was lower in the group with 75% or more of visits in control compared with the group with fewer than 25% of visits in control by 40, 42 and 50%, respectively. When included together in a model, the proportion of visits in control (continuous variable) and mean follow-up SBP were both predictive of PO risk.[38]

Depression & Quality of Life

Among INVEST participants who responded to surveys at baseline and year 1, CES-D scores improved significantly from baseline to 1 year in the verapamil SR strategy (n = 617; 14.00 vs 12.54; p < 0.001) while remaining unchanged in the atenolol strategy (n = 575, 14.27 vs 14.00; p = 0.44). Baseline predictors of higher CES-D scores (more depression) at 1 year were higher CES-D scores at entry (p < 0.001), history of depression diagnosis (p = 0.03), history of stroke (p < 0.001) and randomization to the atenolol strategy (p < 0.001).[16]

With regard to quality of life, follow-up SBP between 150 and 160 mmHg and above 160 mmHg were associated with a significant increase in the odds of feeling fair/poor (adjusted OR [95% CI]: 1.90 [1.81–2.00] and 2.53 [2.41–2.66], respectively). Those who reported angina in the 4 weeks prior to a protocol visit had 2.2-times greater odds of reporting fair/poor subjective well being (adjusted OR: 2.2; 95% CI: 2.13–2.27).[16,39]

Safety & Tolerability

Both treatment strategies were well tolerated. Adverse event rates were low and consistent with what has been previously reported for the study drugs. Patients in the verapamil SR strategy reported more constipation, while patients in the atenolol strategy reported more symptomatic bradycardia and wheezing. Importantly, there were no differences in episodes of gastrointestinal bleeding, cancer, Parkinson's disease, Alzheimer's disease, autoimmune disease or other adverse events comparing the strategies.


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