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

Expert Commentary & Five-year View

Findings from INVEST demonstrate that both readily available therapeutic strategies, which now contain only generic medications, when deployed to lower BP to goal result in equivalent outcomes. This supports the notion that selection of antihypertensive agents should be based on the patients' comorbidities and other risk factors (e.g., risk for diabetes), and not necessarily any given drug should be used in all hypertensive patients. Conclusions from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included the recommendation that thiazide diuretics should be used as first-line BP-lowering drugs, regardless of patient characteristics, and despite the increased risk of diabetes in patients who received chlorthalidone.[7] While BP was lower in the chlorthalidone-treated group, there was no significant difference in the occurrence of cardiovascular (CV)-related adverse outcomes evaluated, with the exception of heart failure.[7] It is not clear why this lower BP did not result in reduced outcomes (particularly death, MI and stroke).

In a recently published summary from ALLHAT, it was reiterated that because thiazide diuretics are superior in preventing heart failure and new-onset diabetes, which occurred more frequently in the chlorthalidone-treated patients and was not associated with increased CV outcomes, thiazides should continue to be the drug of first choice.[40] However, we and others have shown that risk from diabetes that develops during antihypertensive treatment is associated with significant morbidities and mortality which is similar to diabetes of other etiologies, although there may be a lag in onset.[40–43]

β-blockers have recently fallen out of favor, in part related to poor BP control among elderly patients and metabolic and safety concerns. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which enrolled 9193 hypertensives with left ventricular hypertrophy, and compared once-daily atenolol to losartan with add-on HCTZ in both groups, superior BP-lowering and CV outcome prevention was observed in the losartan group.[44] Similarly, in the Anglo–Scandinavian Cardiac Outcomes Trial (ASCOT), which compared once-daily atenolol plus HCTZ to amlodipine plus perindopril, there was similar brachial BP-lowering in the two groups, but superior reduction in CV outcomes in the amlodipine-treated patients.[45] In a substudy of ASCOT patients who underwent central BP assessment, it was determined that patients in the amlodipine group had lower central pressure, and it was hypothesized that it may be this differential effect on central pressure that was responsible for the decreased risk for CV outcomes.[6] However, in INVEST, where atenolol was dosed twice daily rather than once daily as in LIFE and ASCOT, BP-lowering and CV outcomes were equivalent. Importantly, we observed no increased risk of stroke in atenolol-treated patients, as has been observed in some meta-analyses.[4,5]

For the first time in high-risk CAD patients, a calcium antagonist has been shown to be a safe and beneficial component of a BP-lowering regimen, including subpopulations with diabetes, post MI, prior coronary revascularization and the elderly. In the period since INVEST was completed, ASCOT[45] and the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) study,[46] which compared benazepril plus amlodipine to benazepril plus HCTZ, have confirmed these findings. In the overall population, ACCOMPLISH demonstrated superior BP reduction and CV risk reduction in the benazepril plus amlodipine group. While some suggested that the CV benefit was derived solely from the greater BP reduction, recent data from an ABPM substudy in 573 patients showed a mean 1.6 mmHg lower SBP in the benazepril plus HCTZ patients, but this was not statistically significant, and over the 24-h mean daytime and night-time periods, pressures and surges in BP showed the combinations were equivalent, which does not explain the CV benefit observed in the amlodipine-treated group.[47] Opie recently suggested that in patients with stable angina and no prior MI, a calcium antagonist may be as beneficial as a β-blocker, but without the adverse effects of insulin resistance, weight gain, decreased exercise tolerance, and sexual dysfunction.[48]

The INVEST study, through its recruitment of large numbers of elderly patients, women, Hispanics, and blacks, provides an important and here-to-for unknown, understanding of the response to treatment in these subgroups and direct evidence for the generalizability of the findings to these growing populations worldwide. We demonstrated that in some patients, particularly the lean elderly, risk for adverse CV outcomes increased as BP was lowered, suggesting the need to question recommendations for significant BP-lowering in all, especially in those with CAD.

In the recent past, many of the professional societies have revised and updated their guidelines and recommendations for the treatment of hypertension. The European Society for Hypertension/European Society of Cardiology are no longer endorsing thiazide diuretics or β-blockers in hypertensive patients with diabetes[49] and the American Association of Clinical Endocrinologists recommends thiazide diuretic use only at low dosage and only with adequate potassium replacement and β-blocker use only as second- or third-line agents in patients with diabetes.[50] The National Institute for Health and Clinical Excellence, together with the British Hypertension Society, recently published guidelines which indicate that β-blockers are no longer a suitable first-line treatment option in uncomplicated hypertensive patients largely due to increased incident diabetes and they recommend use of renin–angiotensin system inhibitors as first-line therapy in younger patients, with diuretics reserved for the elderly or black patients of any age.[45] In the USA, the National Heart Lung and Blood Institute recently constituted and convened JNC 8, which will synthesize and deliberate data from INVEST as well as all of the other hypertension mega-trials published in the last decade to establish new guidelines and recommendations which will inform treatment of hypertension in the next 5 years and beyond.


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