INVEST TRIAL SHOWS NONDIHYDROPYRIDINE CALCIUM CHANNEL BLOCKER IS EQUIVALENT TO β BLOCKER AS INITIAL THERAPY
Beta‐blocker therapy has been the standard of care in patients who have coronary artery disease (CAD), especially patients who have either had a myocardial infarction (MI) or with angina. To evaluate how a heart‐rate limiting calcium antagonist would perform as initial therapy compared with a β blocker as initial therapy, the International Verapamil SR/TrandolApril Study (INVEST) was undertaken. Conducted in 14 countries across 862 sites between September 1997 and February 2003, this randomized, open‐label, blinded end point trial evaluated the occurrence of cardiovascular disease in patients with hypertension and CAD treated with a calcium antagonist‐based regimen compared with a noncalcium antagonist treatment program. The study enrolled 22,576 subjects aged 50 years or older (mean age 67 years) using multiple‐drug strategies in each arm (the dosing and order of additional drugs was prespecified).
The trial compared a regimen including the nondihydropyridine calcium antagonist verapamil and the angiotensin‐converting enzyme (ACE) inhibitor trandolApril plus the diuretic hydrochlorothiazide, as necessary, with a regimen using the β blocker atenolol with both hydrochlorothiazide and trandolApril, as required. Patients with New York Heart Association class I–III heart failure were included in the trial. Patients taking β blockers within 2 weeks of randomization or with an MI that occurred within the previous 12 months were excluded.
In accordance with the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI), which was the latest JNC report at the time of the study, a goal blood pressure (BP) of <140/90 mm Hg or <130/85 mm Hg in those with diabetes or renal disease was targeted. Systolic blood pressure of <140 mm Hg or <130 mm Hg for those with diabetes or renal disease was achieved in 65% of patients who received the calcium antagonist‐based regimen and 64% of patients who received the noncalcium antagonist treatment program. Diastolic BP of <90 mm Hg and <85 mm Hg, respectively, was achieved in 88% of both groups. Overall, 72% of patients on the calcium antagonist‐based regimen and 71% of patients on the noncalcium antagonist treatment program achieved a systolic BP of <140 mm Hg and diastolic BP of <90 mm Hg. To achieve this level of BP control, 82% of the calcium antagonist‐based regimen group were taking verapamil, 63% were taking trandolApril, and 44% were taking hydrochlorothiazide. In the noncalcium antagonist treatment program group, 78% were taking atenolol and 60% and 52% were taking hydrochlorothiazide and trandolApril, respectively. After 24 months of treatment, 80% of each arm required the use of two or more antihypertensive agents to control BP. The study's primary end point was a composite of first occurrence of all‐cause mortality, nonfatal stroke, or nonfatal MI.
After a mean 2.7 years of treatment, there was no difference between the verapamil‐based and atenolol‐based treatment strategies in the study's primary outcome, even when adjusted for prespecified covariates, including age, race, gender, previous MI, and previous heart failure. Secondary outcome measures, including cardiovascular death, angina, adverse events, hospitalization, and BP control, were also not different between the calcium antagonist‐based regimen and noncalcium antagonist treatment program groups. There was, however, an unexpected 15% reduction in new‐onset diabetes in the verapamil/trandolApril strategy compared with the β‐blocker/diuretic group.
The authors conclude that a verapamil/trandolApril‐based strategy is as effective, but not more effective, than an atenolol/hydrochlorothiazide‐based treatment regimen for the management of patients with hypertension and CAD.—Pepine C, Handberg E, Cooper‐DeHoff R, et al. A calcium antagonist vs a non‐calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil‐TrandolApril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805–2816.
Comment
Thiazide‐type diuretics, with or without β‐blocker therapy, have been the gold standard initial treatment for elderly patients with hypertension unless there was a compelling indication for another agent. In the recently published Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, initial therapy with controlled‐onset extended‐release verapamil achieved similar cardiovascular outcomes as atenolol‐based treatment programs in overweight elderly hypertensive subjects. While these agents have been successful in improving outcomes when studied individually, prior studies have not been designed specifically in patients with CAD or to compare the use of multiple, prespecified drug strategies on cardiovascular outcomes.
INVEST, the second largest hypertension trial ever conducted, evaluated the multidrug protective effects of a strategy that included initial therapy with sustained‐release verapamil. The ACE inhibitor trandolApril was added as the second‐step agent. This was compared with the standard‐of‐care regimen; that is, beginning with the β blocker atenolol and adding the thiazide‐type diuretic hydrochlorothiazide. About 50% of patients in both groups required a third agent to achieve BP control. Few of these patients were taking a β blocker alone, which is less effective in elderly persons with hypertension when used as monotherapy. INVEST results suggest that therapy with a nondihydropyridine calcium antagonist plus an ACE inhibitor is equivalent but not better in preventing death, stroke, and MI than the gold standard (diuretic/β‐blocker) therapy. This alternative strategy, which required a diuretic as a third drug in about half of the patients, allowed effective control of BP and had a favorable effect on outcome. The exact role of this more expensive regimen is unclear but it should be recommended when there is a contraindication to β‐blocker use.
The side effect profile in the calcium antagonist/ACE inhibitor group was favorable; fewer than 2% of all patients stopped therapy for either constipation or cough. Of note, in clinical practice the rate of constipation is much less with the sustained‐release form of verapamil than practitioners are used to seeing with the short‐acting form of verapamil, which is no longer recommended for use. Patients also developed symptomatic bradycardia less often with the verapamil‐based than with the atenolol‐based regimen.
An unexpected finding in the 72% of patients without diabetes on entry was the relative 15% reduction in new‐onset diabetes in the calcium antagonist‐based regimen group (this level of difference might prevent one case of diabetes for every 100 patients treated per year). This finding is in keeping with the Heart Outcomes Prevention Evaluation (HOPE) trial, in which subjects taking an ACE inhibitor reported a 34% reduction in being told they had diabetes compared with placebo and the Losartan Intervention for End Point Reduction in Hypertension (LIFE) trial, where use of an angiotensin‐receptor blocker compared with the β blocker atenolol (as used in INVEST) was associated with a relative 25% reduction in laboratory‐detected new‐onset diabetes. No difference in outcome occurred in the 28% of INVEST patients with diabetes on trial entry, and as in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), primary outcome was similar in the diuretic‐based group compared with the ACE‐inhibitor or calcium channel blocker‐based groups in patients with diabetes. Participants in INVEST had a mean body mass index of 29 (waist circumference was not reported), 28% had diabetes, 100% had hypertension, and 55% had a history of hypercholesterolemia or were on lipid‐lowering medication. Many of the INVEST subjects, therefore, may have had the metabolic syndrome. It still remains unclear whether so‐called diabetic‐sparing antihypertensive agents such as those used in INVEST reduce cardiovascular events more effectively than β‐blocker and thiazide‐type diuretic therapy in the management of the metabolic syndrome. Beta‐blocker therapy has been associated with slight weight gain, and these agents should be used with caution in patients with the metabolic syndrome unless a compelling indication for their use exists.
Recent clinical trials including ALLHAT, HOPE, the Second Australian National Blood Pressure Study (ANBP2), and CONVINCE led the authors of the seventh JNC report to recommend thiazide‐type diuretic, β‐blocker, calcium‐antagonist, and ACE‐inhibitor therapy in patients at high risk for, but not necessarily with, CAD. Effective BP control remains paramount in reducing cardiovascular risk. The INVEST trial gives practitioners an alternative to β‐blocker/diuretic combination therapy that is well tolerated and effective in patients with hypertension and CAD. More studies on the long‐term consequences that specific therapies have on developing diabetes are needed. Trials just being started, like the Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) study, which will compare the initial use of combinations of agents (ACE inhibitor/diuretic vs. ACE inhibitor/calcium antagonist) on cardiovascular outcomes, are many years away from publishing their results. Until then, we should continue to use the antihypertensive agents that have shown results unless they cannot be used. Then this evidence‐based alternative is nice to have.
LOW‐DOSE RAMIPRIL DOES NOT REDUCE CARDIOVASCULAR OR RENAL RISK IN PERSONS WITH TYPE 2 DIABETES
The Heart Outcomes Prevention Evaluation (HOPE) study found that in high‐risk patients, including persons with diabetes, a multiple‐drug regimen including the angiotensin‐converting enzyme (ACE) inhibitor ramipril 10 mg/d reduced the risk of myocardial infarction, stroke, and cardiovascular and total mortality compared with a multiple‐drug regimen that did not include ramipril. While the trial investigators suggested that most of the benefit could not be explained by differences in blood pressure (BP) between the two groups, this has remained a major point of controversy.
The non‐insulin‐dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CArdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, double‐blind, parallel group, multicenter study established to test whether the addition of 1.25 mg ramipril daily to existing therapy would reduce cardiovascular and renal morbidity and mortality in persons with type 2 diabetes with clinical proteinuria (i.e., urinary albumin excretion at least 20 mg/L in two consecutive samples, and serum creatinine not more than 149 μmol/L). Conducted mostly by primary care practitioners in 16 European and North African countries, the study enrolled 4912 patients of whom 56% had a BP >140/90 mm Hg or were taking antihypertensive medication (mean BP 145/82 mm Hg). Eligible patients were at least 50 years old and were being treated with at least one oral antidiabetic medication, but were not taking insulin, an ACE inhibitor, or an angiotensin‐II‐receptor blocker. Only 22% had preexisting cardiovascular disease. They were examined every 6 months and followed for a median duration of 47 months (range 3–6 years). Sitting BP was measured once at each examination every 6 months using a mercury sphygmomanometer.
The primary end point of the study was the combined incidence of cardiovascular death (including sudden death), nonfatal acute myocardial infarction, stroke, heart failure requiring admission to a hospital, and end‐stage renal failure (defined as a requirement for hemodialysis or renal transplant). These outcomes were also analyzed separately.
The use of low‐dose ramipril did not result in reductions in any of the primary end points, including sudden death. This occurred independent of baseline BP status. Patients receiving ramipril experienced some reduction in BP compared with the placebo group (intergroup difference at 2 years: systolic 2.43 mm Hg, diastolic 1.06 mm Hg; at final evaluation: systolic 1.51 mm Hg, diastolic 0.30 mm Hg) as well as a trend toward more reduction of proteinuria and microalbuminuria. No difference in body weight or serum glucose concentration was noted between the two groups. More participants stopped taking ramipril than placebo because of cough (3.3% vs. 0.9%) with no difference in the rate of angioedema (one in each group).
The authors conclude that ramipril at a low dose (1.25 mg daily) did not prevent cardiovascular events in patients with type 2 diabetes and albuminuria, although a slight reduction in BP and albuminuria did occur. High‐dose ramipril (10 mg), as utilized in the Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO‐HOPE) study, is the only dose of ramipril that effectively antagonizes the renin‐angiotensin axis in patients with diabetes.—Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ. 2004;328:495.
Comment
The HOPE investigators have stated that the major benefit of a 10‐mg daily dose of ramipril in improving survival and preventing recurrent ischemic vascular disease was mainly due to interruption of the renin‐angiotensin system and its subsequent benefit on improving endothelial function as well as reducing atherosclerosis and thrombogenesis. They have stated that the modest BP‐lowering effects witnessed in the trial accounted for, at most, one third of the benefit seen. The hypertension community criticized the study because of the lack of appropriate standardization for the measurement of BP and the fact that BP was only measured five times during the entire study. In the HOPE trial, the actual BP‐lowering effects of ramipril may have been underestimated. An ambulatory BP study in a small subset of patients from the HOPE trial suggests that there was a much larger BP difference than reported in the main study and that this, rather than specific therapy, may have explained the improved outcome.
This latest trial from a group of investigators not associated with HOPE or MICRO‐HOPE seems to add to the evidence that a required amount of angiotensin II blockade needs to occur to achieve an improvement in cardiovascular and renal outcomes. The fact that low‐dose ramipril in the DIABHYCAR study reduced BP to a small degree, produced a trend toward albuminuric reduction, and was more likely to cause cough than placebo suggests that there was a biologic effect from the addition of ramipril. The failure to show any benefit to the primary cardiovascular or renal outcomes suggests that a certain amount of angiotensin II blockade may be required to effectively antagonize this maladaptive neurohormonal system.
The results of this study agree with the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). In that study, 10 mg (and not 2.5 mg) ramipril was associated with a reduction in carotid intima‐media artery thickness measured by B‐mode carotid ultrasound.
One area of concern is the crossover that occurred in the use of angiotensin II receptor antagonists or ACE inhibitors other than ramipril during the study. More participants randomized to placebo (23%) than ramipril (20%) added these agents during the study. This tends to minimize the ability to show any differences in the primary outcome.
Debate will continue over the uniqueness of ramipril and whether or not a specific dose is necessary to achieve vascular benefit. For now, 10 mg ramipril once daily in addition to other cardiovascular therapies seems to improve cardiovascular and renal outcomes as defined in these trials. If ramipril is not chosen, an alternative ACE inhibitor should be used at a dosage associated with effective renin‐angiotensin system antagonism.