Manitoba steps in to help diabetic - Winnipeg Free Press

Manitoba steps in to help diabetic - Winnipeg Free Press: "'NPH insulin and Lantus are equally effective treatment options for Type 2 diabetes,' the spokesman said. The difference is that NPH must be taken twice a day"

ontarget arbs and acei

Summary

In high-risk patients with controlled blood pressure but without heart failure, the angiotensin-receptor blocker (ARB) telmisartan is equally effective in reducing cardiovascular risk as the angiotensin-converting enzyme (ACE) inhibitor ramipril and less likely to cause angioedema. Surprisingly, despite a 2 to 3 mmHg additional reduction in blood pressure, combining these drugs in full doses provided no additional clinical benefit — and evidence of some harm — compared with ramipril therapy alone (1). Thus, the ONTARGET [Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial] results, presented at ACC.08 and published simultaneously in the New England Journal of Medicine, confirm that dual blockade with both an ARB and ACE inhibitor produces a greater better blood pressure-lowering effect and more patients with an increase in potassium level of >5.5 mmol/L, yet the combination of telmisartan and ramipril produces more adverse events than either drug alone.

Background

Unlike ACE inhibitors, the ARBs have not been shown to reduce mortality and morbidity in high-risk patients with coronary disease, peripheral vascular disease, cerebrovascular disease, or diabetes. However, in patients with type 2 diabetes, ACE-inhibitor and ARB agents have individually been shown to improve endothelial dysfunction and reduce microalbuminuria. Due to the different mechanisms of action of telmisartan and ramipril, there is the potential for complementary cardiovascular effects independent of their blood pressure-lowering effects. For example, the combination might fully suppress the deleterious effects of angiotensin II and improve endothelial function (2).

ONTARGET is the first long-term prospective trial to investigate the cardioprotective effect of an ACE-inhibitor (ramipril) plus an ARB (telmisartan) in high-risk patients (3). Telmisartan was selected for study because it provides sustained antihypertensive activity effect over the 24-hour period between doses; ramipril was chosen based on the Heart Outcomes Protection Evaluation (HOPE - Ramipril) trial, which showed that ramipril therapy reduced the incidence of cardiovascular events compared to placebo when used in a similar patient population to that planned for ONTARGET (4,5).

Results and Conclusions

The double-blind trial enrolled more than 25,000 patients who were assigned to receive 10 mg ramipril (n = 8,576), 80 mg telmisartan (n = 8,542), or both drugs (n = 8,502) daily. The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.

Compared to the ramipril group, mean blood pressure was lower in both the telmisartan group (a reduction of 0.9/0.6 mmHg) and in the combination therapy group (a reduction of 2.4/1.4 mmHg). At a median follow-up of 56 months, telmisartan was shown to be not inferior to ramipril based on the primary outcome, which had occurred in 1,412 patients in the ramipril group (16.5%) versus 1,423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94-1.09). At the targeted dose of 80 mg once daily, telmisartan preserved 94% (95% CI, 83-105) of the benefit of ramipril 10 mg daily in the HOPE trial.

Also, compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%; p < 0.001) and angioedema (0.1% vs. 0.3%; p = 0.01), but this benefit was partially offset by a higher rate of hypotensive symptoms (2.6% vs. 1.7%; p < 0.001). This is consistent with the slightly better blood-pressure lowering effects seen in the ARB group. Importantly, the rate of syncope was the same in the two groups (0.2%).

In the combination therapy group, the primary outcome results were surprising. Despite a reduction in systolic blood pressure of 2-3 mmHg beyond that seen in the ramipril group — a decrease that should have translated into a risk reduction of 4% to 5% — no significant benefit was seen in the primary composite endpoint, which occurred in 1,386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92-1.07) receiving combination therapy.

However, the two-drug regimen significantly increased the risk of hypotension, syncope, renal dysfunction, and hyperkalemia, with a trend toward an increased risk of renal dysfunction requiring dialysis. These safety results are similar to an analysis of the combined effects of an ARB and an ACE inhibitor (versus an ACE inhibitor alone) in four previous trials (7).

The ONTARGET results are similar to those of the VALIANT study, in which the combination of a full dose of captopril plus half-dose valsartan did not significantly reduce the occurrence of the primary outcome, but did increase hypotension (8). On the other hand, the findings contrast with the CHARM Added study of patients with symptomatic heart failure who had candesartan added to existing therapy including an ACE inhibitor in variable doses (fewer than half of patients received full doses) (9), as well as the Valsartan Heart Failure Trial, in which about 90% of patients had background ACE-inhibitor therapy (again, at variable doses) (10).

In the published results of ONTARGET, the authors admitted that the lack of an additional benefit from greater blood pressuring lowering is puzzling. Perhaps successful treatment with other drugs left little additional clinical benefit possible. Alternatively, they wrote, some harm might be produced with full-dose combination therapy that may offset any gains.

Until additional data become available, the ONTARGET investigators concluded that telmisartan and ramipril are equally effective at reducing cardiovascular risk in patients with vascular disease or high-risk diabetes, even when heart failure is not present. The choice of agent, they said, will depend on the preferences of patients and physicians as well as an individual patient’s susceptibility to specific adverse events.

Guidelines

Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. JAMA 2003;289:2560-72.