Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 2011 Canadian Hypertension Congress Annual Scientific Meeting

Alliston, Ontario / October 2-5, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The Canadian Hypertension Education Program (CHEP) guidelines indicate that lifestyle modification is a primary goal for the treatment of hypertensive adults without other compelling indications. Physicians also have up to 5 different classes of antihypertensives to choose from. As Dr. George Dresser, Associate Professor of Medicine, University of Western Ontario, London, noted, most patients require at least 2 agents to achieve blood pressure (BP) control and very often 3.

According to Dr. Raj Padwal, Associate Professor of Internal Medicine, University of Alberta, Edmonton, most obese hypertensive patients require multiple drug classes for BP control. While it has been shown that using low doses of 2 BP-lowering drugs together produces a greater reduction in BP than uptitrating a single drug, “A lot of the patients we see have refractory hypertension and are already on ASA, a number of anti-diabetic agents and now, you are going to add multiple antihypertensive agents. Adherence becomes a huge problem for them because of drug burden,” Dr. Padwal told delegates.

Single-pill Combination

According to Dr. Ellen Burgess, Professor of Nephrology and Endocrinology, University of Calgary, Alberta, recent CHEP guidelines suggest that in select high-risk patients, adding an ACE inhibitor to a long-acting dihydropyridine is preferable to adding it to a thiazide or thiazide-like diuretic.

This recommendation was based on the ACCOMPLISH study in which 2 fixed-dose combinations with the ACE inhibitor benazepril were compared in hypertensive patients at high risk for cardiovascular (CV) events. BP control rates were similar in the benazepril/calcium channel blocker (CCB) amlopidine group and the benazepril/hydrochlorothiazide (HCTZ) group. “When we look at event rates, however, there was a healthy and significant 20% relative risk reduction between the 2 groups in favour of the ACE inhibitor/CCB arm (P=0.0002),” Dr. Burgess reported.

In order to reduce pill burden, an effective single-pill combination (SPC) of such agents for the initial treatment of hypertension can simplify physician decision-making and help patients maximize the likelihood of achieving target BP goals. For example, in the STITCH trial, family practices that used a simple algorithm based on a fixed-dose combination approach were more likely to achieve BP targets (~65%) than those using a guidelines-based approach (~50%).

The first SPC comprising the angiotensin receptor blocker (ARB) telmisartan and the CCB amlodipine has been approved in Canada. Both agents have proven effective in reducing BP. This SPC is regarded as a means of simplifying treatment decision-making, increasing adherence and the likelihood of achieving target BP goals with fewer side effects in a cost-effective fashion.

ß-Blocker Heterogeneity

In patients with hypertension, first-line therapies include thiazide diuretics, ACE inhibitors, ARBs, long-acting CCBs and ß-blockers. However, ß-blockers are not recommended as first-line in patients >60 years old. But many hypertensive patients with angina, heart failure (HF) or post-myocardial infarction (MI) require ß-blocker therapy. “It’s here—as well as for hypertensive patients with tachycardia—that we need a better ß-blocker,” stated Luc Poirier, BPharm, Hypertension Clinic, Centre hospitalier universitaire de Québec, Québec City. He cited 3 studies showing statistically significant reductions in BP relative to baseline with nebivolol, atenolol, bisoprolol and metoprolol with no difference between agents.

The main mechanism of action by which ß-blockers reduce BP is by decreasing heart rate and cardiac output. However, as a heterogeneous class of medications they possess different pharmacokinetic as well as pharmacodynamic properties.

Non-cardioselective ß-blockers such as propranolol block ß1 receptors in the heart and also ß2 receptors found in a variety of organs, including the lungs. In contrast, the third-generation ß-blocker nebivolol is a highly selective ß1-receptor blocker with a long half-life of 11 to 33 hours. “Its other main action is vasodilatation mediated by nitric oxide,” Poirier explained. “While [it] blocks ß1 receptors in the heart and decreases heart rate like any other ß-blocker, it is the only one that dilates vessels via nitric oxide.”

Carvedilol and labetalol also have vasodilatory properties but they do so via a-receptor blockade. Unlike labetalol, nebivolol has no intrinsic sympathomimetic activity (ISA). Those with ISA can increase peripheral vascular resistance and attenuate decreases in heart rate and cardiac output, thereby potentially negating benefit in at-risk CV populations.

Also, their degree of liposolubility differs, with pindolol and timolol being highly lipophilic and nebivolol moderately lipophilic. “This suggests that nebivolol may penetrate the blood-brain barrier,” Poirier noted, although in earlier studies, investigators did not see side effects that are typical of lipophilic ß-blockers such as fatigue, nightmares and erectile dysfunction. Nor should any of the highly cardioselective ß-blockers cause side effects such as cold extremities which occur with ß-blockers that impinge on ß2 receptors.

Figure 1.

Study Findings

In a Cochrane Collaboration analysis of 13 trials involving over 90,000 patients, 75% of ß-blocker-treated subjects involved atenolol (Cochrane Database Syst Rev 2007;1:CD002003). Differences between atenolol and the third-generation nebivolol include their effect on cardiac output. In a study by Kamp et al. (Am J Cardiol 2003;92:344-8), findings revealed that from baseline, atenolol decreased cardiac output by 24% vs. an increase of 7.1% for nebivolol (Figure 1). Investigators concluded that BP-lowering effects of atenolol are therefore strongly related to reductions in both cardiac output and heart rate, and that BP-lowering effects of nebivolol are related to a reduction in peripheral resistance and an increase in stroke volume, with preservation of cardiac outcome—properties that may be important in treating HF.

The ß-blockers have been shown to be less cardioprotective than other classes of antihypertensive agents. In ASCOT, the CCB amlodipine (±ACE inhibitor) was compared to a traditional regimen of the ß-blocker atenolol (±diuretic) in uncomplicated hypertensive patients. Results showed that the CCB-based regimen conferred not only significantly greater benefit against CV events but patients were also one-third less likely to develop new-onset diabetes than the ß-blocker-based regimen.

In their own pivotal trial, Poirier and colleagues evaluated the effect of nebivolol and atenolol on insulin sensitivity and hemodynamics (J Hypertens 2001;19:1429-35). At the end of 16 weeks, hypertensive adults with impaired glucose tolerance randomized to atenolol had a 10% reduction in insulin sensitivity compared with no decrease among nebivolol-treated patients.

Results from 5 randomized controlled trials of first-line ß-blockers showed less benefit in reducing total stroke, total CV events and coronary heart disease than first-line thiazide trials. “In 4 of the 5 ß-blocker trials, atenolol was the agent used and it is possible that the lesser effectiveness of first-line ß-blockers is limited to atenolol,” Poirier observed. One possible explanation for this may be that atenolol is associated with more arterial stiffness. This would suggest that the vasculature is not as compliant in its presence, which might explain the higher morbidity and mortality rates, as Poirier explained.

In the pivotal Canadian studies, Lacourcière et al. found that both nebivolol and nifedipine induced similar clinical and 24-hour ambulatory BP values, and no deleterious effects on lipids were seen with either drug (Am J Ther 1998;5(4):237-43). Both alone and in combination with HCTZ, the same ß-blocker can result in important reductions in both systolic and diastolic BP. Investigators have also shown that it has similar efficacy and safety in poor and extensive metabolizers of the drug (Br J Clin Pharmacol 2006:63:575-82).

“We do not yet know if all of these new properties will translate into better morbidity and mortality outcomes,” Poirier stated, “but we need a ß-blocker that is better tolerated and which has a different mechanism of action, with less of a decrease in cardiac output and better vasodilatation in the periphery.”

Summary

With established efficacy of the different classes of antihypertensive agents, the availability of the newly approved telmisartan/amlodipine once-daily SPC provides a simple option to treat hypertension that may encourage patient adherence. Additionally, for patients with angina or HF, the advent of a more efficient and tolerable third-generation ß-blocker is an encouraging advance.

Note : At the time of printing, nebivolol is not licensed in Canada.