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PRIORITY PRESS - 2012 Canadian Hypertension Congress

Toronto, Ontario / October 25-28, 2012

Toronto - For the prevention, diagnosis and treatment of high blood pressure (BP), the Canadian Hypertension Education Program (CHEP) guidelines provide a template against which physicians can tailor antihypertensive regimens according to individual patient needs. A key strategy to help patients achieve target BP is optimizing efficacy of antihypertensive therapy and minimizing pill burden. Five drug classes continue to be recommended as first-line agents. With regards to b-blockers, data presented at the congress suggest that third generation b-blockers are more potent and better tolerated than those of previous generations as well as other antihypertensive agents. Increasing data for getting patients to BP targets more quickly than the standard approach supports single-pill multiple-mechanism combination agents. These are becoming indispensable for hypertensive patients with co-morbid conditions which frequently require multiple drug therapy on their own.

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

A CHEP Review

The CHEP (Canadian Hypertension Education Program) expresses the importance of global cardiovascular (CV) risk management and vascular protection in treating hypertension. At the core of hypertension management is lifestyle modification such as weight loss, reduced alcohol consumption and more exercise. These have been shown to have a positive impact on blood pressure (BP) reduction.

For hypertensive patients with no other compelling indications, CHEP recommends a BP target of <140/90 mm Hg. When initiating medical therapy there are 5 antihypertensive drug classes to choose from, including thiazide or thiazide-like diuretics, ACE inhibitors (ACEi), angiotensin II receptor blockers (ARBs), long acting calcium channel blockers (CCBs) and b-blockers, which are not indicated as first-line therapy in patients >60 years of age. A combination of 2 first-line agents may also be considered as initial therapy if baseline systolic BP is ≥20 mm Hg or diastolic BP is ≥10 mm Hg above target.

CHEP also suggests that low doses of multiple agents may be more effective and better tolerated than high doses of fewer agents. Notably, if a patient requires multiple agents, a fixed-dose combination of these should replace taking multiple pills where feasible. However, ACEi/ARB combinations should not be used, except in a few select cases. On average, patients with comorbid conditions, diabetes in particular, require ≥3 different agents to reduce BP to the stricter target of <130/80 mm Hg. 

Effective BP-lowering

The success of any antihypertensive regimen is based on the efficacy and tolerability of the agents selected. Another factor of success is getting to target BP quickly, as shown by results from VALUE (Valsartan Antihypertensive Long-term Use Evaluation) (Lancet 2004;363:2022-31). In the early course of VALUE, small differences in BP resulted in important differences in cause-specific outcomes in high-risk patients.

In the first “real-world” comparison of its kind, Rajeev Ayyagari, Analysis Group, Boston, Massachusetts, and colleagues, analyzed retrospectively the tolerability and effectiveness of metoprolol, amlodipine, hydrochlorothiazide (HCTZ) or nebivolol as first add-on therapy in 1600 patients whose hypertension was not adequately controlled on initial therapy. At baseline, systolic BP across the 4 groups was approximately 153 mm Hg while diastolic BP was approximately 90 mm Hg.

In this study, more patients on nebivolol (57%), achieved BP targets at 2 months than HCTZ (45 %), metoprolol (41%) and amlodipine (40%). At 6 months, these increased to 78%, 69%, 68% and 67%, respectively. Goal was defined by The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines of BP <130/80 mm Hg in patients with diabetes or 140/90 mm Hg in chronic kidney disease patients with comorbidities.

The percent of patients experiencing medication-related side effects for nebivolol, HCTZ, metoprolol and amlodipine was 5.25%, 7.75%, 10.25% and 16.25%, respectively.

Advances in b-blockade

Historically, for uncomplicated hypertension, the b-blockers have not been agents of first choice because, “The older b-blockers often had central nervous system effects like fatigue, nightmares, difficulties sleeping, depression in some patients and impotence,” Luc Poirier, B.Pharm, Hypertension Clinic, Centre Hospitalier Universitaire de Québec, Quebec City, explained in an interview here. Fatigue was usually the worst, an inevitable effect of b-blockers due to reducing heart rate, which lowers BP, but also causes exercise intolerance.

The second generation b-blockers, atenolol, bisoprolol and metoprolol, are more cardioselective than the non-cardioselective first generation. The third generation b-blocker, nebivolol is significantly more b₁-selective than either metoprolol or bisoprolol, as noted by Dr. John Cockcroft, Professor of Cardiology, University of Nottingham, UK. Other third generation b-blockers (carvedilol and labetalol) are non-selective and have both a- and b-blocking properties.

The third generation b-blockers have ancilliary characteristics such as peripheral vasodilating properties. Carvedilol and labetalol vasodilate through a-blockade. Nebivolol is the only b-blocker that decreases vascular resistance through vasodilating effects mediated by nitric oxide release. Nitric oxide is also intrinsically involved in erectile function and speakers at the congress agreed that impotence is much less likely to occur with nebivolol.

Several comparisons with other antihypertensive agents demonstrated that atenolol is less effective in reducing central BP. In one study cited by Dr. Cockroft (J Hyperten 2008:26(2):351-6), Dhakam et al. found that reduction in brachial pressure was similar between atenolol and nebivolol, but aortic pulse pressure was significantly lower following treatment with nebivolol (P<0.05). It has been suggested that the reason why atenolol does not reduce CV risk in older hypertensive subjects is because of its failure to reduce central BP to the same extent as other antihypertensive agents.

A study by Kamp et al., cited by Dr. Cockroft, showed that both atenolol and nebivolol effectively reduced BP. However, the BP-lowering effect of atenolol was related to reduction in both cardiac output and heart rate while the BP-lowering effect of nebivolol was related to a reduction in peripheral resistance and an increase in stroke volume, with preservation of cardiac output—properties that may be important in heart failure (Am J Cardiol 2003;92:344-8).

Another possibility b-blockers appear to be less effective than other agents at improving CV outcomes in hypertension may be related to their lack of effect on arterial stiffness, a major factor in CV risk. In one of his own studies (Hypertension 2004:44:305), Dr. Cockcroft and colleagues demonstrated that nebivolol but not atenolol reduced arterial stiffness.

The Single-pill Combination Approach

As CHEP emphasized in their 2012 recommendations, lifestyle change remains critical in the prevention and management of hypertension but patients still have to “buy-into” any regimen that is prescribed.

Starting patients on a single-pill combination appears to reduce BP to a greater extent and get more patients to goal faster than the standard approach recommended by CHEP. For example, the STITCH study, (Hypertension 2009;53:646-53) compared a simplified treatment algorithm consisting initially of a low-dose ACEi/diuretic or ARB/ diuretic combination to the CHEP approach. At 6 months, some 65% of patients on the single-pill combination achieved BP goals compared with approximately 53% of their CHEP counterparts.

Change in BP was also greater at 22.6 mm Hg with the single-pill combination compared with 17.5 mm Hg for those treated with the CHEP approach. Curtailing daily pill counts is particularly helpful in hypertensive patients with comorbid conditions, such as diabetes, which in itself requires multiple agents to control. The use of single-pill multiple mechanism combinations simplifies multiple drug regimens and helps promote adherence.

Barring contraindications, most patients with diabetes should be on some form of renin-angiotensin-system inhibition, a diuretic and a long-acting CCB. Recently, in order to provide highly effective BP control, telmisartan has been combined with the CCB amlodipine.

Among the many single-pill formulations consisting of an ACEi or an ARB combined with a thiazide diuretic, the newer generation ARB, azilsartan has been formulated in a single tablet with chlorthalidone, a potent diuretic. 

Summary

CHEP has long dispensed recommendations for the prevention and control of hypertension and serves as an important guide to initial drug selection as well as add-on therapies. Despite significant efforts to prevent and control hypertension in Canada over the last decade, 34% of patients are still uncontrolled. According to CHEP, hypertension is significant risk factor for cerebrovascular disease, heart failure and coronary artery disease. New treatments continue to emerge which build on the current armamentarium and provide physicians with better options to solidify adherence and effectiveness of antihypertensive therapy. 

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