IX. Treatment of Hypertension in Association With Left Ventricular Hypertrophy

Prevention and Treatment

Subgroup Members: Simon W. Rabkin, MD; Gordon W. Moe, MD, MSc; Jonathan G. Howlett, MD
Central Review Committee: Doreen M. Rabi, MD, MSc; Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Kerry McBrien, MD, MPH; Kevin C. Harris, MD, MHSc; Alexander A. Leung, MD, MPH
Chair: Raj Padwal, MD, MSc

This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can J Cardiol 2016; 32(5): 569-588.

Recommendations

  1. Hypertensive patients with left ventricular hypertrophy (LVH) should be treated with antihypertensive therapy to lower the rate of subsequent cardiovascular events (Grade C).
  2. The choice of initial therapy can be influenced by the presence of left ventricular hypertrophy (LVH) (Grade D). Initial therapy can be drug treatment using ACE inhibitors, ARBs, long-acting CCBs, or thiazide/thiazide-like diuretics. Direct arterial vasodilators such as hydralazine or minoxidil should not be used.

Background

1. Hypertensive patients with left ventricular hypertrophy (LVH) should be treated with antihypertensive therapy to lower the rate of subsequent cardiovascular events (Grade C).

A meta-analysis of 39 high quality, randomized trials confirmed BP reduction with various agents does lead to reduction in left ventricular mass (7). The magnitude of LVH regression was related to left ventricular mass at baseline, degree of BP reduction and duration of therapy. After adjustment for differences in duration of treatment, there was some suggestion drug class may influence the degree of LVH regression; angiotensin-converting enzyme (ACE) inhibitors were associated with a decrease in left ventricular mass index of 13.3% (95%CI, 9.9%–16.8%), calcium channel blockers (CCBs) 9.3% (95%CI, 5.5%–13.1%), diuretics 6.8% (95%CI, 3.0%–10.7%) and beta-adrenergic antagonists (β-blockers) 5.5% (95%CI, 2.3%–8.6%) (7). However, this meta-analysis was small (1200 patients received active treatment; 189 received placebo), and mean duration of therapy was only 25 weeks. Subsequent studies have shown similar degrees of LVH regression with other agents, including alpha-blockers (ɑ-blockers) and angiotensin II receptor antagonists (ARBs) (8–10). Thus, further randomized trial evidence is required before any conclusions can be made regarding whether specific classes provide greater benefits in patients with hypertension who have LVH.

2. The choice of initial therapy can be influenced by the presence of left ventricular hypertrophy (LVH) (Grade D). Initial therapy can be drug treatment using ACE inhibitors, ARBs, long-acting CCBs, or thiazide/thiazide-like diuretics. Direct arterial vasodilators such as hydralazine or minoxidil should not be used.

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and is a strong risk factor (independent of blood pressure [BP]) for stroke, myocardial infarction (MI), congestive heart failure and other cardiovascular events (1).  The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial enrolled 9193 patients with hypertension who had LVH, and was designed to establish whether selective blocking of angiotensin II improved LVH beyond reducing BP and, consequently, reduced cardiovascular morbidity and death (4). Results showed that after an average treatment time of 4.8 years, treatment that was based on losartan was better than treatment based on atenolol for reducing stroke risk. In other words, interpretation of outcomes would infer losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in BP, and is better tolerated. Because substantial reduction in cardiovascular morbidity and mortality favouring losartan persisted even after accounting for differences in BP, there was substantial debate within the RTF as to whether losartan may exert particular protective effects in patients with LVH beyond BP reduction. However, because atenolol was thought to be a suboptimal control agent in a predominantly elderly population (20), a majority of the RTF thought although LIFE supported claims that ARBs were effective in reducing LVH and preventing cardiovascular events, there was insufficient evidence to conclude that these agents were more beneficial than other effective antihypertensive agents.

However, after re-evaluating the LIFE trial results, the RTF removed β-blockers from the list of initial therapies for LVH (5,6). This study found a significant reduction in the composite endpoint of death, MI or stroke favouring losartan (risk reduction [RR], 0.87; 95%CI, 0.77–0.98), even after accounting for differences in trial BPs. Although superiority of ARBs compared with antihypertensives other than β-blockers could not be established (thus, the drug classes are not assigned evidence Grades), the LIFE trial demonstrated the inferiority of β-blockers in patients with LVH.

A post hoc analysis of the HOPE Study found patients randomly assigned to ramipril had higher rates of LVH regression and prevention than patients receiving placebo (91.9% vs. 90.2%, P=0.007), even after accounting for differences in BP (21). This study, although not a hypertension trial per se, supports the findings of a meta-analysis (7) demonstrating ACE inhibitors promote LVH regression, and also extends the findings by indicating ACE inhibitors significantly prevent onset of LVH in those patients with and without hypertension. Further, this study showed patients who had either prevention or regression of LVH had a lower risk of death, MI or stroke than those patients who had developed or maintained LVH (12.3% vs. 15.4%, P<0.001). This study supported the recommendation that ACE inhibitors may be used as first-line therapy for treating patients with hypertension and LVH.

In the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) trial, 303 patients with echocardiographically determined LVH were randomly assigned to enalapril or nifedipine (22). Although this study reported no difference in left ventricular mass regression between the two treatment arms, the almost 30% loss of patients to follow-up limits the ability to rule out important differences between the two drugs.

In summary, while antihypertensive therapy improves left ventricular mass and reduces cardiovascular morbidity and mortality in patients with LVH, no one anti-hypertensive class is superior to all others. Most major classes of antihypertensive agents (except direct arterial vasodilators, such as hydralazine or minoxidil) have been shown to cause LVH regression, but not always to the same degree in relation to the amount of BP lowering achieved. Therefore, antihypertensive treatment should include an agent from one of the five major classes in patients with LVH, with care given to the inferiority of β-blockers in patients with LVH (6,29,30).

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