Prevention and Treatment
Central Review Committee: Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Alexander A. Leung, MD, MPH; Kevin C. Harris, MD, MHSc; Kerry McBrien, MD, MPH; Sonia Butalia, BSc, MD; Meranda Nakhla, MD, MSc
Chair: Doreen M. Rabi, MD, MSc
- Hypertensive patients with left ventricular hypertrophy should be treated with antihypertensive therapy to lower the rate of subsequent cardiovascular events (Grade C).
- The choice of initial therapy can be influenced by the presence of left ventricular hypertrophy (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.
1. Hypertensive patients with left ventricular hypertrophy 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 (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).
- Padwal R, Straus SE, McAlister FA. Cardiovascular risk factors and their impact on the decision co treat hypertension: an evidence-based review. BMJ 2001;322:977-80.
- Devereux RB, Roman MJ. Left ventricular hypertrophy in hypertension: stimuli, patterns, and consequences. Hypertens Res 1999;22:1-9.
- Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 1998;97:48-54.
- Dahlöf B, Devereux R, de Faire U, et al. The Losartan Intervention for Endpoint Reduction (LIFE) in Hypertension Study: Rationale, design, and methods. J Hypertens 1997;10:705-13.
- Dahlöf B, Devereux RB, Kjeldsen SE, et al., for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995-1003.
- Lindholm LH, Ibsen H, Dahlof B, et al; LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:1004-10.
- Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996;275:1507-13.
- Langenfeld MR, Gatzka CD, Weidinger G, Schobel HP. Impact of alpha- versus beta-blockers on hypertensive target organ damage: results of a double-blind, randomized, controlled clinical trial. Am J Hypertens 1997;10:985-91.
- Thurmann PA, Kenedi P, Schmidt H, Rietbrock N. Influence of the Angiotensin II antagonist valsartan on left ventricular hypertrophy in patients with essential hypertension. Circulation 1998;98:2037-42.
- Tedesco MA, Ratti G, Aquino D, et al. Effects of losartan on hypertension and left ventricular mass: a long-term study. J Hum Hypertens 1998;12:505-10.
- Franz IW, Tonnesmann U, Muller JFM. Time course of complete normalization of left ventricular hypertrophy during long-term antihypertensive therapy with angiotensin converting enzyme inhibitors. Am J Hypertens 1998;11:631-9.
- SHEP Co-operative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-64.
- Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-6.
- Liebson PR, Grandits GA, Dianzumba S, Prineas RJ, Grimm RH Jr, Neaton JD, et al. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 1995;91:698-706.
- Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension. Comparison of six antihypertensive agents. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Circulation 1997;95:2007-14.
- Ofili ED, Cohen JD, Stvrain JA, Pearson A, Martin TJ, Uy ND, et al. Effect of treatment of isolated systolic hypertension on left ventricular mass. JAMA 1998;279:778-80.
- Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, et al. Prognostic significance of serial changes. Circulation 1998;97(1):48-54.
- Lorell BH, Carabello BA. Left vemricular hypertrophy: Pathogenesis, detection, and prognosis. Circulation 2000;102:470-9.
- Verdecchia P, Carini G, Circo A, et al., for the MAVI (MAssa Ventricolare sinistra nell’lpertensione) Study Group. Left ventricular mass and cardiovascular morbidity in essential hypertension: The MAVI study. J Am Coll Cardiol 2001;38:1829-35.
- Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? JAMA 1998;279:1903-7.
- Mathew J, Sleight P, Lonn E, et al., for the Heart Outcomes Prevention Evaluation (HOPE) Investigators. Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipriL Circulation 2001;104:1615-21.
- Devereux RB, Palmieri V, Sharpe N, et al. Effects of once-daily angiotensin-converting enzyme inhibition and calcium channel blockade-based antihypertensive treatment regimens on left ventricular hypertrophy and diastolic filling in hypertension: The PRospective randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) triaL Circulation 2001;104:1248-54.
- Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006;368:1449-56.
- Solomon SD, Appelbaum E, Manning WJ, et al. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation 2009;119:530-7.
- Six Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients With Acute Decompensated Heart Failure (ASTRONAUT). ClinicalTrials.gov Identifier: NCT00894387.
- Parving HH, Brenner BM, McMurray J, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio- Renal Endpoints (ALTITUDE): Rationale and study design. Nephrol Dial Transplant 2009;24:1663-71.
- Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity/mortality in Patients With Chronic Heart Failure (ATMOSPHERE). ClinicalTrials.gov Identifier: NCT00853658.
- Lambers Heerspink HJ, Perkovic V, de Zeeuw D. Renal and cardioprotective effects of direct renin inhibition: A systematic literature review. J Hypertens 2009;27:2321-31.
- Campbell NR, Khan NA, Hill MD, et al. 2009 Canadian Hypertension Education Program recommendations: The scientific summary – an annual update. Can J Cardiol 2009;25:271-7.
- Khan NA, Hemmelgarn B, Herman RJ, et al. The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – Therapy. Can J Cardiol 2009;25:287-98.