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Author: Kristin Watson, PharmD, BCPS-AQ Cardiology

The 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America Heart Failure guidelines and the 2017 High Blood Pressure Clinical Practice guidelines recommend that guideline directed medical therapy (GDMT) be prescribed and titrated to a systolic blood pressure (SBP) < 130 mmHg for patients with hypertension and heart failure with reduced ejection fraction (HFrEF). The High Blood Pressure guidelines also recommend attainment of a diastolic blood pressure (DBP) < 80 mm Hg.1,2Although achieving these goals is important, specific blood pressure (BP) thresholds should not be the only indicator for which patients receive appropriate doses of GDMT.

The benefits of inhibitors of the renin-angiotensin system (RAS), including angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), and ARB/neprilyisin inhibitor (ARNI) therapy are not solely dependent on their vasodilatory properties. RAS inhibitors have been shown to reduce the risk of death, HF hospitalization, and other outcomes in patients with HFrEF and New York Heart Association (NHYA) class II-IV symptoms independent of improvements in BP.3-7Data from three landmark trials involving these therapies in populations with HFrEF are highlighted in Table 1. As shown in the table, the mean SBP at enrollment was already “at goal” yet a large proportion of patients were still able to achieve target doses of therapy.

Table 1. Systolic blood pressure values in select landmark clinical trials 3-5
Trial Mean baseline SBP (mmHg) SBP reduction Mean daily dose achieved                       (% achieving target dose)
SOLVD Treatment Placebo: 124.5

Enalapril: 125.3

At ~ 41 mo, 4.7 mmHg ¯w/ enalapril Placebo: 10.6 mg (49.1%)

Enalapril: 11.2 mg (49.3%)

Val-HeFT Placebo: 124 ± 18.6
Valsartan: 123 ± 18.4
At 1 yr, 5.2 ± 16.0 mmHg ¯  w/ valsartan Placebo: 283 mg (93%)

Valsartan: 254 mg (84%)

PARADIGM-HF LCZ696: 122 ± 15

Enalapril: 121 ± 15

At 8 mo, 3.2 ± 0.4 mmHg ¯  w/ LCZ696 LCZ696: 375±71 mg (>99%)

Enalapril: 18.9 ± 3.4 mg (>99%)*

*42% of patients in the sacubitril/valsartan (LCZ696) arm and 43% in the enalapril arm required a dose reduction at some point during the study.
SOLVD –  Studies of Left Ventricular Dysfunction; Val-HeFT –Valsartan Heart Failure Trial;  PARADIGM-HF – Prospective Comparison of ARNI with ACEi to Determine Impact on Global Mortality and Morbidity in HF Trial

 

It is recommended that RAS inhibitors be titrated to the “target” dose or the highest dose tolerated (shown in Table 21,8,9), as this practice is associated with an incremental improvement in outcomes over lower doses. In the Assessment of Treatment with Lisinopril and Survival (ATLAS) study, high-dose lisinopril (32.5 – 35 mg daily) was associated with a lower risk of all-cause and HF hospitalization compared to low-dose therapy (2.5 – 5 mg daily). At three months, the SBP was 4.4 mmHg lower in the high-dose group. In theHeart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEALL) study, high-dose losartan (150 mg daily) was associated with lower risk of all-cause death or HF hospitalization compared to low-dose therapy (50 mg daily). The risk of HF hospitalization as a singular endpoint was also reduced in the high-dose group. The SBP was 1.4 mmHg lower in the high-dose group at six months. Discontinuation of the study drug was similar between groups in both studies.10,11Up-titration of RAS inhibitor therapy was also shown to improve the composite of all-cause death or HF hospitalization in a cohort study of titration of therapy during and after a hospitalization for HF.12

 

Table 2. Target doses of renin-angiotensin inhibitor therapy 1,8,9

Class Agents Initial dose Target dose
Angiotensin Converting Enzyme Inhibitor Captopril 6.25 mg 3 times 50 mg 3 times
Enalapril 2.5 mg twice 10 to 20 mg twice
Lisinopril 2.5 to 5 mg once 20 to 40 mg once
Perindopril 2 mg once 8 to 16 mg once
Fosinopril 5 to 10 mg once 40 mg once
Quinapril 5 mg twice 20 mg twice
Ramipril 1.25 to 2.5 mg once 10 mg once
Angiotensin II Receptor Blocker Candesartan 4 to 8 mg once 32 mg once
Valsartan 20 to 40 mg twice 160 mg twice
ARB/Neprilysin Inhibitor

(Sacubitril/Valsartan)

No ACEi/ARB use 24/26 mg BID  

97/103 mg BID

Switching from low-dose ACEi/ARB* 24/26 mg BID
Switching from high-dose ACEi/ARB† 49/51 mg BID

*Low-dose ACEi equivalent: total daily dose ≤ 10 mg of enalapril, ≤ 10 mg of lisinopril, ≤ 5 mg of ramipril or equivalent dose of another ACEi; low-dose ARB equivalent total daily dose of ≤ 160 mg valsartan, ≤ 50 mg losartan, ≤ 16 mg of candesartan or equivalent dose of another ARB
†High-dose ACEi equivalent: total daily dose > 10 of enalapril, > 10 mg of lisinopril, > 5 mg of ramipril or equivalent dose of another ACEi; high-dose ARB equivalent total daily dose of > 160 mg of valsartan, > 50 mg of losartan, > 16 mg of candesartan or equivalent dose of another ARB
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker

 

The percentage of patients who receive target doses of RAS inhibitor therapy in the real-world is low despite the known benefits.13-15Based on our experience, one reason that titration does not occur is that there is concern for the risk of hypotension with higher doses. Additionally, the dose is often decreased in patients with “low” BP readings even in the absence of symptoms. Patients with more advanced disease tend to have lower SBP but are also most likely to derive benefit from therapy. A low SBP has been shown to be an independent prognostic indicator of worse outcomes in patients with HFrEF and is a mechanism of the disease.6,16-18

Dosing of RAS inhibitor therapy should be evaluated at each patient encounter. Doses should be titrated every 2-4 weeks until the patient is at the target or maximum tolerated dose, although this frequency may not be feasible in all patients. Reasons for not titrating therapy include symptomatic hypotension, hyperkalemia, unstable renal function, and volume depletion. Caution should be exerted in those with SBP < 90 mmHg. Patients should be counseled that the benefits of therapy are independent of the BP effects and that their dose should not be lowered or discontinued for a “low” BP reading in the absence of hypotensive symptoms. Patients should be counseled to take their time when rising from a supine or seated position and to notify their prescriber should dizziness/lightheadedness occur rather than stopping therapy on their own.

In general, when symptomatic hypotension occurs, one must ensure that the etiology is in fact due to excess dosing of RAS inhibitor therapy before making adjustments. Clinicians should ensure that loop diuretic doses are not too high, which could result in volume depletion. Providers must also ensure that RAS inhibitor therapy is titrated before adding other therapies that reduce BP but do not improve HF outcomes (e.g., amlodipine, thiazide-type diuretics, clonidine and non-selective α-1 blockers such as terazosin). If the use of one of these therapies precludes the up-titration of a RAS inhibitor, therapy should be discontinued or the dose lowered to allow RAS inhibitor titration. Tamsulosin should be used as an alternative to non-selective α-1 blockers for the treatment of benign prostatic hyperplasia.

Bottom line: A patient’s BP should not be the sole driver for titrating RAS inhibitor therapy. The dose should be titrated to the target or the highest tolerable dose.

 

 
Kristin Watson, PharmD, BCPS-AQ Cardiology

Kristin Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal

References:

  1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Card Fail 2017;23:628-51.
  2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017.
  3. Investigators S, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
  4. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
  5. Cohn JN, Tognoni G, Valsartan Heart Failure Trial I. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.
  6. Bohm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 2017;38:1132-43.
  7. Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004;110:2618-26.
  8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
  9. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). European journal of heart failure 2013;15:1062-73.
  10. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840-8.
  11. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312-8.
  12. Verbrugge FH, Duchenne J, Bertrand PB, Dupont M, Tang WH, Mullens W. Uptitration of renin-angiotensin system blocker and beta-blocker therapy in patients hospitalized for heart failure with reduced versus preserved left ventricular ejection fractions. Am J Cardiol 2013;112:1913-20.
  13. Heywood JT, Fonarow GC, Yancy CW, et al. Comparison of medical therapy dosing in outpatients cared for in cardiology practices with heart failure and reduced ejection fraction with and without device therapy: report from IMPROVE HF. Circulation Heart failure 2010;3:596-605.
  14. Asghar H, Rahko PS. Quality of heart failure management: a comparison of care between a comprehensive heart failure program and a general cardiology practice. Congestive heart failure (Greenwich, Conn) 2010;16:65-70.
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  16. Ambrosy AP, Vaduganathan M, Mentz RJ, et al. Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial. Am Heart J 2013;165:216-25.
  17. Li S, Li X. Prognostic Significance of Low Systolic Blood Pressure at Discharge in Patients with Heart Failure and Preserved Ejection Fraction. High Blood Pressure & Cardiovascular Prevention 2017;24:405-12.
  18. Rouleau JL, Roecker EB, Tendera M, et al. Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Journal of the American College of Cardiology 2004;43:1423-9.
Titration of Renin-Angiotensin System Inhibitors in Patients with Heart Failure with Reduced Ejection Fraction and an “At-Goal” Blood Pressure

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