298

the

ACEI perindopril failed to reduce the incidence of the primary end point (all-cause

mortality or HF hospitalizations), but did reduce symptoms and improved functional

capacity. The CHARM-preserved trial

156 also failed to show any difference in CV

mortality, but fewer hospitalizations were seen in the candesartan group (see Case

14-1, Question 13).

The Valsartan in Diastolic Dysfunction (VALIDD)

299

trial compared the effects of

valsartan or placebo added to standard antihypertensive therapy (which included

diuretics, β-blockers, CCBs, or α-blockers) in patients with mild HTN and diastolic

dysfunction. The hypothesis of this trial was that RAAS inhibition with an ARB

would be associated with greater improvement in diastolic function, due to more

regression of LVH or myocardial

p. 301

p. 302

fibrosis. Patients with a history of stage 1 or 2 essential HTN were randomly

assigned to receive either valsartan 160 mg, titrated up to 320 mg, or matching

placebo. Patients who did not achieve a target BP goal of less than 135/80 mm Hg

received additional therapy starting with a diuretic followed by a CCB or a βblocker, then an α-blocker. ARBs, ACEIs, and aldosterone blockers were excluded.

The primary end point was the change in diastolic myocardial relaxation velocity

from baseline to 9 months with a secondary end point of change in LV mass. During

the study, the placebo group received more concomitant antihypertensive therapy

compared with the valsartan group. A small, but significant, increase was seen in

diastolic relaxation velocity in both groups from baseline to follow-up, but there was

no significant difference between the treatment groups. BP reduction did not differ

significantly between the two treatment groups, and was associated with significant

improvement in diastolic function. The authors concluded that aggressive BP control

—even in mild HTN—was associated with improvement in diastolic dysfunction,

irrespective of whether BP reduction was achieved with a RAAS inhibitor or other

antihypertensive agent.

CHARM-Preserved

156

investigated the role of candesartan in patients with HFpEF.

The trial enrolled 3,023 subjects who met the overall CHARM trial inclusion criteria

with an EF of more than 40% (mean, 54%). Subjects had symptomatic HF with

normal (preserved) EF. They received either an ARB alone ( n = 1,514) or placebo;

only 20% of subjects in both groups were taking an ACEI at randomization, 56% a βblocker, and 11% spironolactone.

156 After a median follow-up of 36.6 months, a

trend was noted toward reduction in the primary outcome of CV death or hospital

admission for HF in the candesartan group (22%) compared with placebo (24.3%; p

= 0.118). CV deaths and all-cause mortality were nearly identical in both groups, but

the total number of hospitalizations for HF was significantly reduced in the

candesartan group. The most common side effects with candesartan were hypotension

(2.4%), increase in creatinine (4.8%), and hyperkalemia (1.5%). Discontinuation

because of an adverse event occurred in 17.8% of those treated with candesartan

compared with 13.5% of placebo recipients (p = 0.001) (Table 14-13). Overall, in

symptomatic patients with HFpEF, no significant improvement in mortality occurs

with candesartan compared with placebo, but there was a significant reduction in

HF-related hospitalizations.

I-PRESERVE evaluated irbesartan titrated to 300 mg daily or placebo for the

management of HFpEF.

300 The patient population was 60 years of age or older with

NYHA class II through IV symptoms, EF of at least 45%, and hospitalized for HF

within 6 months prior, or have persistent class III or IV symptoms (n = 4,128). There

was no difference in the primary end point (death from any cause or hospitalization

for a CV cause) between irbesartan (36%) and placebo (37%). The irbesartan group

had more patients experiencing hyperkalemia than placebo. One possible reason for

the neutral results of I-PRESERVE included the high rate of dual RAAS blockade at

baseline (39% ACEI use in the irbesartan group and 40% in the placebo group; 28%

spironolactone use in the irbesartan group and 29% in the placebo group). Based on

this high use, the study is less likely to find benefit with ARBs in addition to other

RAAS agents. Another potential limitation of the study included the high study

discontinuation rate (34%). Overall, irbesartan showed no benefit in reducing

morbidity or mortality in HFpEF patients.

Table 14-13

Clinical Trials of Pharmacotherapy in Heart Failure with HFpEF

Study

Patient

Population

Therapy

Intervention Outcome

Treatment

Duration Results

Aronow et al.

325 NYHA III; Prior

MI, EF >50%; (n

= 21)

Enalapril vs.

placebo

NYHA class,

treadmill exercise

time (seconds)

3 months Enalapril:

NYHA class

from 3 ± 0 to

2.4 ± 0.5 (p =

0.005), exercise

time from 224 ±

27 to 270 ± 44

(p <0.001) vs.

no difference in

placebo

Lang et al.

326 HF symptoms >3

months; EF

>50%; (n = 12)

Lisinopril vs.

placebo

crossover

Dyspnea and

fatigue

5 weeks for

each treatment

arm

No significant

differences

Cleland et al.

298

PEP-CHF

Diastolic

dysfunction; CV

admission within

6 months; EF

Perindopril vs.

placebo

Primary:

composite of allcause mortality

or hospitalization

Mean 26.2

months

Primary: 23.6%

in perindopril

group vs. 25.1%

in placebo (HR

>40%; n = 850) for HF 0.92 [0.70–

1.21], p =

0.545)

Zi et al.

327 NYHA class II

or III; EF ≥40%;

(n = 74)

Quinapril vs.

placebo

6-minute walk

test, QoL,

NYHA class

6 months No significant

differences

Yusuf et al.

156

CHARMPreserved

NYHA II–IV;

hospitalization for

CV causes; EF

>40%; (n =

3,023)

Candesartan vs.

placebo

Primary: CV

death or hospital

admission for HF

Median 36.6

months

Primary: 22% in

the candesartan

group vs. 24%

in the placebo

group (adjusted

HR 0.86 [0.74–

1.00], p =

0.051).

Massie et al.

300

I-PRESERVE

NYHA II–IV;

hospitalized for

HF in last 6

months; EF

≥45%; (n =

4,122)

Irbesartan vs.

placebo

Primary: allcause death or

hospitalization for

CV causes

Mean 49.5

months

Primary: 36% in

the irbesartan

group vs. 37%

in the placebo

group (HR 0.95

[95% CI 0.86–

1.05], p = 0.35)

Yip et al.

328 NYHA II–IV;

history of HF in

last 2 months; EF

>45%; (n = 151)

Ramipril vs.

irbesartan

QoL, 6-minute

walk test, HF

hospital

admission

12 months No significant

differences

p. 302

p. 303

Warner et al.

329 Diastolic

dysfunction;

DOE; EF >50%;

SBP >150, <200

mm Hg (n = 20)

Losartan vs.

placebo

crossover

Exercise time,

QoL

2 weeks for

each treatment

arm

Increase in

exercise time

(11.3 minutes at

baseline,

improved to

12.3 ± 2.6

minutes with

losartan vs. 11.0

minutes with

placebo, p

<0.05) and

improvement in

QoL (25 at

baseline,

improved to 18

with losartan vs.

22 with

placebo); p <

0.05 for both

end points

Parthasarathy et

al.

330

Diastolic

dysfunction;

DOE; EF >40%;

Valsartan vs.

placebo

Primary: exercise

time

14 weeks No significant

differences

(n = 152)

Takeda et al.

331 NYHA II–III

and stage C heart

failure; EF ≥45%

Carvedilol vs.

placebo

Plasma BNP,

NYHA class,

exercise capacity

12 months NYHA class

improved by

0.77 (carvedilol)

vs. 0.25

(placebo) (p <

0.02), exercise

capacity in

METs improved

0.69 (carvedilol)

vs. worsened by

0.07 (placebo)

(p = 0.01).

Flather et al.

301

SENIORS

HF hospital

admission in last

year; EF ≤35%;

subgroup EF

≥35%

Nebivolol vs.

placebo

Primary:

composite of allcause mortality

or hospitalization

for a

cardiovascular

cause

Mean 21

months

EF >35%,

primary event

rate 17.6% in

nebivolol and

21.9% in

placebo (HR

0.86 [95% CI

0.74–0.99], p =

0.039).

Aronow et al.

332 NYHA II–III;

prior Q-wave

MI; EF >40%; n

= 158)

Propranolol vs.

placebo

All-cause

mortality, allcause mortality

plus nonfatal MI

32 months All-cause

mortality (56%

propranolol

group vs. 76%

placebo group, p

= 0.007) and allcause mortality

plus nonfatal MI

(59%

propranolol vs.

82% placebo, p

= 0.002).

Setaro et al.

333 Abnormal

diastolic filling;

EF >45%; (n =

20)

Verapamil vs.

placebo

Exercise

capacity

2 weeks for

each crossover

Exercise

capacity (10.7

minutes at

baseline,

improved to

13.9 minutes

with verapamil

vs. 12.3 minutes

with placebo, p

<0.05).

Ahmed et al.

334

DIG

NYHA I–IV; EF

>45%; (n = 988)

Digoxin vs.

placebo

Primary:

composite of HF

hospitalization or

mortality

Mean 37

months

102 (21%) in

the digoxin

group vs. 119

(24%) in the

placebo group

(HR 0.82

[0.63–1.07], p =

0.136).

Pitt et al.

302 Symptomatic HF; Spironolactone Primary: Mean 39 320 (18.6%) in

TOPCAT EF >45%; (n =

3445)

vs. placebo composite of CV

death, HF

hospitalization, or

aborted cardiac

arrest

months the

spironolactone

group vs. 351

(20.4%) in the

placebo group

(HR 0.89

[0.77–1.04], p =

0.14).

BNP, B-type natriuretic peptide; CV, cardiovascular; DOE, dyspnea on exertion; EF, ejection fraction; HF, heart

failure; HR, hazard ratio; METs, metabolic equivalents; MI, myocardial infarction; NA, not available; NYHA, New

York Heart Association; QoL; quality of life; SBP, systolic blood pressure.

β-Blockers or nondihydropyridine CCBs are other classes of drugs of interest in

HFpEF. Part of their value is to control HTN, a risk factor for all forms of HF. More

specific to HFpEF, β-blockers and CCBs (especially verapamil) possess negative

inotropic properties that may favorably influence the pathophysiology of diastolic

dysfunction by (a) slowing the HR to allow more time for complete ventricular filling

particularly during exercise; (b) reducing myocardial oxygen demand; and (c)

controlling BP. Both pharmacologic classes are beneficial in decreasing ischemia in

patients with CAD.

p. 303

p. 304

Most HF trials with β-blockers demonstrating decreased morbidity and mortality

have focused on HFrEF. The Study of the Effects of Nebivolol Intervention on

Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) study

301

evaluated β-blocker use in elderly HF patients irrespective of LV function. The trial

randomly assigned patients to nebivolol or placebo. Nebivolol is a selective β1

-

adernergic receptor blocker with vasodilator properties that are mediated through

NO release. This effect may be beneficial in elderly patients who tend to have low

reserves of endothelial vasodilation.

The primary end point of the study was the combination of all-cause mortality and

CV hospital admissions. The end point was significantly reduced by 14% in the

nebivolol group, regardless of the EF. Prospective subgroup analyses of the primary

outcome by LVEF (≤35% or >35%), sex, or age (≤75 years or >75 years) showed

benefits across all subgroups. Patients with EF greater than 35%, however, appeared

to benefit a little more than those with low EF%, and all-cause mortality was lower

in patients older than 75 years treated with nebivolol compared with placebo. The

study reinforces the current recommendations that all HF patients with reduced EF

should receive β-blockers. Only 35% of the patients had preserved LV function, and

were mostly men. This is not typical of patients with HFpEF, who are frequently

women. Further studies are required to define the role of β-blockers in HFpEF.

No randomized controlled trials have demonstrated mortality benefits with CCBs

in HFpEF. Nondihydropyridine CCBs can be used in patients who have a

contraindication to β-blockers to control BP and HR. Nondihydropyridine CCBs

should not be used in patients with HFrEF.

The role of aldosterone antagonists in the management of patients with HFpEF has

been evaluated in the Treatment of Preserved Cardiac Function Heart Failure with an

Aldosterone Antagonist (TOPCAT) trial.

302 This trial evaluated the impact of

spironolactone versus placebo on CV morbidity and mortality in patients older than

50 years of age with an EF greater than 45%. There was no difference in the primary

end point (composite of CV death, aborted cardiac arrest, and hospitalization for HF)

between the spironolactone and placebo treatment arms with a HR 0.89 (95% CI

0.77–1.04; p = 0.14). There was a significant reduction with spironolactone versus

placebo in the secondary end point of hospitalization for HF (HR 0.83 [95% CI

0.69–0.99; p = 0.04]). There has also been a sub-analysis of the TOPCAT study

evaluating differences in patients enrolled in the Americas compared to

Russia/Georgia relative to the primary and secondary end points. When only looking

at patients enrolled from North or South America, there was a significant reduction

with the spironolactone-treated patients compared to placebo in the primary end

point (HR 0.82 [95% CI 0.69–0.98]) and all secondary end points.

303 Based on these

findings, the 2017 ACC/AHA/HFSA Focused Update recommend aldosterone

receptor antagonists (class IIb) in HFrEF. An aldosterone receptor antagonist can be

considered to decrease hospitalizations in patients with EF ≥ 45%, an elevated BNP

or recent hospitalizations. If spironolactone is initiated, then potassium and renal

function should be closely monitored (EGFR>30mL/min, creatinine, 2.5mg/dL,

potassium <5.0mEq/L).

6

D.F. fulfills the criteria for having HFpEF, based on her history of long-standing

HTN, which has been poorly controlled. Her BP is not at goal, and her HR is

elevated. Therefore, antihypertensive therapy is warranted. Tachycardia alone can

compromise the ventricle filling time and cause myocardial ischemia. So far, no data

support the use of one agent over another. β-Blockers and nondihydropyridine CCBs

can each reduce BP and HR. β-Blockers are not considered first-line

antihypertensive medications based on recent guidelines without a compelling

indication. The use of a nondihydropyridine CCB would be supported in HFpEF

patients to reduce both BP and HR. D.F. can be started on a nondihydropyridine CCB

such as diltiazem sustained-release (120 mg daily).

Herbal Products and Nutritional Supplements

CASE 14-8

QUESTION 1: W.L., a 60-year-old man recently diagnosed by his naturopath with HF, is concerned about his

decreasing exercise capacity and increasing SOB during his morning walks. The naturopath wants to initiate

hawthorn and coenzyme Q10 to control his HF symptoms. The patient has uncontrolled HTN (170/85 mm Hg),

and has 2+ ankle edema. He distrusts medical doctors because in the past he was given HCTZ for BP

reduction, but stopped taking it after a few days because he did not tolerate the urinary urgency it caused. What

is the role of herbal products and nutritionalsupplements in HF?

HAWTHORN

Hawthorn extracts from the leaves and flowers of Crataegus monogyna and Crataegus

oxyacantha have been reported to have beneficial effects in mild HF.

304,305

Oligomeric procyanidins and flavonoids are considered the key active ingredients.

Hawthorn extracts have shown positive inotropic effects, weak ACE inhibition,

vasodilating properties, and increased coronary blood flow in vitro and in animal

models. In short-term (8 weeks or less), placebo-controlled trials in patients with the

equivalent of NYHA class II HF, modest improvements were noted in exercise

tolerance and subjective symptoms as well as decreases in HR and BP. Patients with

more advanced HF were excluded. A systematic review by Pittler et al. also

concluded that hawthorn extract was efficacious in the treatment of HF when given

with standard HF therapy.

306 Conversely, the results of the Hawthorne Extract

Randomized Blinded Chronic Heart Failure (HERB-CHF) trial failed to provide any

evidence that hawthorn was beneficial in patients with HF who were already

receiving standard medical therapy.

307

In clinical trials, side effects of hawthorn

include nausea, vomiting, diarrhea, palpitations, chest pain, and vertigo. These side

effects are more common when doses exceed 900 mg/day, but in some trials they

have not occurred more often than with placebo. The risks and benefits of using

hawthorn and digoxin together, both of which have positive inotropic effects, are not

known.

To further investigate the longer term benefits of hawthorn, additive effects to

conventional therapy and effect on mortality were tested in the Survival and

Prognosis: Investigation of Crataegus Extract WS 1442 in Congestive Heart Failure

(SPICE) trial.

308 The trial enrolled 2,681 patients with NYHA class II or III, LVEF of

35% or less, who were randomly assigned to hawthorn or placebo for 2 years.

Although the study failed to show any clear benefits in the treatment of chronic HF,

hawthorn was well tolerated.

COENZYME Q

Coenzyme Q, also known as ubiquinone and ubidecarenone, is an endogenously

synthesized provitamin that is structurally similar to vitamin E, serves as a lipidsoluble electron transport carrier in mitochondria, and aids in the synthesis of

adenosine triphosphate.

309,310

It may also have membrane-stabilizing properties,

enhance the antioxidant effects of vitamin E, and stabilize calcium-dependent slow

channels. In animal models, it has positive inotropic effects, although weaker than

those of digoxin. More than 18 open-label and double-blind, randomized clinical

trials have been conducted

p. 304

p. 305

of coenzyme Q in patients with HF ranging from NYHA classes II to IV.

309 Doses

varied from 50 to 200 mg/day. Patients in many of these trials were also taking

diuretics, ACEIs, and digoxin. Different trials used different end point measurements.

Positive effects on subjective symptoms, NYHA class improvement, EF, quality of

life, and hospitalization rates have all been observed. Two trials, however, failed to

demonstrate significant changes in EF, vascular resistance, or exercise tolerance.

None of the trials had sufficiently large samples sizes or adequate duration of

assessment to detect reduction in mortality. Side effects were minimal, but included

nausea, epigastric pain, diarrhea, heartburn, and appetite suppression. Mild increases

in lactate dehydrogenase and hepatic enzymes have been rarely reported with

coenzyme Q doses in excess of 300 mg/day.

Because no clinical trials have demonstrated improved survival with

nutritional/herbal supplements, the current guidelines do not recommend these agents

in patients with current or prior symptoms of HFrEF.

W.L. has poorly controlled systolic HTN and HF that is beginning to interfere with

his activities of daily life. Although evidence indicates that patients with NYHA

class II HF obtain symptomatic improvement with hawthorn and coenzyme Q, this

does not address W.L.’s HTN. Conflicting data exist on the value of coenzyme Q in

lowering BP.

309 The results of the SPICE trial did not demonstrate any mortality

benefits, and no incremental benefits were seen when combined with standard

therapy. Uncontrolled HTN in patients with HF leads to cardiac remodeling, and

worsening HF. Currently W.L. is presenting with symptomatic HF; therefore, he

should be started on a diuretic to alleviate his symptoms. Starting with a 20-mg dose

of furosemide and titrating slowly may be one approach. For all of the reasons cited

throughout this chapter, one must also argue strongly for starting an ACEI to control

his HTN. He should be counseled that the urinary frequency he experienced

previously should diminish after a few days. Once he is euvolemic, a β-blocker

should be started.

The guidelines clearly state that natural products should not be used to treat

symptomatic HF. Agents such as ephedra (which contain catecholamines), ephedrine

metabolites, or imported Chinese herbs are contraindicated in HF because of

increased risk of mortality and morbidity. No regulatory oversight, quality control, or

regulations exist on the use of natural supplements. Because of the widespread use of

nutritional supplements and herbal therapies and their potential to cause drug

interactions, clinicians should routinely inquire about their use.

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