update on heart failure with reduced and preserved ejection … · 2019. 8. 13. · update on heart...

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]

5/20/191

Update on Heart Failure with Reduced and Preserved Ejection Fraction

Van N Selby, MDUCSF Advanced Heart Failure and Heart Transplant ProgramMay 20, 2019

Disclosures

Honoraria (consulting): Alnylam Pharmaceuticals, Akcea Therapeutics

ObjectivesUnderstand the role of new therapies in the management of chronic heart failure with both reduced (HFrEF) and preserved ejection fraction (HFpEF):

§Angiotensin-Neprilysin Inhibitors§ Ivabradine

§SGLT2 inhibitors

§Remote hemodynamic monitoring

§Mineralocorticoid receptor antagonists for HFpEF

Medical Therapy for HFrEF: 2013

§ACE Inhibitors (Class Ia)o ARB as an alternative (Class Ia)

§Beta-blockers (Class Ia)

§Mineralocorticoid receptor antagonists (Class Ia)

§Hydralazine/Isosorbide for African-Americans (Class Ia)

§Other: Diuretics, digoxin, etc

Yancy CW et al, Circulation 2013


5/20/192

Sacubitril-valsartan: HF pathways

Sauer AJ et al, Heart Failure Reviews. Mar 2019, 24(2); 167–176

PARADIGM-HF

§8442 patients with NYHA class II, III, or IV chronic heart failure

o LVEF < 35-40%

o SBP ≥ 95, GFR ≥ 30, K ≤ 5.4

o Tolerated enalapril 10 mg daily or equivalent for ≥ 4 weeks

§Randomized to enalapril 20 mg daily vs sacubitril-valsartan 400 mg daily

§Primary outcome was a composite of cardiovascular death or

HF hospitalization

McMurray JJV et al, N Engl J Med 2014


T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 371;11 nejm.org september 11, 2014998

specified that three interim efficacy analyses should be conducted after the accrual of one third, one half, and two thirds of the events, and the statistical stopping guideline for a compel-ling benefit required a one-sided nominal P value of less than 0.0001 at the first analysis and less than 0.001 at the second and third analyses in favor of LCZ696 for both death from cardiovas-cular causes and the primary end point. On March 28, 2014, at the third interim analysis (after enrollment had been completed), the com-mittee informed the two coprincipal investiga-tors that the prespecified stopping boundary for an overwhelming benefit had been crossed. The

executive committee voted to stop the trial and selected March 31, 2014, as the cutoff date for all efficacy analyses; the sponsor accepted this decision.

We included data from all patients who had undergone a valid randomization in the analyses of the primary and secondary outcomes, accord-ing to the intention-to-treat principle. A sequen-tially rejective procedure was used for analysis of the secondary efficacy end points, with the first two secondary end points at the highest level of the testing sequence. (For details, see the statisti-cal analysis plan in the Supplementary Appendix.) Time-to-event data were evaluated with the use

Enalapril

EnalaprilEnalapril

Enalapril

Cum

ulat

ive

Prob

abili

ty

1.0

0.4

0.6

0.5

0.3

0.2

0.1

1.0

0.4

0.6

0.5

0.3

0.2

0.1

1.0

0.4

0.6

0.5

0.3

0.2

0.1

1.0

0.4

0.6

0.5

0.3

0.2

0.1

0.00 180 360 540 900720 1080 1260

Days since Randomization

C Hospitalization for Heart Failure

A Primary End Point

Hazard ratio, 0.80 (95% CI, 0.73–0.87)P<0.001

No. at RiskLCZ696Enalapril

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

Cum

ulat

ive

Prob

abili

ty

0.00 180 360 540 900720 1080 1260


B Death from Cardiovascular Causes

Hazard ratio, 0.80 (95% CI, 0.71–0.89)P<0.001


41874212

40564051

38913860

32823231

24782410

17161726

1005994

280279

Cum

ulat

ive

Prob

abili

ty

0.00 180 360 540 900720 1080 1260


Hazard ratio, 0.79 (95% CI, 0.71–0.89)P<0.001


41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

Cum

ulat

ive

Prob

abili

ty

0.00 180 360 540 900720 1080 1260


D Death from Any Cause

Hazard ratio, 0.84 (95% CI, 0.76–0.93)P<0.001


41874212

40564051

38913860

32823231

24782410

17161726

1005994

280279

LCZ696

LCZ696LCZ696

LCZ696

AUTHOR:

FIGURE:

ARTIST:

OLF:Issue date:

AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.

Please check carefully.

McMurray

2 of 3

ts

09-11-14 8/30-9/3

Figure 2. Kaplan–Meier Curves for Key Study Outcomes, According to Study Group.

Shown are estimates of the probability of the primary composite end point (death from cardiovascular causes or first hospitalization for heart failure) (Panel A), death from cardiovascular causes (Panel B), first hospitalization for heart failure (Panel C), and death from any cause (Panel D).

The New England Journal of Medicine Downloaded from nejm.org at SAN FRANCISCO (UCSF) on September 13, 2015. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.


PARADIGM-HF: Primary endpoint: CV Death or Hospitalization 2016 Heart Failure Guideline Update

Yancy, CW et al. Circulation 2016


5/20/193

Yancy CW, et al Heart Failure Focused Update on Pharmacological Therapy

10

indications may be continued on ARBs if they subsequently develop HF. ARBs should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARBs are alternatives for patients with ACE inhibitor–induced angioedema, caution is advised because some patients have also developed angioedema with ARBs.

Head-to-head comparisons of an ARB versus ARNI for HF do not exist. For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised.

I ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality (19).

See Online Data Supplements 1 and

18.

Benefits of ACE inhibitors with regard to decreasing HF progression, hospitalizations, and mortality rate have been shown consistently for patients across the clinical spectrum, from asymptomatic to severely symptomatic HF. Similar benefits have been shown for ARBs in populations with mild-to-moderate HF who are unable to tolerate ACE inhibitors. In patients with mild-to-moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥600 pg/mL; or 2) BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril. The target dose of the ACE inhibitor was consistent with that known to improve outcomes in previous landmark clinical trials (10). This ARNI has recently been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily (29). Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema (30).

III: Harm B-R

ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (31, 32).

See Online Data Supplement 3.

Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to angioedema and concomitant use is contraindicated and should be avoided. A medication that represented both a neprilysin inhibitor and an ACE inhibitor,

by guest on September 19, 2016

http://circ.ahajournals.org/D

ownloaded from

2016 Guideline Update


Compared to enalapril, sacubitril-valsartan is also associated with improvements in:

o CV Death

o HF Hospitalizationo All-cause mortality

o Coronary outcomes

o Clinical progression of HFo Functional mitral regurgitation

o Physical and social activities

o Attenuation of diabetic nephropathy

oMarkers of myocardial fibrosis

PARADIGM-HF: Secondary analyses

McMurray JJV et al, N Engl J Med 2014. Kang DH, et al. Circulation. 2018Smith KR et al, Pharmacotherapy 2018

PIONEER-HF: Sacubitril/Valsartan for hospitalized patients§881 patients hospitalized for acute HF

• 52.1% were not previously treated with ACEi/ARB

§Randomized to enalapril vs sacubitril/valsartan

§All patients were hemodynamically stable prior to randomization• No IV vasodilators or diuretics in the previous 6 hours

• No inotropes in the previous 24 hours

§The primary outcome of reduction in NT-proBNP was significantly greater in patients receiving sacubitril/valsartan

§Rehospitalization for HF was lower in sacubitril/valsartan group

§No significant differences in hypotension or worsening renal function

Velazquez EJ et al, NEJM 2018.

Sacubitril/Valsartan§Can be used to replace ACEi or ARB in patients with chronic

HFrEF or as initial therapy

• 36 hour washout period for patients previously treated with ACE-I

• For patients hospitalized with acute heart failure, start Entrestoafter at least 6 hours of hemodynamic stability, and no inotropes for at least 24 hours

§Starting dose is 49/51 mg BID

o Start with a reduced dose of 24/26 mg for those not previously taking ACE/ARB, or those on a low dose

§Double the dose every 2-4 weeks to a target dose of 97/103 mg§May need to reduce diuretic dose


5/20/194

Ivabradine: The SHIFT Trial

§Heart rate is an independent predictor of mortality in heart failure

§ Ivabradine is an inhibitor of the If current in the SA node

§The SHIFT trial enrolled 6558 patients:

o Symptomatic HFrEF (LVEF ≤ 35%)

o HR ≥70 in sinus rhythmo At least one HF hospitalization in the past year

o On background HF therapy including beta-blockers if tolerated

§Randomized to ivabradine (titrated to a max of 7.5 mg BID) vs placebo

Swedberg K et al, Lancet 2010 Sep 11;376(9744):875-85.

Articles

www.thelancet.com Vol 376 September 11, 2010 881

heart rate of 70 bpm or higher, in whom ivabradine reduced both myocardial infarctions and coronary revascularisations.24 Important diff erences between the populations included in these two trials were resting heart rate and background cardiac condition, as well as studied endpoints that could account for the recorded diff erences in outcomes.

Most cardiovascular endpoints (death from heart failure, hospital admission for heart failure, any cardiovascular admission, and the secondary composite of cardiovascular death, hospital admission for heart failure, or non-fatal myocardial infarction) were signifi cantly reduced by ivabradine. Cardiovascular and all-cause deaths were not signifi cantly reduced by ivabradine. Sudden cardiac death

did not seem to be aff ected by ivabradine. This fi nding could be attributable to the eff ect of the background β-blocker treatment (used in 89% of patients), which, unlike ivabradine, has intrinsic electrophysiological eff ects and is known to aff ect sudden cardiac death.6,25,26

In the subgroup of patients receiving at least 50% of the target dose of β blocker, the reduction in heart rate was similar to that in the overall population. Eff ects on cardiovascular outcomes were not signifi cant apart from hospital admission for heart failure, which was signifi cantly reduced by 19%. This fi nding might have been related to the lower event rate in this subgroup (13% per year for primary endpoint) than in the overall population, reducing the power of this secondary analysis.

Figure 3: Kaplan-Meier cumulative event curves for (A) the primary composite endpoint of cardiovascular death or hospital admission for worsening heart failure, (B) hospital admission for worsening heart failure, and (C) cardiovascular death

Number at riskPlacebo group

Ivabradine group

0 6 12 18 24 30

32643241

28682928

24892600

20612173

10891191

439447

Months

0

10

20

30

40

Patie

nts w

ith p

rimar

y com

posit

e end

poin

t (%

)

Placebo (937 events)Ivabradine (793 events)

HR 0·82 (95% CI 0·75–0·90), p<0·0001

0

32643241

0

10

20

30

Patie

nts w

ith fi

rst h

ospi

tal a

dmiss

ion

for w

orse

ning

hea

rt fa

ilure

(%)

HR 0·74 (95% CI 0·66–0·83), p<0·0001

6 12 18 24 30

28682928

24892600

20612173

10891191

439447

Months


Number at riskPlacebo group

Ivabradine group

0 6 12 18 24 30

32643241

30943085

28172818

23912428

13181376

534531

Months

0

10

20

30

Patie

nts w

ith ca

rdio

vasc

ular

dea

th (%

)


HR 0·91 (95% CI 0·80–1·03), p=0·128

A B

C

Swedberg K et al, Lancet 2010

SHIFT: HF Death or Hospitalization

2016 Guideline Update

Yancy CW, et al Heart Failure Focused Update on Pharmacological Therapy

11

omapatrilat, was studied in both hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema (31, 32) and associated significant morbidity. This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema (32, 33). An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor.

III: Harm C-EO ARNI should not be administered to patients with a history of angioedema.

N/A

Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF (31). In a very large RCT of hypertensive patients, ompatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril (32). Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat (34, 35). In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension (36) and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF (19). ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema.

7.3.2.11. Ivabradine: Recommendation See the Online Data Supplement

(http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000435/-/DC2) for evidence

supporting this recommendation.

Recommendation for Ivabradine COR LOE Recommendation

IIa B-R

Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (37-40).

See Online Data Supplement 4.

Ivabradine is a new therapeutic agent that selectively inhibits the If current in the sinoatrial node, providing heart rate reduction. One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF hospitalization (38). The benefit of ivabradine was driven by a reduction in HF hospitalization. The study included patients with HFrEF (NYHA class II-IV, albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) ≤35%, in sinus rhythm with a resting heart rate of ≥70 beats per minute. Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in

by guest on September 8, 2016

http://circ.ahajournals.org/D

ownloaded from


§No patients enrolled from the US

§Only 23% were on target dose beta-blockero There was no significant improvement in the primary outcome

among patients taking at least 50% target dose beta-blocker at randomization

o With true target doses of beta-blockers, the heart rate will usually fall below 70

Therapies for heart failure with preserved ejection fraction (HFpEF)


5/20/195

Spironolactone for HFpEF: Background§No medical therapy has been proven to improve outcomes for HFpEF

§Mineralocorticoid receptor antagonists (MRA) improve outcomes in HFrEF and post-MI with LV dysfunction

§Small studies suggested MRAs may improve diastolic function as well

TOPCAT: Spironolactone for HFpEF

§The TOPCAT trial randomized patients with HFpEF to spironolactone vs placebo

§A negative trial overall: No significant difference in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or HF hospitalization

§However, there were significant differences in the patient populations depending on country of enrollment

Pitt B, NEJM 2014 Jul 10;371(2):181-2.

TOPCAT: Americas Sub-Analysis

§ Patients enrolled from the Americas appeared to have much higher-risk baseline characteristics compared to those enrolled from Russia/Georgia§ Higher rates of many co-morbidities§ More likely to be enrolled based on high BNP level

§ Among patients randomized to placebo, those from the Americas had much higher event rates than those from Russia/Georgia§ Suggesting the patients from the Americas were a

sicker population

Pfeffer MA et al, Circulation 2015 Jan 6;131(1):34-42.

TOPCAT: Americas Sub-AnalysisPfeffer et al Regional Variation in TOPCAT 39

amplified in additional sensitivity analysis restricted to patients reported to be on study medication at that visit (Table VIII in the online-only Data Supplement). All values obtained through the first year of follow-up are shown in Figure 2. The average mag-nitude of the systolic blood pressure reduction associated with spironolactone relative to placebo was greater in the Americas (4.2 mm Hg; P<0.001) than in Russia/Georgia (0.6 mm Hg: P=0.10; interaction P<0.001). Similarly, the average magni-tude of the increase in potassium associated with spironolactone

relative to placebo was greater in the Americas (0.26 mmol/L; P<0.001) than in Russia/Georgia (0.08 mmol/L; P<0.001; inter-action P<0.001), and the average magnitude of the increase in creatinine associated with spironolactone relative to placebo was greater in the Americas (0.10 mg/dL; P<0.001) than in Russia/Georgia (0.02 mmol/L; P=0.002; interaction P<0.001). These 3 differences in magnitude of treatment response similarly per-sisted in adjusted models using these serial measurements.

DiscussionThis post hoc analysis was based on the observation of an unusu-ally large difference in the placebo event rates between the sites conducting TOPCAT in the 4 countries in the Americas com-pared with those in Russia and Georgia.14 In addition to the marked differences in prognosis, this regional analysis revealed many additional important dissimilarities in patient characteris-tics; the potassium, creatinine, and blood pressure responses to spironolactone; and reports of adherence to study medications. Regional differences have complicated the interpretations of other randomized trials in cardiovascular medicine.1–7,20–22 The prior observed pattern of fewer events in patients from Eastern Europe2,5,7 may have been amplified in TOPCAT because Russia and Georgia contributed 49% of the total enrollment. However, the observed difference between regions in TOPCAT is striking in magnitude, exceeding that anticipated by variations in practice patterns; indeed, it is the marked difference in the placebo groups that distinguishes this from many previous reports of regional variation. This observed difference in population risk profiles obfuscates our ability to unite the results from these 2 disparate regions to draw conclusions about the results of the overall study.

The regional differences in almost every important base-line variable suggest that clinical diagnostic criteria were not uniformly interpreted or applied. Making the assessment that the dyspnea and fatigue of a patient with a preserved ejection fraction are attributed to heart failure rather than to the com-monly associated comorbidities is notoriously difficult.23–30 The additional protocol inclusion criterion in TOPCAT of either a prior hospitalization in which heart failure was a prominent feature or an elevated natriuretic peptide level was intended to both improve diagnostic certainty and to augment risk. The assumption that those with a prior hospitalization would have higher risk31–35 was confirmed only for the patients random-ized from the Americas, suggesting that the nonadjudicated qualifying hospitalization criterion enrolled different patient populations. However, multifold lower event rates were also observed in the patients qualifying by natriuretic peptides from Russia/Georgia. The event rates of those enrolled from the Americas were reflective of other clinical trial populations with symptomatic heart failure and preserved ejection frac-tion,36,37 whereas the observed heart failure hospitalization rate of 1 per 100 patient-years in the placebo arm of the Russia/Georgia cohort is quite consistent with rates reported in hyper-tension trials such as the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Valsartan Antihypertensive Long-Term Use Evaluation (VALUE), and Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), and it is 5-fold lower than the 2 prior heart failure with preserved ejection fraction trials, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity

Figure 1. Kaplan-Meier plots of primary outcome and 2 major components. A, Time to primary outcome; B, time to cardiovascular (CV) death; and C, time to first confirmed hospitalization for heart failure.

by guest on September 13, 2015http://circ.ahajournals.org/Downloaded from

Pfeffer et al Regional Variation in TOPCAT 39

amplified in additional sensitivity analysis restricted to patients reported to be on study medication at that visit (Table VIII in the online-only Data Supplement). All values obtained through the first year of follow-up are shown in Figure 2. The average mag-nitude of the systolic blood pressure reduction associated with spironolactone relative to placebo was greater in the Americas (4.2 mm Hg; P<0.001) than in Russia/Georgia (0.6 mm Hg: P=0.10; interaction P<0.001). Similarly, the average magni-tude of the increase in potassium associated with spironolactone

relative to placebo was greater in the Americas (0.26 mmol/L; P<0.001) than in Russia/Georgia (0.08 mmol/L; P<0.001; inter-action P<0.001), and the average magnitude of the increase in creatinine associated with spironolactone relative to placebo was greater in the Americas (0.10 mg/dL; P<0.001) than in Russia/Georgia (0.02 mmol/L; P=0.002; interaction P<0.001). These 3 differences in magnitude of treatment response similarly per-sisted in adjusted models using these serial measurements.

DiscussionThis post hoc analysis was based on the observation of an unusu-ally large difference in the placebo event rates between the sites conducting TOPCAT in the 4 countries in the Americas com-pared with those in Russia and Georgia.14 In addition to the marked differences in prognosis, this regional analysis revealed many additional important dissimilarities in patient characteris-tics; the potassium, creatinine, and blood pressure responses to spironolactone; and reports of adherence to study medications. Regional differences have complicated the interpretations of other randomized trials in cardiovascular medicine.1–7,20–22 The prior observed pattern of fewer events in patients from Eastern Europe2,5,7 may have been amplified in TOPCAT because Russia and Georgia contributed 49% of the total enrollment. However, the observed difference between regions in TOPCAT is striking in magnitude, exceeding that anticipated by variations in practice patterns; indeed, it is the marked difference in the placebo groups that distinguishes this from many previous reports of regional variation. This observed difference in population risk profiles obfuscates our ability to unite the results from these 2 disparate regions to draw conclusions about the results of the overall study.

The regional differences in almost every important base-line variable suggest that clinical diagnostic criteria were not uniformly interpreted or applied. Making the assessment that the dyspnea and fatigue of a patient with a preserved ejection fraction are attributed to heart failure rather than to the com-monly associated comorbidities is notoriously difficult.23–30 The additional protocol inclusion criterion in TOPCAT of either a prior hospitalization in which heart failure was a prominent feature or an elevated natriuretic peptide level was intended to both improve diagnostic certainty and to augment risk. The assumption that those with a prior hospitalization would have higher risk31–35 was confirmed only for the patients random-ized from the Americas, suggesting that the nonadjudicated qualifying hospitalization criterion enrolled different patient populations. However, multifold lower event rates were also observed in the patients qualifying by natriuretic peptides from Russia/Georgia. The event rates of those enrolled from the Americas were reflective of other clinical trial populations with symptomatic heart failure and preserved ejection frac-tion,36,37 whereas the observed heart failure hospitalization rate of 1 per 100 patient-years in the placebo arm of the Russia/Georgia cohort is quite consistent with rates reported in hyper-tension trials such as the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Valsartan Antihypertensive Long-Term Use Evaluation (VALUE), and Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), and it is 5-fold lower than the 2 prior heart failure with preserved ejection fraction trials, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity

Figure 1. Kaplan-Meier plots of primary outcome and 2 major components. A, Time to primary outcome; B, time to cardiovascular (CV) death; and C, time to first confirmed hospitalization for heart failure.

by guest on September 13, 2015http://circ.ahajournals.org/Downloaded from

Pfeffer MA et al, Circulation 2015 Jan 6;131(1):34-42.

HR 0.82 HR 0.74


5/20/196


ACCEPTED MANUSCRIPTYancy, et. al. 2017 ACC/AHA/HFSA Heart Failure Focused Update

1

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

Developed in Collaboration with the American Academy of Family Physicians, American

College of Chest Physicians, and International Society for Heart and Lung Transplantation

WRITING GROUP MEMBERS*

Clyde W. Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair Mariell Jessup, MD, FACC, FAHA, Vice Chair

Biykem Bozkurt, MD, PhD, FACC, FAHA*† Steven M. Hollenberg, MD, FACC# Javed Butler, MD, MBA, MPH, FACC, FAHA*‡ JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA*¶ Donald E. Casey, Jr, MD, MPH, MBA, FACC§ Frederick A. Masoudi, MD, MSPH, FACC** Monica M. Colvin, MD, FAHA║ Patrick E. McBride, MD, MPH, FACC†† Mark H. Drazner, MD, MSc, FACC, FAHA, FHFSA‡ Pamela N. Peterson, MD, FACC, FAHA‡ Gerasimos S. Filippatos, MD* Lynne Warner Stevenson, MD, FACC*‡ Gregg C. Fonarow, MD, FACC, FAHA, FHFSA*‡ Cheryl Westlake, PhD, RN, ACNS-BC, FAHA, FHFSA¶ Michael M. Givertz, MD, FACC, FHFSA*¶

ACC/AHA TASK FORCE MEMBERS

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, FACC, FAHA, Chair-Elect

Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair‡‡ Sana M. Al-Khatib, MD, MHS, FACC, FAHA Federico Gentile, MD, FACC Kim K. Birtcher, PharmD, MS, AACC Samuel Gidding, MD, FAHA Biykem Bozkurt, MD, PhD, FACC, FAHA Mark A. Hlatky, MD, FACC Ralph G. Brindis, MD, MPH, MACC‡‡ John Ikonomidis, MD, PhD, FAHA Joaquin E. Cigarroa, MD, FACC José Joglar, MD, FACC, FAHA Lesley H. Curtis, PhD, FAHA Susan J. Pressler, PhD, RN, FAHA Lee A. Fleisher, MD, FACC, FAHA Duminda N. Wijeysundera, MD, PhD

*Writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. †ACC/AHA Task Force on Clinical Practice Guidelines Liaison. ‡ACC/AHA Representative. §ACP Representative. ║ISHLT Representative. ¶HFSA Representative. #CHEST Representative. **ACC/AHA Task Force on Performance Measures Representative. ††AAFP Representative. ‡‡Former Task Force member; current member during the writing effort. This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Association Science Advisory and Coordinating Committee, the American Heart Association Executive Committee, and the Heart Failure Society of America Executive Committee in April 2017. The American College of Cardiology requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA

Cardiac amyloidosis in HFpEF

Cardiac amyloidosis, especially transthyretin (TTR), is now recognized as an overlooked cause of HFpEF

• TTR identified in 13% of patients > 60 years hospitalized for HFpEF1

• TTR found in 25% of patients > 85 years at autopsy2

• TTR identified in approximately 1 in 7 patients undergoing TAVR3

1González-López E et al, Eur Heart J 2015; 36:2585-2594. 2Tanskanen M et al, Ann Md 2008; 40:232-239.3Castaño A et al, Eur Heart J, Volume 38, Issue 38, 7 Oct 2017, 2879–2887.

When to suspect cardiac amyloidosis§Echocardiography:

• Thick LV with low ECG volts

• Thickened RV free wall, valves

§New hypertrophic cardiomyopathy

with an alternative explanation§ Intolerance of beta-blockers/ACEi

§Low or normal BP in a previously hypertensive patient

§Bilateral carpal tunnel syndrome§Peripheral or autonomic neuropathy, orthostatic hypotension

§Family history (hATTR), African American > 60 years

When to suspect cardiac amyloidosis§Echocardiography:

• Thick LV with low ECG volts

• Thickened RV free wall, valves

§New hypertrophic cardiomyopathy

with an alternative explanation§ Intolerance of beta-blockers/ACEi

§Low or normal BP in a previously hypertensive patient

§Bilateral carpal tunnel syndrome§Peripheral or autonomic neuropathy, orthostatic hypotension

§Family history (hATTR), African American > 60 years


5/20/197

Tafamidis improves all-cause survival in TTR cardiac amyloidosis

Maurer MS et al, NEJM 2018

Therapies for heart failure with preserved or reduced ejection fraction

Sodium-glucose transporter-2 inhibition

§Block sodium/glucose uptake in the proximal tubule, inducing glycosuria

• Also induce natriuresis

§Reduces A1c levels by approximately 1%

§SGLT2 inhibitors reduce blood pressure and body weight

§ In multiple clinical trials of SGLT2 inhibitors, a significant decrease in heart failure hospitalizations was observed

• Osmotic diuresis

• Reduces plasma volume without sympathetic activation

• Decrease vascular stiffness, improve endothelial function

SGLT2 Inhibitors associated with reduction in heart failure hospitalizations

Zelniker TA et al, Lancet 2019; 393.31-19.


5/20/198

Melanie J. Davies et al. Dia Care 2018;41:2669-2701 Melanie J. Davies et al. Dia Care 2018;41:2669-2701

Melanie J. Davies et al. Dia Care 2018;41:2669-2701

SGLT2 initiation pathway


5/20/199

SGLT2 Inhibitors: Considerations§Possible increased risk of Fournier gangrene

• Now associated with all SGLT2 inhibitors

§Urinary tract/genital infections, urosepsis

§May cause/worsen hypovolemia

Remote Hemodynamic Monitoring for HF

Adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

Remote Hemodynamic Monitoring for HF

Adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

CardioMEMS


5/20/1910

CHAMPION TRIAL

§NYHA Class III heart failure§Previous HF hospitalization

§No ejection fraction criteria

§Randomized to a wireless implantable hemodynamic monitoring system vs control

§At least 6 months follow-up

§Primary outcome: re-hospitalization

Abraham WT et al, Lancet 2011 Feb 19;377(9766):658-66.

CHAMPION

Abraham WT et al, Lancet 2011 Feb 19;377(9766):658-66.

Risk reduction: 36%Risk reduction: 29%

CardioMEMS

§ Inserted via venous catheter, requires selective pulmonary angiogram (10 cc contrast)

§No batteries or leads§ Indication:

o Wirelessly measuring and monitoring PA and HR

o In patients with functional class III heart failure with at least one hospitalization in the past year

o Hemodynamic data are used with the goal of better HF management and to reduce hospitalization

CardioMEMS: Improved survival among patients with HFrEF on GDMT

Givertz MM et al, J Am Coll Cardiol. 2017 Oct 10;70(15):1875-1886.


5/20/1911

CardioMEMS for HFpEF

Adamson et al Hemodynamic Management of Patients With HFpEF 941

management compared with preserved EF control group sub-jects (average of 8.0 HF medication changes for a total of 495 in treatment subjects versus an average of 4.1 HF medication changes for a total of 232 in control subjects; P<0.0001). Simi-lar findings were also observed in reduced EF subjects (average of 9.5 HF medication changes for a total of 1973 in treatment subjects versus an average of 3.7 HF medication changes for a total of 825 in control subjects; P<0.0001; Table 7).

The differences in medical management between treatment and control group subjects were because of medication changes in response to elevated PA pressure (Table 8). Most of the 260 medication changes (73.5%; n=191) in response to elevated PA pressures in the treatment group involved an increase or decrease in loop or thiazide diuretic dosing (Table 8). Nitrates and hydralazine changes represented 33 (12.7%) of the responses to elevated PA pressures. Similar findings were also observed in reduced EF subjects. Most of the 1002 medica-tion changes (64.9%; n=650) in response to elevated PA pres-sures in the treatment group involved a loop or thiazide diuretic (Table 8). Nitrates and hydralazine changes represented 110 (12.6%) of the responses to elevated PA pressures (Table 8).

Diuretic changes in response to elevated PA pressures typi-cally included increases in dose or frequency during a 2- to 3-week time period. When PA pressures were adequately lowered in response to these changes, physicians typically reduced the dose and frequency back to the patient’s baseline regimen. As a result of this dynamic process, treatment group patients received

diuretic adjustment only when hemodynamically warranted for limited time intervals. Although the change in total daily dose of diuretics and nitrates, when evaluated at baseline and the end of the 6-month time period, does not fully characterize this dynamic process, this analysis does provide a snapshot of how access to PA pressures resulted in differential treatment profiles between the treatment and control groups (Tables 9 and 10).

For treatment group patients with preserved EF, the total daily dose of loop diuretics was increased from baseline by 52.1 mg (furosemide equivalent) compared with only 0.4 mg in control group patients (P=0.0045; Tables 9 and 10). The change in total daily dose from baseline for nitrates was not different between treatment group and control group preserved EF patients. For patients with reduced EF, the total daily dose of nitrates was increased from baseline by 18.2 mg compared with only 2.6 mg in control group patients (P=0.0230). The change in total daily dose from baseline for loop diuretics was not different between treatment group and control group reduced EF patients (Tables 9 and 10).

Changes in PA PressureAt device implantation and randomization, patients with pre-served EF had similar PA mean pressures between the treat-ment and control groups (27.1 versus 26.5 mm Hg; P=0.5327; Table 1). Using area under the curve methods, treatment group patients had a median reduction of −3.0 mm Hg days versus an increase of 97.7 mm Hg days in control group patients during the 6 months of primary follow-up.

In patients with preserved EF, the increase in average mean PA pressure was 3.4±4.6 mm Hg before a HF hospitalization compared with 0.7±4.8 mm Hg before a non-HF hospitaliza-tion (P=0.0174). The same pattern was observed in patients with reduced EF. The increase in mean PA pressure was 1.3±5.6 mm Hg before a HF hospitalization compared with −0.3±5.5 mm Hg before a non-HF hospitalization (P=0.0034).

DiscussionPatients with HF and preserved LVEF were the only prespeci-fied subgroup analysis in the CHAMPION trial. Significant and clinically meaningful reductions in hospitalization rates were accomplished in the patient with HFpEF group by primarily adjusting diuretic therapy to maintain control of remotely mon-itored PA pressure measurements. Hospitalization reductions were similar between patients in the prespecified subgroup with LVEF ≥40% and the additional analysis performed in the group with LVEF ≥50%. Hospitalization reductions were significant after 6 months of hemodynamic-guided care and at an even greater magnitude after an average of 17.6-month

Table 6. Heart Failure Hospitalization Rates by Baseline Ejection Fraction Subgroup: Full Duration of Randomized Follow-Up (17.6 Months)

Ejection Fraction

Randomization Group

No. of Heart Failure

Hospitalizations

Annualized Rate of Hospitalization for Heart Failure

Incidence Rate Ratio (95% CI; P Value)

≥40% Treatment group (n=62)

29 0.43 0.50 (0.35–0.70; <0.0001)Control group

(n=57)59 0.86

≥50% Treatment group (n=35)

13 0.41 0.30 (0.18–0.48; <0.0001)Control group

(n=31)31 1.39

<40% Treatment group (n=208)

153 0.67 0.74 (0.63–0.89;

0.0010)Control group (n=222)

220 0.90

CI indicates confidence interval.

Table 7. Total Medication Changes

Preserved (EF≥40%) Reduced (EF<40%)

Treatment (n=62)

Control (n=57) P Value*

Treatment (n=208)

Control (n=222) P Value*

Mean±SD 8.0±6.6 4.1±6.5 <0.0001 9.5±7.6 3.7±3.9 <0.0001Median (Q25, Q75) 6.0 (3.0, 12.0) 2.0 (1.0, 5.0) 8.0 (3.0,13.5) 3.0 1.0, 5.0)

Sum 495 232 1973 825

EF indicates ejection fraction.*P value testing treatment vs control obtained from exact Wilcoxon rank-sum test.

by guest on September 12, 2015http://circheartfailure.ahajournals.org/Downloaded from

Abraham WT et al, Lancet 2011

Conclusions

§For patients with HFrEF, sacubitril/valsartan is associated with improvements in multiple clinical outcomes compared to ACE inhibitors

§Spironolactone is associated with improved outcomes in appropriately selected patients with HFpEF

§Do not miss cardiac amyloid in patients with HFpEF!

§Consider SGLT2 inhibitors for patients with DM and HF (or atherosclerotic cardiovascular disease)

§CardioMEMS remote hemodynamic monitoring reduces hospitalization in chronic HF regardless of EF

Thank [email protected]

update on heart failure with reduced and preserved ejection … · 2019. 8. 13. · update on heart...

Documents