Updates in heart failure,lipidology

1. ACC 2020 UPDATES
Their Implications in Clinical Practice
Dr.Nagula Praveen, MD,DM
Assistant Professor,
Dept. of Cardiology,
Osmania General Hospital,
Hyderabad.
drpraveennagula@gmail.com
Twitter: @kizashipraveen

2. HEART FAILURE

3. Correcting the Endothelial
dysfunction can we improve the heart
failure?
Everything lies in the barrier (endothelium)
Keep the barrier intact, keep the function intact

4. Vericiguat in Patients with
Heart Failure
and Reduced Ejection Fraction
(VerICiguaT GlObal Study in Subjects With Heart Failure With
Reduced EjectIon FrAction)
VICTORIA Trial
NEJM. March 28, 2020 DOI: 10.1056/NEJMoa1915928

6. Study Design
 Phase III,
 Randomized, double blinded, placebo – controlled trial
 5050 patients
 Chronic heart failure ( NYHA class II,III or IV )
 LV EF < 45%
 Vericiguat (10mg OD) vs placebo in addition to GDMT
 Started at dose of 2.5mg od – 5mg od – 10mg od
 Primary outcome – composite of death from CV cause or first hospitalization for heart
failure.
NEJM. March 28, 2020 DOI: 10.1056/NEJMoa1915928

7. Characteristics of the Patients at Baseline
NEJM. March 28, 2020 DOI: 10.1056/NEJMoa1915928

8. Primary Outcome and Secondary Outcome
 CV death or hospitalization for heart failure
 35.5% (vericiguat) vs 38.5% placebo [HR 0.90, p = 0.02)
 Risk of the primary outcome vericiguat vs placebo
 Those aged < 75 years (HR = 0.84)
 Those with >75 years (HR = 1.04)
 CV death: 16.4% (vericiguat) vs 17.5% (placebo); p = 0.27
 All – cause death: 20.3% (vericiguat) vs 21.2% (placebo); p = 0.38.
 HF hospitalization: 27.4% (vericiguat) vs 29.6% (placebo); p = 0.05.

9. Estimates of the Cumulative Incidence of the Primary Outcome and Secondary Outcomes
NEJM. March 28, 2020 DOI: 10.1056/NEJMoa1915928

10. Subgroup Analysis
NEJM. March 28, 2020 DOI: 10.1056/NEJMoa1915928

11. Clinical Implications
• Among patients with CHF with recent decompensation,
 increasing s GC activity with vericiguat was effective.
• Vericiguat compared with placebo
 Was effective at reducing CV death or hospitalization for HF.
 Had enhanced benefit among patients <75 years of age.
 Had no apparent reduction in all-cause mortality.
 was safe and well tolerated and did not require monitoring of renal function or
electrolytes.

12. ARNI made a
PARADIGM SHIFT in HFREF Rx….
can it be a model of excellence in
HFPEF Rx??
Does the history repeat?

13. Prospective Comparison of ARNI With
ARB Global Outcomes in HF With
Preserved Ejection Fraction -
PARAGON-HF
PARAGON - a person or thing viewed as a model of excellence

14. Study design
 Randomized double blind controlled trial
 Active-comparator trial
 HFPEF, 4800 patients
 Sacubitril/Valsartan 97/103 mg daily vs Valsartan 160 mg bid
 Primary outcome:
 Rate of CV death or hospitalizations for HF 12.8% vs 14.6% (P = NS)
 Secondary outcomes:
 NYHA class improvement 15% vs 12.6% ( P < 0.05)
 Renal composite outcome, 1.4% vs 2.7% (P< 0.05)

15. Primary and Secondary Outcomes

16. Effect of drug does vary according to sex?

17. Benefit of sacubitril-valsartan according to sex
Sacubitril-valsartan hazard ratios (HRs) for the primary outcome according to sex:
27% reduction in Female vs 3% worsening in Men
As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart
failure hospitalization more in women than in men.

18. Does the time of initiation of drug
from HF hospitalization have effect on
its benefit
Time is Benefit/Gain

19. • Sacubitril-valsartan vs. placebo
• the absolute reduction in CV death or hospitalisation for HF
When initiated
• < 30 days from index hospitalization
• 6.4% reduction
• 30-90 days from index hospitalization
• 4.6% reduction
• 91-180 days after index hospitalization
• 3.4% reduction
• >180 days after index hospitalization
• No benefit
• This finding needs prospective validation
Results

20. NT Pro BNP levels are markers of prognosis
in HFPEF
Does the use of ARNI have effect on
levels???

21. J Am Coll Cardiol HF 30 March 2020
• The prognostic significance of baseline NT-proBNP was evaluated.
• Whether NT-proBNP levels modified the treatment response to sacubitril/valsartan ?
• The treatment effect of sacubitril/valsartan on NT-proBNP levels overall ?
• In key subgroups (AF, Obesity) ?
• NT-proBNP was measured
• at screening in all patients and
• at 5 subsequent times in >2,700 patients:
• before, run in period
• between, run in period
• after sequential run-in periods,
• At 16 weeks and
• At 48 weeks post-randomization.

22. Association Between Screening Visit NT-proBNP and Primary Endpoint
Event Rate in Patients With/Without AF and Obesity
J Am Coll Cardiol HF 30 March 2020
• NT-proBNP was associated with the primary
endpoint, total HF hospitalizations and CV
death (rate ratio [RR] 1.68 per log increase in
NT-proBNP, p < 0.001).
• This relationship was stronger with atrial
fibrillation (p for interaction < 0.001) and
weaker with obesity (p for interaction <
0.001).
• Sacubitril/valsartan compared with valsartan
reduced NT-proBNP by 19%.

23. Variation in Primary Endpoint Event Rate and Sacubitril/Valsartan Treatment Effect
by Screening Visit NT-proBNP
J Am Coll Cardiol HF 30 March 2020
• Baseline NT-proBNP did not modify
the treatment effect of sacubitril-
valsartan compared with valsartan (p
for interaction = 0.96).

24. Clinical Implications
Among patients with HFpEF, sacubitril-valsartan compared to valsartan
 1. Not effective at reducing the incidence of CV death or HF hospitalization
 2. There was less decline in renal function
 3. There was reduction of the primary outcome in women, but not in men.
 4. Patients benefiting from this drug is not predicted by NT-proBNP levels

25. What is the effect of statins in chemotherapy
induced cardiac dysfunction
Does their pleomorphic effects show benefit in
this subset?

28. Statins Are Associated With Lower Risk of Heart Failure After
Anthracycline And Trastuzumab Chemotherapy For Early Stage
Breast Cancer
Methods :
 A population-based retrospective cohort study was conducted of women aged ≥66 years diagnosed with
early stage breast cancer (EBC) in Ontario from 2007-2017.
 Women were studied who received anthracyclines or trastuzumab in the year after diagnosis as
separate cohorts.
 Propensity scores (PS) were used to match statin-treated with unexposed women (1:1) in each cohort;
trastuzumab-treated women were also matched on prior anthracycline use.
 Cumulative incidence functions was used to describe the risk of hospitalization or emergency
department (ED) visits (hospital visits) for heart failure (HF) and causespecific regression to quantify the
relative rate of HF.

29. Results
• Over a median follow-up period of 5
years, results indicated statin use was
associated with a significantly lower risk
of HF compared to those who did not
receive statins.
• Specifically, patients in the trastuzumab-
treated group experienced a 66%
reduction and patients in the
anthracycline-treated group experienced
a 58% reduction in risk of HF.

30. Clinical implications
Presented at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 29,
2020.
 Cardiovascular disease is the leading and competing cause of death among
older early stage breast cancer survivors.
 Statin use is associated with a significantly lower risk of developing HF
requiring hospital-based care among women with early stage breast cancer who
received one of these cancer therapies.

31. LIPIDOLOGY

32. Lesser LDL cholesterol Lesser CV events
High dose of statins have adverse effects…
Can we incline for more lesser LDL levels ???
Hunt for lower levels…
ORION trial

34. ORION Phase III Pooled Analysis
 New pooled data from a trio of pivotal phase 3 trials assessing inclisiran, show the first-
in-class siRNA drug’s significant and durable benefit for LDL-C reduction in
patients with ASCVD.
The ORION trial program includes data pooled from ORION-9, -10, and -11 showing
reduction in LDL-C of 51% when used in addition to other lipid-lowering therapies
(LLT) over 17 months of treatment.
 Fewer MACE events 7.1% vs 9.6 % ( p < 0.0001)
 SC administration, 0,3, every 6 months thereafter

35. Add-On Inclisiran found to reduce LDL-C by 51% Over 17 Months
in ASCVD Patients – ORION Phase III Pooled Analysis
 Patients treated with inclisiran also reported good tolerance, with a safety profile
similar to placebo.
 The most common adverse reactions reported to occur in ≥3% of treated patients &
more frequently than those with placebo included: DM; HTN; nasopharyngitis;
arthralgia; back pain; dyspnea; bronchitis; and URTI.
 The therapy is currently under USFDA review for use in adults with ASCVD or
heterozygous familial hypercholesterolemia (HeFH) who have elevated LDL-C while
being on a maximum tolerated dose of an LLT.

36. Clinical Implications
 Inclisiran is the novel approach to reduce the level of LDL-C
- With twice yearly administration it provides robust & durable LDL-c reduction over 18
months on top of maximally tolerated oral therapies.
- Effects were consistent in patients with HeFH, ASCVD or ASCVD risk equivalence.
- The safety profile was similar to placebo in a high risk population.
 Twice yearly administration will coincide with typical twice yearly patient visits
with health care providers, thereby assuring treatment adherence.

37. What is the effect of PCSK9 Inhibitors
in Familial Hypercholesterolemia?

40. Alirocumab Efficacy And Safety In Adults With Homozygous
Familial Hypercholesterolemia (ODYSSEY HoFH)
Study design
Presented at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

41. Baseline Characteristics
Alirocumab (n=45) Placebo
(n=24)
Age, years, mean (SD) 42.3 (14.1) 45.4 (15.8)
Male, n (%) 21 (46.7) 13 (54.2)
Race, n (%)
White 36 (80.0) 18 (75.0)
Black or African American 2 (4.4) 0
Asian 7 (15.6) 5 (20.8)
Body mass index, kg/m2, mean (SD) 25.1 (5.4) 25.1 (5.1)
History of CHD, n (%) 21 (46.7) 9 (37.5)

42. Lipid-Lowering Therapy at Screeninga
n (%)
Alirocumab
(n=45)
Placebo
(n=24)
Any statin 44 (97.8) 23 (95.8)
High-intensity statinb 38 (84.4) 21 (87.5)
Ezetimibe 31 (68.9) 19 (79.2)
Statin + ezetimibe 30 (66.7) 19 (79.2)
Lomitapide 7 (15.6) 3 (12.5)
Apheresis + other LLT 6 (13.3) 4 (16.7)
aA patient can be counted in several categories.
bHigh-intensity statin corresponds to atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily.

43. Baseline Lipids
Alirocumab
(n=45)
Placebo
(n=24)
LDL-C, mg/dL, mean (SD) 295.0 (154.6) 259.6 (175.8)
Non-HDL-C, mg/dL, mean (SD) 320.5 (160.4) 282.0 (177.4)
Apolipoprotein B, mg/dL, mean (SD) 193.3 (87.6) 175.0 (95.1)
HDL-C, mg/dL, mean (SD) 43.8 (14.8) 43.2 (12.0)
Triglycerides, mg/dL, median (Q1:Q3) 110.0 (79.0:160.0) 80.5 (61.0:128.5)
Lp(a), mg/dL, median (Q1:Q3) 36.0 (10.0:68.0) 32.5 (12.0:52.5)

44. Primary Endpoint: LDL-C % Change vs. Placebo at Week 12a
-10
-20
-30
-40
20
10
0
8 12
LSmean(SE)percentchangefrom
baselineinLDL-C(%)
Time (weeks)
0 4
aMixed effect model with repeated measures approach (intention-to-treat analysis).
LS, least squares; SE, standard error.
LS mean difference (SE) versus placebo:
–35.6 (7.8)%,P<0.0001
–26.9 (4.6)%
−62.8 (14.0) mg/dL
8.6 (6.3)%
8.9 (19.0) mg/dL
∆ Alirocumab 150 mg Q2W (n=45) ○ Placebo (n=24)

45. % Change in LDL-C at Week 12 by Genotype
80
60
40
20
0
-20
-40
-60
-80
-100
ChangefrombaselineinLDL-Cat
Week12(%)
*
*
*
**
Alirocumab 150 mg Q2W
Placebo
Null/null (LDLR activity <2%)
Single null LDLRvariant
*
†
††
†
†
No mutation
identified
Double heterozygous
(LDLR + APOB or PCSK9)
Compound
heterozygous (LDLR)
Heterozygous
(LDLR + other benign
variants)
Homozygous (LDLR)
Homozygous (LDLRAP1)
Homozygous (PCSK9)

46. Change In Other Atherogenic Lipids at Week
12
20
10
0
-10
-20
-30
-40
TC Lp(a)
%changefrombaseline
Alirocumab (n=45)
ApoB
6.6 7.2 8.0 8.8
−19.8 −22.5
−24.8
−19.6
Placebo (n=24)
Non-HDL-C
LS mean (SE)
difference vs placebo
−29.8 (6.3)
P<0.0001
−32.9 (7.4)
P<0.0001
−28.4a (6.7)
P<0.0001
LS means, SEs and P-values for lipid parameters were calculated using a mixed-effect model with repeated measures approach, except for Lp(a), which were calculated using multiple imputation followed by
robust regression analysis (intention-to-treat analysis). aCombined estimate for adjusted mean difference. ApoB, apolipoprotein B; TC, total cholesterol.
−26.5 (6.2)
P<0.0001

47. % of Patients Who Achieved LDL-C Reductions of ≥30%
and ≥50% at week 12

48. Conclusion
• Largest RCT in HoFH patients to date
• Statistical significant reduction in LDL –C at 12 weeks versus placebo.
• Reduction in LDL-C was seen in al groups consistently, even in patients on
apheresis.
• Along with LDL- C there is significant reduction of ApoB, non-HDL-C, TC and Lp(a)
• It is well tolerated.

49.  LDL-C % reduction with alirocumab is less pronounced in patients with HoFH than
in other forms of hypercholesterolemia as HoFH is characterized by severely
impaired LDLR function
 LDLR-independent therapies include lomitapide, and ANGPTL3 inhibitors are also
in development

50. 1. Vericiguat, the soluble guanylate cyclase enhancer is the novel drug in HFREF.
2. In HFPEF, the ARNI though effective in women, is not effective at reducing the
incidence of CV death or HF hospitalization – benefit is not predicted by NT
proBNP levels.
3. Statins are beneficial in preventing HF among patients treated with
anthracyclines.
4. Inclisiran, the novel approach in LDL reduction was found beneficial in ORION
trial.
5. Alirocumab founds beneficial in Familial Homozygous Hypercholesterolemia..

51. Follow SMS and be Safe
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