1. Paul J Kovack, DO, FACC, FACOI
PCSK-9 Inhibitors
Paul J Kovack, DO, FACC, FACOI

2. Diagnosis of HeFH Lipid screening Phenotypic characteristics
Heterozygous versus Homozygous
Family history
British Simon Broome Registry
MED PED
Dutch Lipid Clinic criteria

10. MED PED score

12. Phenotypic characteristics HeFH

13. Phenotypic characteristics HeFH

14. CV events and LDL

15. Bile Acid Sequestrates Statins Ezetimibe PCSK9 inhibitors
Medications currently indicated for Heterogeneous Familial Hyperlipidemia (HeFH)
Bile Acid Sequestrates
Statins
Ezetimibe
PCSK9 inhibitors

18. Diet and HeFH Limit alcohol intake
Low calorie diet with total fat intake less that 3 percent

19. Exercise The Bolivians (the Tsimane)
Hunters and gatherers, fishing, farming
85% aged 45 to 90 had no coronary calcium. 13% had scores less than 100
Average LDL was 92 and HDL was 40
ACC/AHA Current recommendations are 30 minutes moderate exercise 5 times per week

20. Let’s get real about diet
Let’s get real about diet. Important to set appropriate expectations regarding LDL and diet with our patients
MEGA Trial, decreased LDL cholesterol by only 3% (Pravastatin is same trial decreased LDL by 18%)
Dean Ornish (diet, exercise, stress reduction, and social support) can decrease LDL by almost 40% (But TOUGH!)
Vegan diet (JAHA October, 2015) Tchol decreased by 14 mg/dl, LDL reduced by 13 mg/dl
Overall, expect a person who is very motivated with their diet to drop their cholesterol by 5-10%

21. Helpful information for your patients: Diet in addition to appropriate medical therapy
DASH Diet
Mediterranean diet: The South Beach Diet
Vegan diet: Prevent and Reverse Heart Disease (Caldwell B Esselstyn, Jr, MD)
Dean Ornish Diet: Reversing Heart Disease

22. PREDIMED
N Eng J med 2013; 368:
Mediterranean diet (MD) vs MD plus 1 tablespoon olive oil per day vs 1 handful of tree nuts per day
7500 patients followed for 5 years
Endpoint was MI, stroke or death (MACE)
Either group, olive oil or tree nuts were 30% Less likely to achieve the major endpoint (driven primarily by stroke)

24. Medications that are indicated for secondary prevention of CAD and PAD
Statins
ASA
ACEI
Beta blockers
Plavix

27. Effect of statins on mortality in patients with CAD

28. Lower is better: There is no too low!

29. Statin Intolerant Patients have worse prognosis after MI JACC 2017;69:1386-95
Increased risk for recurrent MI and CHD events
Statin discontinuation associated with elevated risk of ischemic stroke, all cause mortality, all major events and any hospitalization
50% increased risk of MI
51% increased risk of all CV events

30. Outcomes in patients who discontinued vs maintained statins after stroke JAHA 2017;doi:10.1161
Discontinued group
Maintained group
Adjusted Risk
(95% CI)
Ischemic Stroke
5.6%
3.9%
1.45
All-cause mortality
1.4% 1%
1.37
All major events
7.8%
1.38
Any hospitalization
31.7%
27.1%
1.19

31. What is the nocebo effect?
nonpharmacological, harmful, or undesirable effects occurring after active or inactive therapy
frequency of adverse events can dramatically increase by informing patients about the possible side effects of the treatment, and by negative expectations on the part of the patient
eg; Patients who were told that they might experience sexual side effects after treatment with β-blocker drugs reported these symptoms between three and four times more often than patients in a control group who were not informed about these symptoms

32. What is the nocebo effect?
ASCOT-LLA trial, 10,000 patients
Almost all had never been on a statin before
Blinded phase events muscle related events similar between groups (2%)
Unblinded phase AE when patients knew they were on a statin, incidents of myalgias rose 41%

33. Treating Statin Intolerance
1-5% in clinical studies
11-29% in observational cohorts
Nocebo Effect
Change dose, change statin
Hydration
Exercise, stretching
supplements

34. Cleveland Clinic Observational Study of Statin intolerant Patients
1600 patients referred with history of statin intolerance
73% remained on statin therapy for 31 months
63% daily dosing
9% intermittent dosing
Lower dose
Different statin
Combine with zetia or BAS

35. Mechanism of PCSK-9 inhibitors
LDL receptors bind to LDL in the liver and remove LDL paticles
LDL-R then return to cell surface to repeat the process
PCSK9 binds to the LDL-R and promotes degradation
Block PCSK9 and increase availability or LDL-R to remove LDL from the circulations

36. Current Approved Indications of PCSK9 inhibitors in the US
Praluent (alirocumab)
HeFH or CVD
Adjunct to diet and maximally tolerated statin for treatment of adults with HeFH or clinical atherosclerotic CVD who require additional lowering of LDL-C
Repatha (evolocumab)
HoFH
Adults and adolescents > 13 years with HoFH in combination with other lipid lowering therapies

37. Samples of efficacy of PCSK9 inhibitors an a small group of the trials done thus far
Drug
Result
LONG TERM
Alirocumab in addition to maximally tolerated LLT
LDL reduced by 61% vs placebo
COMBO II
LDL reduced by 50.6%
CHOICE I
LDL reduced by 58.7%
LAPLACE-2
Evolocumab +/-statin
LDL reduced by 75%
GAUSS-2 Trial
Evolocumab, statin intolerant
LDL reduced by 56%
RUTHERFORD-2 Trial
Evolocumab in HeFH on maximally tolerated LLT
LDL reduced by 60%

38. PCSK9 – The good Highly effective, up to 70% reduction in LDL Safe
Well tolerated

39. PCSK9 – The Bad Adverse events
Muscle related symptoms similar to placebo
Rhabdomyolysis 0.1%, same as placebo
Transaminases greater than 3 times normal 1.5%, same as placebo
Creatine kinase greater than 5 times 0.7%, same as placebo.
Injection site reactions (2.1% vs 1.6% in placebo)
In trials, discontinuation rates the same for drug vs placebo
Limited outcomes data for CV events

40. PCSK9 – The Ugly Sticker shock -$14,000 per year
Overcoming this barrier is difficult and time intensive but there is help
Copay cards
Proper documentation
Diagnosis details
Recent lipid panel
History of other lipid lowering treatments
Appeals

41. Insurance Coverage Patient has established CVD
Patient has tried high efficacy statin and failed to get LDL less than 100 mg/dl (or less than 70 mg/dl)
May also require adding Zetia first

42. Amgen Safety Net Foundation can cover at no cost up to 500% federal poverty level (FPL) REPATHA
Family Size
100% FPL
500% FPL 1
$12,060
$60,300 2
$16,240
$81,200 3
$20,420
$102,100 4
$24,600
$123,000

43. GAUSS-3 trial 511 patients intolerant to 3 or more statins
Randomized to zetia vs PCSK9 inhibitor
No difference in muscle related side effects
53% reduction LDL evolocumab
17% reduction with zetia

44. FOURIER Trial N Eng J Med 2017;376:1713-1722
1242 sites in 49 countries
27,564 patients
Patients with prior MI, stroke, and/or symptomatic PAD with 70 mg/dl or higher LDL on high or moderate efficacy statin
Repatha 140 mg every 2 weeks or 420 mg every month vs placebo average FU 2.5 years
Primary endpoint major CV event (MI, stroke, CV death, hospitalization for USA or coronary revascularization

45. FOURIER Trial: Results
Primary endpoint, ARR 1.5% (11.3 vs 9.8%) 15% RRR
Secondary endpoint CV death, MI stroke (MACE) ARR 1.5% (9.9 vs 7.9%) 20% RRR
Extra 59% reduction of LDL beyond statin alone (median 92 mg/dl to 30 mg/dl)

46. FOURIER Trial No difference in /adverse events
Rare injection site reactions
Discontinuation rate similar between each group

47. FOURIER trial: Results in PAD
PAD without history of stroke or MI, MACE events with placebo 10.3% (7.6% if MI or Stroke but no PAD)
Treatment group had event rate of 5.5%
NNT 21 for 2.5 years
PAD with history of MI or stroke, MACE events was 14.9%
Treatment group had event rate of 11.4%
NNT 29 for 2.5 years

48. FOURIER trial: Results in PAD
MACE or MALE* (major adverse leg events) in patients with PAD but no MI or stroke was 12.8% in control goupd and 6.5% of treatments group.
6.3 absolute risk reduction
NNT 16.
Bottom line, get LDL as low as possible inpatients with PAD.
*MALE includes: acute limb ischemia, major amputation or urgent revascularization

49. ODYSSEY Outcomes study
18,000 patients post ACS patients randomized to alirocumab
Results due early 2018

50. PCSK9 Inhibitors, Economics and Policy JACC 2017;70:2677-87
“The list prices of PCSK9 inhibitors in the United States are over 100-fold higher than statins, and only a small fraction of their higher cost will ever be recouped by prevention of cardiovascular events, especially in lower-risk patients. The projected cost-effectiveness of PCSK9 inhibitors does not meet generally accepted benchmarks for good value, but would improve if their prices were cut substantially.”

51. How can we best help our patients with HeFH and CAD and PAD?
Get them on the right medications and work with them to make sure they tolerate them (and can afford them) and therefore, stay on them.
Strive to be evidence based and guideline driven
Keep your patients focused on statin benefits
Remember the nocebo effect
Remember what the Cleveland Clinic accomplished
Fourier Trial and more to come regarding PCSK9 inhibitors