Lessons from Practice; Which patients benefit most? August 29th, - - PowerPoint PPT Presentation

PCSK9i & LDLc: guidelines, practice and innovation

8th annual PCSK9i symposium at ESC 2020 Five years of PCSK9i:

Lessons from Practice; Which patients benefit most?

August 29th, 2020

ESG Stroes AMC, Amsterdam, Netherlands

Conflicts of Interest

• ES has received ad-board/lecturing fees from:

Amgen, Novartis, Sanofi-Regeneron, Esperion, Athera, Akcea-Ionis

• Other funding:

EU-HORIZON program Dutch Heart Foundation ERA-CVD program

Outline

• Efficacy of PCSK9-inhibition
• Need for PCSK9-inhibition in current practice
• Lessons from (5-yr) practice
• Who needs PCSK9-inhibition most
• Changing landscape in high CV-risk patients

RCT: ODYSSEY - Alirocumab

Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo Approximately 75% of months of active treatment were at the 75 mg dose. Steg P, et al. NEJM 2018

RCT: FOURIER – EVOLOCUMAB

key secondary endpoint

Sabatine MS, et al. New Engl J Med 2017;376:1713–22.

0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% Months from Randomisation CV Death, MI or Stroke 6 12 18 24 30 36 Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001

Evolocumab Placebo 7.9% 9.9%

Placebo Median 92 mg/dL Evolocumab Median 30 mg/dL, IQR 19–46 mg/dL

4 10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks 59% mean reduction (95%CI 58–60), P < 0.001 Absolute reduction: 56 mg/dL (95% CI 55–57)

LDL Cholesterol (mg/dL)

Outline

• Efficacy of PCSK9-inhibition
• Need for PCSK9-inhibition in current practice
• Lessons from (5-yr) practice
• Who needs PCSK9-inhibition most
• Changing landscape in high CV-risk patients

Cumulative incidence of cardiovascular events

• n guideline treatment in ‘recent’ trials

FU Cumulative Yearly Study events Placebo 3 yr 10–15%* 2.5–5%/yr FOURIER Placebo 3 yr 9% 3%/yr COMPASS Placebo 4 yr 14% 3.5%/yr ODYSSEY Placebo 4 yr 16% 4%/yr EMPA-REG Placebo 5 yr 20% 4%/yr CANTOS Placebo 7 yr 34% 4.5%/yr IMPROVE-IT

Dependent upon baseline risk factors: multivessel disease, recurrent myocardial infarction, peripheral arterial disease. FU, follow-up. FOURIER: Sabatine MS, et al. N Engl J Med 2017;376:1713–22. COMPASS: Eikelboom JW, et al. N Engl J Med 2017;377:1319–30. ODYSSEY: Schwartz GG, et al. Presented at ACC 2018. EMPA-REG: Zinman B, et al. N Engl J Med 2015;373:2117–2128. CANTOS: Ridker PM, et al. N Engl J Med 2017;377:1119–31. IMPROVE-IT: Cannon CP, et al. N Engl J Med 2015;372:2387–97.

Do we still need PCSK9-I CV-risk lowering?

Do we still need PCSK9-i LDLc lowering?

Kotseva K, et al. Eur J Prev Cardiol 2015;23:636–48.

87 58 20

10 20 30 40 50 60 70 80 90 100

Prevalence (%)

On lipid-lowering drugs LDL-C <100 mg/dL LDL-C <70 mg/dL

… after a CV event, only 1 in 5 patients in the EU achieve LDL-C < 70 mg/dL, despite statin therapy and good adherence

EUROASPIRE IV

Early LDL-c Lowering:

Cure in Familial hypercholesterolemia?

• Familial

hypercholesterolemia

• Statin started

age 12-15 yrs

Luirink I, N Engl J Med 2019

Outline

• Efficacy of PCSK9-inhibition
• Need for PCSK9-inhibition in current practice
• Lessons from (5-yr) practice
• Who needs PCSK9-inhibition most
• Changing landscape in high CV-risk patients

LESSONS FROM PRACTICE

REAL-WORLD EFFICACY NL

Stoekenbroek, Atherosclerosis 2018

% Reduction in LDL-c

LESSONS FROM PRACTICE

Real-world adherence

Heintjes, EAS 2019

Persistent use after 2 years Impact of ’home delivery’ program

LESSONS FROM PRACTICE

REAL-WORLD EFFICACY US

Kaufman Circ Res 2019

Who needs PCSK9-i LDL-c lowering most?

Cardiovascular benefit dictated by:

• a. absolute risk and b. absolute LDL-c level

CHD – DM: 168 → 84 mg/dL: -9% / 5 yrs CHD + DM: 100 → 50 mg/dL: -11% / 5 yrs

Robinson J, Stone N. Am J Cardiol 2006;98:1405–8.

CHD + diabetes CHD + MS or IFG CHD – no MS or IFG Diabetes – no CVD No CVD – no diabetes Cardiovascular event rate (%) LDL-C (mg/dL) 80 70 60 50 40 30 20 10

10

20 40 60 80 100 120 140 160 180 200

Prior MI – benefit of evolocumab based

• n specific risk factors

ARR, absolute risk reduction; RRR, relative risk reduction. Sabatine MS, et al. Presented at AHA 2017.

Qualifying MI <2 yrs ago

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

24% RRR HR 0.76 (95% CI 0.64-0.89) P<0.001 7.9% 10.8%

Pinteraction=0.18

D 2.9% NNT 35 Evolocumab Placebo 8.3% 9.3% D 1.0% NNT 101 Qualifying MI ≥2 yrs ago 13% RRR HR 0.87 (95% CI 0.76-0.99) P=0.04

6 12 18 24 30 36

1

≥2 Prior MIs 21% RRR HR 0.79 (95% CI 0.67-0.94) P=0.006 12.4% 15.0% Multivessel Disease 9.2% 12.6% D 3.4% NNT 29

2 3

D 2.6% NNT 38

Greater underlying risk, i.e. closer to the index event, multivessel disease and multiple prior CV events, is associated with higher RRR and ARR

Outline

• Efficacy of PCSK9-inhibition
• Need for PCSK9-inhibition in current practice
• Lessons from (5-yr) practice
• Who needs PCSK9-inhibition most
• Changing landscape in high CV-risk patients

Voorbeeld voettekst | juli 2018

1 2 3 4 5 5 10 15 20 LDL cholesterol (mmol/L) Five year risk of a major vascular event, % Control 22% relative risk reduction with 1.0 mmol/L reduction Statin 15% relative risk reduction with 0.5 mmol/L more reduction More statin 34% relative risk reduction with 1.5 mmol/L reduction Statin-ezetimibe 33% relative risk reduction With 1.6 mmol/L reduction* PCSK9 addition 0.8

COMPASS: primary endpoint – CV death, MI, stroke

CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Eikelboom JW, et al. N Engl J Med 2017;377:1319–30.

Cumulative hazard ratios Year

EXAMINE Alo vs. Pbo EMPA-REG Outcome Empa vs. Pbo ELIXA* Lixi vs. Pbo ORIGIN Glargine U100 vs. SOC SAVOR TIMI-53 Saxa vs. Pbo CANVAS Program Cana vs. Pbo FREEDOM-CVO ITCA 650 vs. Pbo DEVOTE Degludec vs. Glargine U100 TECOS* Sita vs. Pbo DECLARE-TIMI 58 Dapa vs. Pbo LEADER Lira vs. Pbo CARMELINA Lina vs. Pbo SUSTAIN-6 Sema vs. Pbo EXSCEL Exe OW vs. Pbo HARMONY Alb vs. Pbo REWIND Dul vs. Pbo

0,1 0,4 0,7 1,0 1,3 HR [95% CI]

Insulin

?

0,1 0,4 0,7 1,0 1,3 1,6 HR [95% CI]

GLP-1RA

0,1 0,4 0,7 1,0 1,3 HR [95% CI]

DPP-4i

0,1 0,4 0,7 1,0 1,3 HR [95% CI]

SGLT2i

CV-BENEFIT OF ‘DIABETIC’ AGENTS

SGLT2-I AND GLP-1 Agonists

*MACE+ White et al. N Engl J Med 2013; 369:1327–35; Scirica et al. N Engl J Med 2013;369:1317–26; Green et al. N Engl J Med 2015;373:232–42; McGuire et al. JAMA. 2019 Jan 1;321(1):69-79. Zinman et al. N Engl J Med 2015; 373:2117- 28; Neal et al. N Engl J Med 2017;377:644– 57; Wiviott et al. N Engl J Med. 2019 Jan 24;380(4):347-357. *MACE+ Pffefer et al. N Engl J Med 2015;373:2247–57; Intarcia press release 06 May 2016; Marso et al. N Engl J Med 2016;375:311–22; Marso et al. N Engl J Med 2016;375:1834–44; Holman et al. N Engl J Med 2017;377:1228–39; Hernandez et al. Lancet. 2018 Oct 27;392(10157):1519-1529.; Gerstein et al. Lancet. 2019 Jun 10. http://dx.doi.org/10.1016/S0140-6736(19)31149-3 Gerstein et al. N Engl J Med 2012;367: 319–28; Marso et al. N Engl J Med 2017;377:723– 32

Voorbeeld voettekst | juli 2018

Starting with simple phenotyping using biomarkers

towards tailored medicine in high-risk patients

• Life style intervention
• Initial guideline recommended medical therapy

Lipid biomarkers (LDL-C; Triglycerides ? Lipoprotein (a) ?)

PCSK9 inhibition

(AB, siRNA?)

Metabolism

(HbA1c, Type-2 Diabetes)

SGLT2- inhibitors, GLP-1 RA

Platelets/ Coagulation

Prolonged DAPT, Low-dose Anticoag.

Inflammation (eg CRP)

IL-1 beta blockade, Colchicin ?

Modified from Reiner Z, Eur Heart J 2019

Absolute risk assessment Most active pathway assessment Affordablility

proteomics

5-years PCSK9-1: Lessons from practice; which patient benefits most?

• PCSK9-i Real world efficacy data concordant with RCT data
• >80% adherence after 2 years
• >10% ‘additional’ benefit in Patient Support Programs
• Most PCSK9-i CV-benefit in
• Very high (calculated) CV-risk (FH, MI + DM, recurrent MI, PAD, multivessel disease, ..)
• Higher residual LDL-c burden
• Tailored treatment combinations based on:
• Major (residual) risk factors (Lipid, metabolic, thrombotic)
• ‘Availability’ & ‘Reimbursement’