associate professor patrick kay - gp cmegpcme.co.nz/pdf/2016...

Associate Professor PatrickKayInterventional cardiologist

Middlemore, Auckland and Mercy Hospitals

Auckland

14:00 - 14:55 WS #45: New Therapies for Lipid Management

15:05 - 16:00 WS #57: New Therapies for Lipid Management (Repeated)

STATIN THERAPYNEW THERAPIES FOR LIPID MANAGEMENT

DR I PATRICK KAY MD PHD

GENERAL AND INTERVENTIONAL CARDIOLOGIST

AUCKLAND

THIS AFTERNOON’S MENU

• CURRENT GUIDELINES

• LONG TERM DATA

• USE OF NON-STATIN THERAPY

• THE FUTURE – “NEW THERAPIES”

INHERENT PROBLEMS WITH STATIN THERAPY

• IN SECONDARY PREVENTION:

Adherence: 90% tolerance, 50% adherence at 1 year

Goals not attained – at patient level and at medical level

• IN PRIMARY PREVENTION:

Efficacy gap – who to treat and how much

Credibility gap – public perception

AHA/ACC GUIDELINES:THERE ARE 4 DEFINED STATIN BENEFIT GROUPS

• Patients with clinical ATHEROSCLEROSIS: ACS, CVA, PVD, PCI, CABG

• LDL greater than 190 mg/dl = 4.9mmol/l

• Patients with diabetes, age 40-75 years

• Age 40-75 years that do not meet above criteria, but have a 10 year risk of >7.5 %

AHA/ACC GUIDELINES:THERE ARE NO LONGER TREATMENT TARGETS FOR LDL OR NON-HDL-C

• This is a huge change for patients and providers.

• No longer treat to target - simply give a medium to high dose of a potent statin

• Doesn’t fit in well with “know your numbers.”

• Goal is no longer “lower is better.”

WHICH ARE THE HIGHLY POTENT STATINS

• ATORVASTATIN – GOAL 80MG

• ROSUVASTATIN – GOAL 20-40MG

SECONDARY PREVENTION

WHY ARE HIGH DOSE STATINS NECESSARY IN ACS?

• Plaque stabilization

• Absolute LDL lowering correlates with a decline in CRP (inflammation)

• High doses of statins heal the vascular bed in mild to moderate disease and

induces regression. In diffusely and severely diseased arteries plaque

stabilization occurs.

• Low-dose statin therapy does not achieve these goals – hence the ACC/AHA

dropped the concept of an LDL goal in preference using the concept of high dose

therapy to achieve a 30-50% reduction in LDL

INFLAMMATION

Inflammation and CV risk: Beyond statins in the treatment of atherosclerosis

8-3-2016, Boston, MA, USA, Paul M RidkerProf. Ridker emphasises the importance of the inflammatory component of residual risk. Trials are currently addressing whether specifically targeting inflammatory residual risk can further reduce CV events in certain patients.

Targeting more upstream inflammatory molecules for atheroprotective therapy

4 / 28

/wEPDwUC9F36B6/wEWAwL

THE STATIN HYPOTHESIS

Pleotropic effects – decrease oxidative stress & inflammation - decrease hs-CRP –

improve endothelial function – enhance the stability of atherosclerotic plaques –

inhibit thrombosis

JUPITER STUDY

JUPITER – 2008 – 17,802 patients with LDL-C < 130mg/dl and hs-CRP ≥ 2 mg/L

randomized to Rosuvastatin 20mg PO daily or placebo – primary endpoint:

composite of MI, stroke, arterial revascularization, hospitalization for unstable

angina, or death from CV causes

LONG-TERM EFFICACY AND STATINS

WOSCOPSLong-Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol

With Statin Therapy

20-Year Follow-Up of West of Scotland Coronary Prevention Study

• Primary prevention trial in 45-64yr men with high LDL

• 6595 men were randomized to receive pravastatin 40 mg OD or placebo for

an average of 4.9 years.

• Poor uptake of statin after initial 5yr of study-mandated treatment

• Subsequent linkage to electronic health records permitted analysis of major

incident events over 20 years.

• Post trial statin use was recorded for 5 years after the trial but not for the last

10 years.

WOSCOPS

Cumulative events over the 20-year follow-up period(Legacy Benefit).

Ian Ford et al. Circulation. 2016;133:1073-1080

Copyright © American Heart Association, Inc. All rights reserved.

Cumulative events over the 20-year follow-up period.

Cumulative incidence functions are provided for the outcomes of death resulting from

(A) all causes, (B) cardiovascular disease, (C) coronary heart disease, and (D) noncardiovascular disease.

All cause events CVD

CHD Non CVD cause

Cumulative numbers of hospital admissions for the outcomes of

(A) cardiovascular disease, (B) myocardial infarction, (C) heart failure, and (D) coronary

revascularization.

Ian Ford et al. Circulation. 2016;133:1073-1080

Copyright © American Heart Association, Inc. All rights reserved.

Cumulative numbers of hospital admissions for the outcomes of

(A) cardiovascular disease, (B) myocardial infarction, (C) heart failure, and (D) coronary revascularization.

CVDCVD MI

HFCoronary

Revascularisation

RESULTS

• For every 1000 patients assigned to Pravastatin, compared with placebo,

over 16 years there were: 26 fewer deaths (31 over 6 years)

• 25 fewer CVD deaths (23 over 6 years)

• 18 fewer CHD deaths (19 over 6 years)

LONG-TERM EFFECTIVENESS AND SAFETY OF PRAVASTATIN IN PATIENTS WITH CORONARY HEART DISEASE: SIXTEEN YEARS OF FOLLOW-UP OF THE LIPID

STUDY

The LIPID (long-term intervention with Pravastatin in ischemic disease)

trial, showed that 6 years of Pravastatin treatment resulted in better

survival, in line with other statin trials.

MAIN RESULTS

• Type of statin treatment: Pravastatin prescription was initially (first 6

years) 49%, and decreased to 25% (last 10 years),

• Simvastatin prescription increased from 27% to 32%

• Atorvastatin prescription increased from 19% to 31%

• Other statins prescription increased from 3% to 11%

RESULTS

• Patients assigned Pravastatin maintained a significantly lower risk of

death compared to the placebo group, regarding: CHD; RR: 0.89; 95%

CI: 0.81−0.97; p=0.009

• CV disease; RR: 0.88; 95% CI: 0.81−0.95; p=0.002

• Any cause; RR: 0.91; 95% CI: 0.85−0.97; absolute RR: 2.6%; p=0.003

Cumulative Risk Of Cause-specific Death Over 16 Years Of Follow-up Among Patients Randomly Assigned To Initial

Pravastatin Or Placebo For An Average Of 6 Years Followed By Optional Statin Therapy

Wendy E. Hague et al. Circulation. 2016;133:1851-1860Copyright © American Heart Association, Inc. All rights reserved.

CONCLUSIONS

• In 7721 patients with a history of CHD who participated in the extended follow-

up of the LIPID study, the absolute survival benefit from 5 years of pravastatin

treatment appeared to be maintained over another 10 years.

• The survival benefit was primarily related to CV-deaths and treatment with statins

did not influence cancer incidence/death nor death from other non-CV causes

during long-term follow-up.

• These results support the long-term use of statin therapy in patients at risk of CV

events.

NON –STATIN THERAPIES

AHA/ACC GUIDELINES:NON-STATIN THERAPIES

• For hyperlipidemia, non statin therapies, alone or in combination with statins, do not

provide acceptable risk reduction benefits compared to adverse effects.

• These include:

• Ezetimibe (in isolation)

• Fibrates

• Fish oil

• Niacin

• For the most part, these should be avoided with few exceptions

Why Don’t Non-statins Play A More Prominent Role In The New

Guidelines?Recent Troublesome Non-statin Trials

• FIBRATE

• ACCORD. N ENGL J MED 2010; 362:1563-1574

• FIELD. LANCET; 366:1849-1861

• FISH OIL

• RISK AND PREVENTION STUDY GROUP. N ENG J MED 2013; 368:1800-1808

• OMEGA-3 FATTY ACID SUPPLEMENTATION AND RISK OF CARDIOVASCULAR

EVENTS. JAMA 2012; 308(10):1024-1033

• SELECT. JNCI 2013; JULY 10

Troublesome Non-Statin Trials

• NIACIN

• HPS2-THRIVE (TREATMENT OF HDL TO REDUCE THE INCIDENCE OF

VASCULAR EVENTS.) EUROPEAN HEART JOURNAL 2013; 34:1279-1291

• AIM-HIGH N ENG J MED 2011; 365:2255-2267

“NOW THIS IS NOT THE END. IT IS NOT EVEN THE BEGINNING OF THE END. BUT IT IS, PERHAPS, THE END OF

THE BEGINNING” WINSTON CHURCHILL, 1942

THE BEGINNING OF THE END?

PCSK9 INHIBITORS

• PCSK9-enzyme associated with cholesterol homeostasis in the liver

• In the liver, the LDL receptor removes LDL cholesterol from the blood.

• PCSK9 binds to the LDL receptor inactivating it. Therefore LDL levels rise.

• If PCSK9 is blocked, more LDL receptors will be present on the

surface of the liver and will remove more LDL cholesterol from the blood.

• Therefore, blocking PCSK9 can lower blood cholesterol levels.

PCSK9Proprotein convertase subtilisin/kexin type 9

PCSK9 STUDIES

• PCSK9 inhibitors are injected monoclonal antibodies

• Dosing weekly to twice monthly

• 3 competing products

• All studies were designed so as to add PCSK9 inhibitors to

existing optimum statin therapy (eg Vytorin)

• Homozygous and Heterozygous FH studied

Alirocumab

Intention to treat analysis. LS = least squares mean.

Alirocumab

LLT=lipid lowering therapy

Alirocumab

Alirocumab

Alirocumab

Alirocumab

WHO GETS TREATED? NICE GUIDELINES

Recommendations For PCSK9 Are In Evolution

Likely medium term recipients will be:

• FH homozygous and heterozygous groups (primary prevention)

• Intolerant to statin therapy (primary and secondary high risk )

• Not achieving goal in a high risk environment

SUMMARY

• Highly potent statins are strongly recommended in secondary

prevention

• Statin effects are robust, in both primary and secondary prevention

• Latest US guidelines dismiss “arbitrary goals” and reinforce the

importance of giving an efficacious dose of statin instead

• PCSK9 are the present and future for those with FH and the high-

risk statin-intolerant patient

STATIN THERAPYNEW THERAPIES FOR LIPID MANAGEMENT

DR I PATRICK KAY MD PHD

GENERAL AND INTERVENTIONAL CARDIOLOGIST

AUCKLAND

NEW GUIDELINES2013 ACC/AHA/NHLBI GUIDELINE ON LIFESTYLE FOR CVD PREVENTION

• EAT A DIETARY PATTERN THAT IS RICH IN FRUIT, VEGETABLES, WHOLE GRAINS, FISH,

LOW-FAT DAIRY, LEAN POULTRY, NUTS, LEGUMES, AND NONTROPICAL VEGETABLE

OILS CONSISTENT WITH A MEDITERRANEAN OR DASH-TYPE DIET.

• RESTRICT CONSUMPTION OF SATURATED FATS, TRANS FATS, SWEETS, SUGAR-

SWEETENED BEVERAGES, AND SODIUM.

• ENGAGE IN AEROBIC PHYSICAL ACTIVITY OF MODERATE TO VIGOROUS INTENSITY

LASTING 40 MINUTES PER SESSION THREE TO FOUR TIMES PER WEEK

RCTS FAILING TO SHOW EVIDENCE OF FURTHER REDUCED RISK WHEN ADDING A NON-STATIN

• STUDY INTERVENTION FINDINGS

• ACCORD 2010

• FENOFIBRATE 160MG ADDED TO SIMVASTATIN THERAPY VS SIMVASTATIN + PLACEBO

• • 5,518 PATIENTS WITH T2DM AT HIGH RISK FOR CVD FOLLOWED 4.7 YEARS • AVERAGE DAILY DOSE OF SIMVASTATIN = 22.3MG DAILY (≤ 40MG) • LDL-C FELL FROM ~ 100 MG/DL

TO 80 MG/DL IN BOTH GROUPS • TG AND TC WERE LOWER IN FENOFIBRATE ARM, HDL INCREASED • SIMVASTATIN + FENOFIBRATE DID NOT REDUCE THE RATE OF FATAL CV EVENTS,

NONFATAL MI, OR NONFATAL STROKE, AS COMPARED TO SIMVASTATIN ALONE.

• AIM-HIGH 2011

• NIACIN + SIMVASTATIN 40 – 80MG (+/- EZETIMIBE 10MG IF NEEDED) TO MAINTAIN LDL-C 40 – 80MG/DL VX PLACEBO + SIMVA (+/- EZETIMIBE)

• • 3,414 PATIENTS WITH CVD; STOPPED EARLY AT 3 YEARS DUE TO NO EFFICACY • HDL-C INCREASED FROM 35 TO 42 MG/DL; TG DECREASED FROM 164 TO 122 MG/DL, AND LDL-

C DECEASED FROM 74 TO 62 MG/DL • ADDITIONAL REDUCTION IN NON-HDL-C [AS WELL AS REDUCTIONS IN APO B, LIPOPROTEIN A, AND TG IN ADDITION TO HDL-C INCREASES

WITH NIACIN DID NOT FURTHER REDUCE ASCVD RISK IN INDIVIDUALS TREATED TO LDL-C LEVELS < 70 MG/DL

• HPS2THRIVE 2014

• (NIACIN 2 GRAMS + LAROPIPRANT 40MG) OR MATCHING PLACEBO ADDED TO SIMVASTATIN 40MG (+/- EZETIMIBE)

• • 25,673 ADULTS WITH ATHEROSCLEROTIC VASCULAR DISEASE FOLLOWED 3.9 YEARS • IN PARTICIPANTS WITH ATHEROSCLEROTIC VASCULAR DISEASE, THE ADDITION OF EXTENDED-

RELEASE NIACIN-LAROPIPRANT TO STATIN-BASED LDL CHOLESTEROLLOWERING THERAPY DID NOT SIGNIFICANTLY REDUCE THE RISK OF MAJOR VASCULAR EVENTS (DESPITE A

10MG/DL (16%) DECREASE IN LDL AND 6MG/DL INCREASE IN HDL) BUT DID INCREASE THE RISK OF SERIOUS ADVERSE EVENTS.

• N

Current evidence indicates that PCSK9 might work at two cellular sites. The first potential location is in a post-ER compartment, depicted here as the Golgi apparatus, where PCSK9 might target

the LDLRs (green) for degradation in an acidic compartment such as the lysosome. In the second possible pathway, the PCSK9 that is secreted binds to LDLRs on the cell surface.

The LDLR–PCSK9 complex is internalized together with the adaptor protein ARH (orange). PCSK9 might prevent the recycling of the LDLR from the endosome back to the cell surface and/or

direct the LDLR to the lysosome where it is degraded. It is currently not known whether PCSK9 directly cleaves the LDLR or whether catalytic activity is required for either pathway.