Current Management of Dyslipidaemia and rational use of

antiplatelets

Management of Dyslipidaemia in General Practice

DR.M.R.Mubarak

Case history

• 43y Male smoker,alcohol,F&B manager who had undergone stenting in 2009.

• Routine check-up done BP125/80,HR 74/min ,HbA1c 6.4%,SGPT 65,TSH 2.1,S.Creat 0.9,

• Total Cholesterol-204,LDL-121,HDL-34,TG-265

• Given Fenofibrate 200mg Noct for 3months

• Your thoughts ?

Case History

• After 2 months admitted with Inferior STEMI

• Loading doses of antiplatelets and statins given.

• Coronary angiogram showed totally occluded mid Right coronary artery stent.

• Primary PCI done.

• On Aspirin 75mg,Clopidogrel 75mg,Atorvastatin 40mg and Ramipril 5mg daily.

Major Cardiovascular risk factors

Non-modifiable

• Age

• Gender

• Family History

• Race

Modifiable

• Smoking

• Diabetes

• Hypertension

• Dyslipidaemia

• Lack of exercise

• Obesity

• Stress

Cardio Vascular disease…….

• CV disease remains the major cause of death despite improvements in outcomes for CVD management.

• CVD mortality reduction is attributed to reduction in Cholesterol, Blood pressure and smoking.

• This favourable trend is partly offset by increase in Obesity and T2DM.

• Ageing of the population also contributes to the increase in absolute number of CV events.

LDL cholesterol and Atherosclerosis

Guidelines recommended specific LDL targets

• LDL < 100 for CAD or CAD equivalents.

• LDL < 130 for 2+ risk factors.

• LDL < 160 for 0-1 risk factors

New Guideline …..

• Recommend to treat blood cholesterol to reduce Atherosclerotic Cardio-Vascular Disease (ASCVD) risk.

• Target values were not given

AtheroSclerotic CardioVascular Disease

(ASCVD)

• Acute coronary syndromes.

• History of MI.

• Stable or unstable angina.

• Coronary revascularization-PTCA/STENT/CABG

• Stroke/TIA.

• Peripheral arterial disease.

‘Myths’ about new guidelines

• Unnecessary prescription of high dose statins.

• Exposed to many side-effects of statins.

• New risk assessment tool is a flaw.

• Influenced by pharmaceutical industry.

This guideline…

• This guideline emphasized Statins as first-line therapy due to the strong body of supporting evidence.

• The data obtained from randomized controlled trials, systematic reviews and meta analyses of these trials.

42y old estate clerk diabetic & smoker on Metformin for for 7years

Statins • Reduce synthesis of cholesterol in the liver by

competitively inhibiting HMG-CoA reductase activity.

• The reduction in intracellular cholesterol concentration induces an increased expression of LDL-R on the surface of the hepatocytes.

• This results in increased uptake of LDL-C from the blood and a decreased plasma concentration of LDL-C and other apo-B containing lipoproteins, including TG-rich particles.

‘Pleiotropic effects’ of statin- -benefit beyond their lipid lowering effects.

• Regression of plaques.

• Enhance stabilization of plaques.

• Reduce oxidative stress and inflammation.

• Reversal of endothelial dysfunction.

• Decreased thrombogenicity.

• Reduction of arrhythmias.

• Beneficial extrahepatic effects on immune system, CNS and bone.

Intensity of statin therapy

High-intensity statin therapy lowers LDL-C more than50%. Atorvastatin 40-80mg Rosuvastatin 20-(40)mg

Moderate-intensity statin therapy lowers LDL-C 30-50% Atorvastatin 10(20)mg Rosuvastatin (5)10mg Simvastatin 20-40mg

Lower-intensity statin therapy lowers LDL-C by less than 30% Simvastatin 10mg

Four statin benefit groups who need high intensity statin therapy

• Individuals with Atherosclerotic CVD

• Individuals with primary elevations of LDL-C≥ 190 mg/dL

• Individuals 40 to 75 years of age with diabetes and LDL-C 70-189 mg/dL

• Individuals without clinical Atherosclerotic CVD or diabetes

who are 40 to 75 years of age with LDL-C 70-189 mg/dL and an estimated 10-year CVD risk of 7.5% or higher.

Side-effects of statins

• Myalgia,myopathy,myositis,rhabdomyolysis,elevated liver enzymes,hepatitis,jaundice,pancreatitis,hepatic failure,gastrointestinal disturbances, sleep disturbance, headache, dizziness, depression, parasthesia, asthenia, peripheral neuropathy, amnesia, fatigue, sexual dysfunction, thrombocytopenia, arthralgia, visual disturbance, alopecia, hypersensitivity reactions, rash, pruritus, urticaria, lupus-like reaction, interstitial lung disease, dyspnoea, cough, weight loss, hyperglycaemia, diabetes

• Nasopharyngitis, epistaxis, pharyngeolaryngeal pain, backpain, pyrexia, anorexia, malaise, chestpain, weight gain, hypoglycaemia, tinnitus, peripheral oedema, neck pain, Stevens-Johnson syndrome, toxic epidermal necrolysis, gynaecomastia, hearing loss

• Proteinuria, haematuria, oedema

• Anaemia, tendinopathy

• Abnormal urination, dysuria, nocturia,frequency.

Primary Prevention of CVD

WHO risk prediction charts

• These charts indicate 10-year risk of a fatal or non-fatal major CV event according to age, sex, blood pressure, smoking status, total cholesterol and presence or absence of diabetes for 14 WHO epidemiological sub-regions.

Primary prevention of CVD

• Risk <10%- advice lipid-lowering diet.

• Risk 10 to <20%- advice lipid-lowering diet.

• Risk 20 to <30%- adults >40 years with high serum cholesterol (>200) and/or LDL cholesterol (>115) despite lipid-lowering diet should be given a statin.

• Risk ≥ 30%- advice lipid-lowering diet and given a statin. Serum cholesterol should be reduced to <200 (LDL<115) or by 25% whichever is greater.

2016 ESC guideline

2016 ESC Guideline

• LDL cholesterol is recommended as the primary target of treatment.

• Total cholesterol should be considered as a treatment target if other analysis are not available

• Non-HDL cholesterol should be considered as a secondary treatment target.

• HDL cholesterol is not recommended as a target for treatment.

Treatment targets for CVD prevention

• Very high risk: LDL-C<70mg/dL or reduction of at least 50% if the baseline is between 70 and 135mg/dL

• High risk: LDL-C <100mg/dL or reduction of at least 50% if the baseline is between 100 and 200mg/dL

• Low to moderate risk: LDL-C<115mg/dL

Fasting or non-fasting?

• Traditionally lipid analysis is done in the fasting state.

• Fasting and non-fasting samples give similar results for TC, LDL-C and HDL-C.

• TGs are affected by food resulting in an average 27mg/dL higher plasma level depending on the composition and time of last meal.

• Non-fasting lipid levels can be used in screening and general risk estimation.

LDL cholesterol

• Friedewald formula:

LDL = TC – HDL – (TG/5)

• The formula cannot be used in high TG levels (>400mg/dL).

• This formula is unreliable under non fasting conditions.

• Direct measurement of LDL-C levels is done now.

• LDL-C is the primary target of treatment.

Non-HDL Cholesterol

• Non-HDL cholesterol is an estimation of the total amount of atherogenic lipoproteins in plasma [VLDL, VLDL remnants, IDL, LDL, Lp(a)]

• Non-HDL cholesterol is easily calculated from total cholesterol minus HDL-C.

• It is recommended that non-HDL-C is a better risk indicator than LDL-C.

• Non-HDL Cholesterol is the secondary target of treatment.

• Goals for non-HDL-C is LDL-C goal plus 30mg/dL.

HDL Cholesterol

• Low HDL-C has been shown to be a strong and independent risk factor.

• HDL-C >40mg/dL in men and >48mg/dL in women indicates lower risk.

• HDL-C is not recommended as a target for treatment.

• Very high levels of HDL-C have not been found to be associated with athero protection.

• Dysfunctional HLD-C may be more relevant to the development of atherosclerosis than the HDL-C levels.

Triglycerides

• High TG levels are often associated with low HLD-C and high levels of small dense LDL particles (atherogenic).

• TG has been shown to be an independent risk factor.

• TG levels <150mg/dL indicates lower risk and higher levels indicate a need to look for other risk factors.

Hypertriglyceridaemia

• Genetic • Obesity • T2 DM • Alcohol • Diet high in simple carbohydrate • Renal disease • Hypothyroidism • Pregnancy • Paraproteinaemia and autoimune diseases(SLE) • Steroids, oestrogens, Tamoxifen, Beta-Blockers,

Thiazides, Isotretinoin, Ciclosporin, Protease inhibitors, phenothiazines…

Hypertriglyceridaemia

• Drug treatment should be considered in high risk patients with TG>200mg/dL.

• Statins may be considered as the first drug of choice for reducing CVD risk in high risk patients with hypertriglyceridaemia.

• In high risk patients with TG>200mg/dL despite statin treatment, Fenofibrate may be considered in combination with statins.

• n-3 fatty acids has an adjunct to diet if TGs are 496mg/dL. The recommended dose of EPA and DHA 2-4g per day.

Non-statin therapy

• Fibrates –FENOFIBRATE

• Cholesterol absorption inhibitors-EZITIMIBE

• PCSK9 Inhibitors-ALIROCUMAB,EVOLUCUMAB

• n-3 Fish oils

Cholesterol absorption inhibitors

• Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat soluble nutrients.

• Ezetimibe reduces the amount of cholesterol delivered to the liver.

• The liver reacts upregulating LDLR expression which in turn leads to increased clearance of LDL-C from the blood.

• Used as second line therapy in association with statins when therapeutic goal is not achieved at the maximal tolerated statin dose

Statin Drug-Drug Interection

• Cyclosporin,Tacrolimus

• Macrolides

• Calcium antagonists

• Protease inhibitors

• Warfarin

• Digoxin

• Fibrates

PCSK9 inhibitors

• These drugs target a protein PSCK9 involved in the control of LDL-R.

• Monoclonal antibodies that reduce LDL-C by 60% independent from the presence of background lipid lowering therapy

• Alirocumab and Evolocumab are approved to use primarily in ASCVD patients on maximally toterated statin therapy ,still LDL>100 and FH

Monitoring statin therapy.

• Smoking status • Alcohol consumption • Blood pressure • BMI • Total C, HDL-C, non- HDL-C • TG • HbA1c • Renal function and eGFR • Transaminase levels • TSH • Vitamin D levels

Monitoring statin therapy

• History of persistent generalized unexplained muscle pain- measure CPK levels.

• If CPK level is 5 times the ULN, re-measure after 7 days. If still 5 times the ULN do not start statin.

Monitoring statin therapy

• If CPK levels are raised but less than 5 times ULN, start statin at a lower dose.

• If people report muscle pain or weakness while taking a statin, explore the other possible causes for it and raised CPK, if they have previously tolerated statin therapy for more than three months.

Monitoring statin therapy

• Measure baseline liver transaminase before starting a statin.

• Measure liver transaminase within 3 months of starting treatment and at 12 months.

• Do not routinely exclude statin therapy in people who have liver transaminase levels that are raised but less than 3 times the ULN.

Monitoring statin therapy

• Do not stop statin due to increased blood glucose level or HbA1c.

• Statins are contraindicated in pregnancy- potential teratogenic risks.

• Advice women planning pregnancy to stop taking statins 3 months before they attempt to conceive and do not restart until breast feeding is finished.

Monitoring statin therapy

• If a person is not able to tolerate high intensity statin, treat with the maximum tolerated dose.

• If someone reports adverse effects when taking high intensity statins try following strategies:

-Stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin

-Reducing the dose with in the same intensity group

-Changing the statin to a lower intensity group

End of first part

Use of Antiplatelets in General Practice

DR.M.R.Mubarak

Antiplatelet therapy

• Aspirin in the prevention of CVD.

• Dual antiplatelet therapy in CVD

• Newer antiplatelet agents in CVD

Case History

• 82y old tourist lady Hypertensive on Ramipril 2.5mg daily and she was on Aspirin 75mg for Primary Prevention of CVD

• No past history of IHD,Stroke/TIA,diabetes or dyslipidaemia.No smoking or alcohol habit.

• Accidental fall near the swimming pool. • ICH,SDH,IVH due to cerebral contusion and on 3%

Saline infusion. • Developed Fast AF with Acute pulmonary oedema and

elevated BP -on ventilator, Amiodarone infusion IV Frusemide infusion…….

• Good recovery after 8 days of ICU stay Air lifted to France !

Primary prevention

• Aspirin and other antiplatelet drugs are no longer routinely recommended for use in primary prevention of CVD including for people with diabetes.

• Risk-benefit analyses of antiplatelet drugs for primary prevention.

Prevention of Cardiovascular Disease

WHO risk prediction charts

• These charts indicate 10-year risk of a fatal or non-fatal major CV event according to age, sex, blood pressure, smoking status, total cholesterol and presence or absence of diabetes for 14 WHO epidemiological sub-regions.

Antiplatelet drugs in Primary Prevention

• Risk < 10% - The harm caused by Aspirin treatment outweighs the benefits. Aspirin should not be given.

• Risk 10 to <20% - Benefits of Aspirin treatment are balanced by the harm caused. Aspirin should not be given.

• Risk 20 to <30% - The balance of benefits and harm from Aspirin treatment is not clear. Aspirin should probably not given.

• Risk ≥ 30% - Low dose Aspirin should be given

Secondary Prevention

• Lifestyle modification • Drug therapy-ASPIRIN • Statins to lower LDL cholesterol • Blood pressure control • Diabetes management • Complete smoking cessation • Regular exercise • Dietary management • Stress management

Anti-platelet drugs

• Irreversible cyclooxygenase(COX-1) inhibitors-ASPIRIN

• Adenosine diphosphate receptor(P2Y12) inhibitors (Thienopyridines)–CLOPIDOGREL, PRASUGREL, TICAGRELOR

• Phosphodiesterase inhibitors-DIPYRIDAMOLE • Glycoprotein IIb/IIIa receptor inhibitors(IV)-

ABCIXIMAB,TIROFIBAN,EPTIFIBATIDE

Loading doses of dual antiplatelet drugs are given in ACS(NSTEMI/STEMI)patients before

undergoing PCI

• Soluble Aspirin 300mg

with

Clopidogrel 600mg or

Prasugrel 60mg or

Ticagrelor 180mg

Antiplatelet therapy in Post-ACS Patients

• Low dose ASPIRIN of 75-100mg is recommended indefinitely after ACS/PCI.

• Stable Angina patients undergoing PCI ,dual antiplatelet therapy with ASPIRIN & CLOPIDOGREL is recommended for at least six months.

• ACS(NSTEMI/STEMI) patients undergoing PCI is recommended at least one year of dual antiplatelet therapy.

Prasugrel

• Thienopyridine group -a prodrug requires conversion to active metabolite.

• Loading dose of 60mg is given to ACS patients before undergoing PCI.

• Maintenance dose is 10mg daily.

Ticagrelor

• Not a prodrug.

• Rapid onset of inhibitory effect on P2Y12receptor

• Useful in ACS patients undergoing urgent coronary intervention

• Greater inhibition of platelet aggregation.

• Dose 90mg BD(Loading dose of 180mg)

• Dyspnoea ,asymptomatic arrythmias

Stent Thrombosis(ST)

• Stent thrombosis is a sudden life threatening complication after PCI.

• Timing of stent thrombosis is defined as ; Acute ( <24h)

Sub acute (24h-30d)

Late (30d-1yr)

Very late (after 1yr)

• Stent thrombosis is associated with mortality rate of 20-45 %

Stent Thrombosis

• Risk of stent thrombosis is increased drastically in patients who prematurely discontinue anti-platelet therapy.

• Always remember this deadly complication when you are planning to stop Aspirin/Clopidogrel prior to any surgery.

• Always get the opinion from the Cardiologist before taking the decision

Anti-platelet therapy

• PPI should be used in patients who have a history of GI bleeding who require DAPT.

• Routine use of PPI is not recommended with DAPT.

• Use of PPI is reasonable in patients with increased risk of bleeding-advanced age,concurrent use of warfarin, steroids,NSAIDS,H.pylori infection.

Take Home Message

• indication for Aspirin in Primary prevention.

• Duration of dual antiplatelet therapy after PCI/ACS

• Caution in withholding antiplatelet therapy.

• Indication for high intensity statin therapy.

• Guideline recommendation for statins in primary prevention.

• Monitoring patients on statin therapy

THANK YOU

mubarakmr@yahoo.co.uk