Stable Angina Pectoris What’s New in 2013? Ranil de Silva FRCP PhD Consultant Interventional Cardiologist Royal Brompton and Harefield NHS Foundation Trust Ealing Hospital NHS Trust

Senior Lecturer in Clinical Cardiology National Heart and Lung Institute, Imperial College London [email protected] T. 07904 867763 0208 242 5927(PA)

Epidemiology of Stable Angina o Incidence increasing o ~2M cases in UK o Age 55-64y – Affects 8% ♂ and 3% ♀

o Age 65-74y – Affects 14% ♂ and 8% ♀

Epidemiology of Stable Angina o In 2009/10 ~45K admission → ~65K bed days o ~67,000 elective PCI’s per year o ~50% of patients undergoing PCI are on no or suboptimal medical Rx o In 2009/10, ~300,000 angina patients attended Cardiology Outpatient appointments

Investigation for Stable CHD o To confirm the clinical diagnosis – Demonstrate myocardial ischaemia

o To assess risk of future adverse cardiovascular events – Burden of myocardial ischaemia – Anatomic severity coronary artery disease – LV function

o Choice of test dependent on clinical probability of CHD

CHD Mortality from 1961-2009 Men

Women

Mortality from CHD has halved from 1961-2009 CVD remains leading cause of death in UK www.heartstats.org

NICE CG 95 and 126

Investigation of CHD

Non-invasive

Invasive

Functional

Anatomical

Exercise ECG Stress echo Stress cardiac MRI PET/CT Stress nuclear MPS FFRCT

CT coronary calcium score CT coronary angiogram

CFR Pressure wire (FFR) iFR IVUS OCT

Coronary angiogram

Involves exposure to ionising radiation

How do we diagnose CHD? Anatomical

Functional

Treatment Objectives o Improve symptoms and QOL o Reduce ischaemia

o Improve prognosis – Reduce risk of MI, heart failure, rehospitalisation, CV death

How to achieve this?

o Lifestyle modification o Medical therapy o Revascularisation

ESC Guidelines 2012

Lifestyle Advice – What’s New?

o Cardiac rehabilitation – High risk patients

o Exercise and interval training – Moderate (60-70% MPHR) and high (80-95% MPHR) intensity interval exercise programmes are safe

Treatment to Improve Prognosis Dyslipidaemia o Statins for all unless contraindicated o Irrespective of cholesterol levels o Initiate as soon as possible  LDL < 1.8 mmol/L or >50% reduction in initial LDL o Aim TG < 1.7 and/or HDL > 1 mmol/L – Emphasise lifestyle change

o Statin intolerant patients: change statin, statin holiday, gradual introduction → alt. daily regimes. o New strategies: anti-PCSK9 antibodies, mepomersin, LDL apheresis o Limited evidence; fibrates, nicotinic acid, ezetimibe, omega-3 supplements

Anti-PCSK9 antibodies o Binds LDL receptors, targeting them for degradation o Familial hypercholesterolaemia (Phase II) – 90% of patients reached LDL target v 17% on atorvastain 80mg (NEJM 2012;367:1891) – ~40-50% reduction in LDL in high dose stating Rx’s patients (MENDEL, LAPLACE-TIMI57 Lancet 2012)

o Sc injections every 2-4 weeks o Well tolerated o Minimal adverse events

How to achieve this?

o Lifestyle modification o Medical therapy o Revascularisation

Management Options for Stable Angina Improves prognosis o Lifestyle – Smoking cessation

o Drugs – – – –

Aspirin/clopidogrel b blockers (post-MI) ACE inhibitors Statins

o Revascularisation by CABG – LM – MVD incl. proximal LAD – Impaired LV

Improves symptoms o Drugs – – – – – – – –

b blocker, no prev.MI Ca antagonists Nitrates Nicorandil Ranolazine Ivabradine Trimetazidine Allopurinol

o PCI o Angina Plan o Pain management

COURAGE – PCI v OMT

Boden et al. NEJM 2007

What is Optimal Medical Therapy - NICE

NICE – CG126 o Initial assessment o Risk stratification o Initial medical therapy with uptitration o Assess risk-benefit of revascularisation o Re-evaluation

Medical Therapy in Stable Angina o Improves prognosis o Improves symptoms o Reduces ischaemia

What is optimal medical therapy (OMT)? o 2 anti-anginal drugs of which at least one should be a b blocker (aim target HR 5560bpm) o Statin therapy to achieve LDL 140/90 mmHg not already on Ca antagonist Not controlled on either drug Add as appropriate: Nicorandil, Dihydropyridine Ca antagonist (do not add amlodipine to diltiazem), Long acting nitrate, Ranolazine

PCI for Patients with Stable CHD o PCI does not reduce death or MI in patients with stable CHD o The rate of death or MI is low and no worse in PCI treated patients o There is an increased risk of urgent hospitalisation for worsening angina or ACS in medically treated patients o PCI should be performed preferably if ischaemia has been objectively demonstrated

PCI v CABG o CABG should remain the preferred revascularisation option for patients with multivessel or left main coronary disease, including those with DM (SYNTAX) o In patients with low to intermediate complexity coronary anatomy, PCI can provide equivalent results to CABG (SYNTAX) o PCI v CABG for left mainstem disease with otherwise low to intermediate complexity coronary anatomy coronary anatomy is currently under investigation (EXCEL)

Case 1 M, 58yrs, retired company director Reason for referral: Severe angina and dyspnoea. Symptoms occur after walking 100yds. Previous CABG and PCI Risk factors: o +ve FH o Current smoker o Hypercholesterolaemia o Type II DM

Case 1 History o 1993 CABG – LIMA to LAD, SVGs to RCA and OM2

o 2003 – recurrent angina  PCI to native circumflex o 2006 – significant increase in angina. Failed PCI to native RCA occlusion – Medical management with aspirin, atenolol, ISMN, and simvastatin

o 2009 - referred to RBH for second opinion – MDT - For myocardial perfusion scan and depending on result proceed to angiography

Case 1 Myocardial perfusion scan

Mild reversible perfusion abnormality in the inferior wall maybe a combination of diaphramatic attenuation and mild reversible ischaemia in the native RCA territory.

Case 1

Case 1 Clinical examination:

BP 113/70 HR 55 Total chol 3.5mmol/L

BMI 29 Glu 5.6mmol/L

o Low ischaemic burden + preserved LV function  good prognosis o Invasive angiography not undertaken o Optimise medical Rx and Angina Plan

Case 1 o Current therapy Aspirin 75mg od Nebivolol 5mg od Amlodipine 10mg od Nicorandil 30mg bd Enalapril 10mg od Atorvastatin 80mg od Metformin 1gm bd

oOptions for optimising medical therapy: – – – –

Increase nebivolol Ivabradine ISMN Ranolazine

Ranolazine 375mg BD added

Case 1 oOptimise medical Rx and Angina Plan

oRanolazine 375mg BD, increased to 500mg BD o Seen in clinic 5 months later – Feeling ‘brilliant’. Only 2 episodes of angina to report – Lost 10lbs in weight. Reduced cigarette consumption but yet to give up completely. – Playing football with grandsons!

Ranolazine Ischemia

Ranolazine ↑ Late INa

Na+ Overload

Ca++ Overload

Diastolic relaxation failure Extravascular compression

Ischemia impairs cardiomyocyte sodium channel function Impaired sodium channel function leads to:

– Pathologic increased late sodium current – Sodium overload – Sodium-induced calcium overload Calcium overload causes diastolic relaxation failure, which:

– Increases myocardial oxygen consumption – Reduces myocardial blood flow and oxygen supply – Worsens ischemia and angina Initiation • Start under consultant supervision • 375mg BD • Titrate to 750 mg BD

Adapted from Belardinelli L. European Heart Journal. 2006;(8): Supplement A:A10-A13

CARISA Trial

Chaitman et al JAMA 2004;291:309

Ranolazine in T2D - TERISA 949 pts, 104 countries CCS2 on 1-2 drugs Single blind Placebo controlled Weekly angina ↓ Weekly GTN use ↓ No significant AE’s

JACC 2013

Ranolazine – Common Adverse Events o AE’s uncommon – Constipation, dizziness, nausea, headache, aesthenia – Myopathy in patients on chronic statin Rx (CYP3A4 inhibition)

o Avoid doses of >500mg BD in elderly and eGFR