Inadequate treatment of angina pectoris - what can

be done in 2019?

Dr Angela Hoye MB ChB, PhD, FRCP

Reader and Honorary Consultant in Cardiology

Hull

May 13th 2019

• The number of people dying from heart and circulatory disease is on the rise in the UK for the first time in 50 years

• The BHF latest analysis of the national health statistics has revealed an upward trend in cardiovascular-related deaths, including heart attack and stroke, before the age of 75.

• The charity says increasing a rising population and increasing rates of diabetes and obesity are partly to blame, and called for more collaboration on research for new treatments, diagnosis and support for at-risk groups.

• In 2014, the number totalled to 41,042 but in 2017 this number rose to 42,385, despite decades of progress that saw the annual death rate from heart and circulatory disease half since the 1960s.

Pathophysiology

• Demand exceeds supply

• Increased myocardial O2 demand can only be met by augmenting coronary blood flow• Perfusion pressure

• Coronary vascular bed resistance

• Duration of diastole

• Angina occurs when coronary flow cannot meet the myocardial O2 demand• Significant obstructive atherosclerotic disease

• Coronary spasm

• Microvascular disease

A Brief History

Sir William Heberden (1710-1801)

• Credited with the first description of anginawhich he presented to the Royal College ofPhysicians in 1768

• “They who are afflicted with it, are seizedwhile they are walking, (more especially if itbe up hill, and soon after eating) with apainful and most disagreeable sensation inthe breast, which seems as if it wouldextinguish life, if it were to increase orcontinue; but the moment they stand still, allthis uneasiness vanishes.”

Burden of Angina

• Stable angina pectoris affects up to 5% of the adult populationover the age 40 in most developed countries

• The prevalence of angina is increasing, with approximately twomillion people in the UK being diagnosed with the condition

• Affecting 14% of men and 8% of women

• There are estimated to be 96,000 new cases each year

www.bhf.org.uk/statistics

Impact• Patients with angina often complain about poor QOL

• They are considered frequent users of healthcare services

• In 2000, the direct cost of angina was £669 million (1.3% oftotal NHS expenditure),

Stewart et al Heart 2003

Treatment

• In 1768 William Heberden noted that symptoms could be improved with • Opium

• “Relief by wine and spiritous cordials”

• 1847: Discovery of nitroglycerine by Ascanio Sobrero in Turin • (1851: joined by Alfred Nobel invented

dynamite)

• 1867 Lauder Brunton used amyl nitrite to relieve angina• Noted pharmacological resistance to

repeated doses

Treatment

• 1946, Stearns et al study of whiskey in 8 patients with stable angina

Stearns et al NEJM 1946;234:578-82

Treatment today

Smoking

• Increases risk of CVD (even if smoke <5 cigarettes a day)

• Induces coronary spasm, increases HR and blood pressure, increases thrombogenicity, decreases HDL levels

• Quitting is associated with a 36% reduction in mortality after myocardial infarction

• After 15 years of quitting, the risk of suffering from coronary artery disease equals that of a non-smoker

• Passive smoking aggravates angina• Study of 10 patients exposed to 15 cigarettes smoked within 2 hours

• Increases in HR and BP

• Duration of exercise until angina fell 22% in a well ventilated room and 38% in an unventilated room

Aronow NEJM 1978;299:21-24

Diet• Aim for a BMI <25kg/m2

ESC guidelines 2013 EHJ 2013;34:2949–3003

• Mediterranean diet• 7,447 participants at high risk of CVD

• Diet supplemented with olive oil vs nuts vs control

Estrucj et al NEJM 2018;378:e34

Diet

Exercise• Lack of exercise is a risk factor for CVD

• Exercise helps improve risk factors for CVD

• Exercise improves endothelial function with increase invascular nitric oxide

• Improve functional capacity and increase the anginalthreshold

• Improves development of collaterals

• Plaque regression (?)

Suaya JA et al. J Am Coll Cardiol 2009;54:25–33. Schuler et al EHJ 2013;34:1790-99. Mobius-Winckler et al. Circulation 2016;133:1438-1448

Diabetes Mellitus

• Poorly controlled diabetes is associated withprogression of atherosclerotic disease

• Aim for HbA1c <7.0%

• There has been an 18% increase in people diagnosedwith diabetes during the past five years

• Estimated 920,000 people having undiagnosed type 2diabetes

Lipids

• Statin therapy irrespective of LDL levels

• Atorvastatin 80mg od in the majority

• Goal of treatment: LDL-C <1.8 mmol/L

• If LDL high:

• Optimise dose of statin

• Add ezetimibe

• Consider PCSK9 inhibitor

• Major risk factor for coronary artery disease

• Almost 5 million people in the UK are estimated to have undiagnosed high blood pressure

• In the presence of CAD, poorly controlled blood pressure will increase the likelihood of angina• Increased workload on the heart

• LVH leading to increased myocardial O2 demand and impaired microvascular perfusion

Hypertension

Meta-analysis of intensive vs less intensive BP lowering

Xie et al Lancet 2016

*Individuals with SBP and DBP in 2 categories should be designated to the higher BP category.

BP indicates blood pressure (based on an average of ≥2 careful readings obtained on ≥2 occasions,

as detailed in DBP, diastolic blood pressure; and SBP systolic blood pressure.

BP Category SBP DBP

Normal <120 mm Hg and <80 mm Hg

Elevated 120–129 mm Hg and <80 mm Hg

Hypertension

Stage 1 130–139 mm Hg or 80–89 mm Hg

Stage 2 ≥140 mm Hg or ≥90 mm Hg

Hypertension: ACC guidelines 2017

Treatment today

PharmacotherapyVasculo-protective therapy

• Aspirin

• Statin

• ACE-inhibitor

First Line

• Beta-blockers

• Calcium channel blockers

Second Line

• Nitrates

• Nicorandil: ATP-dependent K+ channel opener

• Ivabradine: If channel inhibitor

• Ranolazine: late inward Na+ channel inhibitor

Improved symptoms

Improved exercise capacity

Treatment Today

Improved quality of life

Which Agent?

• Potential benefit of a lower heart rate

• Patients with a lower HR have an improved prognosis• Lower myocardial oxygen demand

• Reduced shear stress

Fox et al NEJM 2014;371:1091-9

SIGNIFY TrialDeath or MI

Bangalore S et al , JAMA 2012; 308:1340–1349

REACH RegistryDeath, MI or stroke

Pharmacotherapy

• Ferrari et al undertook a systematic review• 13 studies

• Very few studies comparing different agents• Mostly “non-inferior”

There is a paucity of data comparing efficacy of different agentsLittle evidence that one agent is superior to any other

Ferrari et al EHJ 2019;40:190-94

Decision should be based on co-morbiditieseg hypertension, LV impairmentetc……

Revascularisation

• Importance of complete revascularisation

Revascularisation: PCI

Valenti et al European Heart Journal 29(19):23

Revascularisation: Chronic total occlusions

CTO PCI Success Rate Depends on Expertise

RCA CTO Case

RCA Case

Revascularisation: CABG

But, not possible for some

Refractory Angina

• A chronic condition (≥3 months in duration)characterised by angina in the setting of coronaryartery disease (CAD), which cannot be controlledby a combination of optimal medical therapy,angioplasty or bypass surgery, and wherereversible myocardial ischaemia has beenclinically established to be the cause of thesymptoms.

Treatment today

Enhanced External Counterpulsation (EECP)

• Aortic counterpulsation in order to augment diastolic blood flow

• Inflate at onset of diastole• Improve coronary perfusion

• Sudden deflation at onset of systole• Reduce vascular resistance

• CI in PVD, AAA >3.8cm, aortic insufficiency, poorlycontrolled AF, anti-coagulation

Benefits of EECP

• Mechanism: Shear stress stimulates release of NO andVEGF, thereby promoting angiogenesis and collateralformation

• Demonstrated in the MUST EECP trial

• Blinded RCT of 139 patients

• EECP group had increased exercise duration

• Increased time to 1mm ST-depression

• Decrease in anginal episodes (p<0.05)

EECP for Refractory Angina• Study of 50 patients treated at the Bradford

refractory angina clinic

• CCS 3; evidence of inducible ischaemia; on 3 anti-anginals; no option for revascularisation

Ali et al British Journal of Cardiology 2018;25(2)

Exercise capacity (6MWT)

Angina episodes per week

Extracorporeal Shockwave Therapy

• Low-energy shockwaves delivered to the border zones of ischaemic myocardium guided by ECHO

• Energy 10% that used in urolithiasis

• Induces development of collaterals

Interv Cardiol 2011

• 1954: Beck & Leighninger performedsurgical partial occlusion of the coronarysinus• Relief of angina

• Improved function

• Reduced mortality

• Increases the pressure in the coronarysinus thus re-distributing blood from theepicardium to the more ischaemicendocardium

Coronary Sinus Reduction

• Balloon-expandable, stainless steelhourglass-shaped device

• RCT of 104 patients

• CCS III-IV

Coronary Sinus Reduction

Verheye et al NEJM 2015;372:519-27

Neuromodulation

• Perception of symptoms / pain

Neuromodulation

Spinal Cord Stimulation

• Placement of multipolar electrodes into the epidural space to deliver an electrical current to the dorsal columns between C7 and T1

• Patient controlled

Cell Therapy• Small studies have evaluated bone marrow

mononuclear cells, adipose-derived regenerative cells,CD34+ cells, and CD133+ progenitor cells

• Consistent improvement in angina symptoms

• Induce neovascularization in ischaemic myocardium

• RENEW trial was RCT of bone marrow-derived CD34+cells in patients with refractory angina

Povsik et al JACC Intv 2016;9:1576–85

Change in total exercise time

Conclusions

• CVD is the leading cause of death in Western Society

• The death rate has recently increased• More obesity• More diabetes

• Key message for all physicians is to address lifestyle issues and risk factors

• Angina impacts on quality of life

• Referral to specialist• Interventional Cardiologist• CTO experts• Refractory angina services

Thankyou