Practice Update - ESC Congress 2017

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

EUROPEAN SOCIETY OF CARDIOLOGY CONGRESS 2017 26–30 AUGUST 2017 • BARCELONA, SPAIN

THE BEST OF ESC 2017 The Interleukin-1β Inhibitor Canakinumab Cuts Cardiovascular Disease and Lung Cancer Risk by Reducing Inflammation – CANTOS Trial • Renal Denervation Lowers Blood Pressure in Hypertensive Patients Not Taking Antihypertensive Medication – SPYRAL HTN-OFF MED Trial • Catheter Ablation Improves Outcomes in Patients With Heart Failure and Atrial Fibrillation – CASTLE-AF Trial • Two Results of the PURE Study May Be Game Changers in Heart Disease Prevention

This ESC Congress 2017 PracticeUpdate Conference Series is distributed with the support of A. Menarini Australia.

Nebilet ® (nebivolol hydrochloride) tablets 1.25 mg, 5 mg, 10 mg. INDICATIONS: Essential hypertension. Stable chronic heart failure (CHF) as an adjunct to standard therapies in patients 70 years or older. CONTRAINDICATIONS: Hypersensitivity to the active or any of the excipients; liver insufficiency or liver function impairment; acute heart failure; cardiogenic shock or episodes of heart failure decompensation requiring IV inotropic therapy; sick sinus syndrome, including sino-atrial block; second and third degree heart block (without a pacemaker); history of bronchospasm (e.g. including COPD) and/or asthma; untreated phaeochromocytoma; metabolic acidosis; bradycardia (HR < 60 bpm prior to starting therapy); hypotension (systolic BP < 100 mmHg); severe peripheral circulatory disturbances. PRECAUTIONS: Avoid abrupt cessation unless clearly indicated – reduce dosage gradually over 1-2 wks; refer to full PI. If it must be withdrawn abruptly, close observation is required. Anaesthesia; untreated congestive heart failure, unless stabilised; bradycardia; peripheral circulatory disorders (e.g. Raynaud’s disease, intermittent claudication); first degree heart block; Prinzmetal’s or variant angina; lipid and carbohydrate metabolism – does not affect glucose levels in diabetic patients, but may mask symptomsofhypoglycaemia.Hyperthyroidism;COPD/asthma;phaeochromocytoma; various skin rashes; conjunctival xerosis; oculomucocutaneous syndrome; psoriasis; increased sensitivity to allergens and severity of anaphylactic reactions; galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption; driving vehicles or operating machines. Pregnancy (Cat C). Lactation. Children and adolescents. Renal and hepatic insufficiency – see Dosage and Administration. INTERACTIONS: Combination not recommended: Class I antiarrhythmics; calcium channel antagonists (verapamil/dilitiazem); centrally-acting antihypertensives; other beta-blockers (incl. eye drops). Combination to be used with caution: Class III antiarrhythmic drugs; anaesthetics (volatile); insulin and other oral diabetic medicines; calcium antagonists (dihydropyridine type); catecholamine depleting agents; baclofen; amifostine; for other combinations requiring careful consideration, see full PI. ADVERSE EFFECTS: Headache, dizziness, tiredness, fatigue, paraesthesia, constipation, nausea, diarrhoea, cardiac failure aggravated, bradycardia, hypotension, dyspnoea, oedema, slowed AV conduction/AV-block, bronchospasm. Post-marketing reports of hypersensitivity, angioneurotic oedema, abnormal hepatic function, acute pulmonary oedema, acute renal failure, myocardial infarction, others see full PI. DOSAGE AND ADMINISTRATION: Once daily dosing, can be given with or without meals,consistent approach is recommended. Hypertension: 5 mg daily. Renal insufficiency: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 65 years: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 75 years: caution must be exercised and these patients monitored closely. Chronic Heart Failure: The initial up titration should be done gradually at 1-2 wk intervals based on patient tolerability starting at 1.25 mg once daily, increased to 2.5 mg, then to 5 mg and then to 10 mg once daily. Initiation of therapy and every dose increase should be done under close supervision for at least 2 h. No dose adjustment is required in patients with mild to moderate renal insufficiency. Use in patients with severe renal insufficiency (serum creatinine ≥ 250 µ mol/L) is not recommended. Date prepared 17 December 2015. References: 1. Nebilet Approved Product Information, 14 December 2015. 2. Flather MD et al. Eur Heart J 2005; 26: 215–25. Please review full Product Information before prescribing. The Product Information can be accessed at www.menarini.com.au/pi Nebilet ® (nebivolol hydrochloride) tablets 1.25 mg, 5 mg, 10 mg. INDICATIONS: Essential hypertension. Stable chronic heart failure (CHF) as an adjunct to standard therapies in patients 70 years or older. CONTRAINDICATIONS: Hypersensitivity to the active or any of the excipients; liver insufficiency or liver function impairment; acute heart failure; cardiogenic shock or episodes of heart failure decompensation requiring IV inotropic therapy; sick sinus syndrome, including sino-atrial block; second and third degree heart block (without a pacemaker); history of bronchospasm (e.g. including COPD) and/or asthma; untreated phaeochromocytoma; metabolic acidosis; bradycardia (HR < 60 bpm prior to starting therapy); hypotension (systolic BP < 100 mmHg); severe peripheral circulatory disturbances. PRECAUTIONS: Avoid abrupt cessation unless clearly indicated – reduce dosage gradually over 1-2 wks; refer to full PI. If it must be withdrawn abruptly, close observation is required. Anaesthesia; untreated congestive heart failure, unless stabilised; bradycardia; peripheral circulatory disorders (e.g. Raynaud’s disease, intermittent claudication); first degree heart block; Prinzmetal’s or variant angina; lipid and carbohydrate metabolism – does not affect glucose levels in diabetic patients, but may mask symptomsofhypoglycaemia.Hyperthyroidism;COPD/asthma;phaeochromocytoma; various skin rashes; conjunctival xerosis; oculomucocutaneous syndrome; psoriasis; increased sensitivity to allergens and severity of anaphylactic reactions; galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption; driving vehicles or operating machines. Pregnancy (Cat C). Lactation. Children and adolescents. Renal and hepatic insufficiency – see Dosage and Administration. INTERACTIONS: Combination not recommended: Class I antiarrhythmics; calcium channel antagonists (verapamil/dilitiazem); centrally-acting antihypertensives; other beta-blockers (incl. eye drops). Combination to be used with caution: Class III antiarrhythmic drugs; anaesthetics (volatile); insulin and other oral diabetic medicines; calcium antagonists (dihydropyridine type); catecholamine depleting agents; baclofen; amifostine; for other combinations requiring careful consideration, see full PI. ADVERSE EFFECTS: Headache, dizziness, tiredness, fatigue, paraesthesia, constipation, nausea, diarrhoea, cardiac failure aggravated, bradycardia, hypotension, dyspnoea, oedema, slowed AV conduction/AV-block, bronchospasm. Post-marketing reports of hypersensitivity, angioneurotic oedema, abnormal hepatic function, acute pulmonary oedema, acute renal failure, myocardial infarction, others see full PI. DOSAGE AND ADMINISTRATION: Once daily dosing, can be given with or without meals,consistent approach is recommended. Hypertension: 5 mg daily. Renal insufficiency: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 65 years: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 75 years: caution must be exercised and these patients monitored closely. Chronic Heart Failure: The initial up titration should be done gradually at 1-2 wk intervals based on patient tolerability starting at 1.25 mg once daily, increased to 2.5 mg, then to 5 mg and then to 10 mg once daily. Initiation of therapy and every dose increase should be done under close supervision for at least 2 h. No dose adjustment is required in patients with mild to moderate renal insufficiency. Use in patients with severe renal insufficiency (serum creatinine ≥ 250 µ mol/L) is not recommended. Date prepared 17 December 2015. References: 1. Nebilet Approved Product Information, 14 December 2015. 2. Flather MD et al. Eur Heart J 2005; 26: 215–25. PBS Information: R st icted e efit. Moderate to severe heart failure. Refer to PBS Schedule for full restricted benefit information. Please review full Product Information before prescribing. The Product Information can be acc ssed at www.menarini.com.au/pi Nebilet ® (n bivolol hydrochloride) tablets 1.25 mg, 5 mg, 10 mg. INDICATIONS: Essential hypertension. Stable chronic heart failure (CHF) as an adjunct to standard therapies in patients 70 years or older. CONTRAINDICATIONS: Hypersensitivity to the active or any of the excipients; liver insufficiency or liver function impairment; acut heart failure; cardiogenic shock or episodes of heart failure decompensation requiring IV inotr pic herapy; s k sinus syndrome, inclu i g sino-atri l block; s cond a d third degree heart bl ck (without a pacemaker); history of bronch spasm ( .g. including COPD) and/or asthma; ntreated pha ochromocytoma; metabolic acidosis; br dycar ia (HR < 60 bpm prior to starting therapy); hypotension (systolic BP < 100 mmHg); severe peripheral circulatory disturbances. PRECAUTIONS: Avoid abrupt cessation unless clearly indicated – reduce dosage gradually over 1-2 wks; refer to full PI. If it must be withdrawn abruptly, close observation is required. Anaesthesia; u treated congestive heart failure, unless stabilised; bradycardia; p i h ral circulatory diso de s (e.g Raynaud’s disease, intermitt nt claudication); first degree heart block; Prinzmetal’s or variant angina; lipid and carbohydrate metabolism – does not affect glucose levels in di betic pati nts, but may mask symptomsofhypoglycaemia.Hyperthyroidism;COPD/asthma;phaeochromocytoma; various skin rashes; conjunctival xerosis; oculomucocutaneous syndrome; psoriasis; increased sensitivity to allergens and severity of anaphylactic reactions; galactose intoleran e, Lapp-lactase deficiency or glucose-galactose malabsorption; driving vehicles or operating machines. Pregnancy (Cat C). Lactation. Children and adolescents. Renal and hepatic insufficiency – see Dosage and Administration. INTERACTIONS: Combination not recommended: Class I antiarrhythmics; calcium channel antagonists (verapamil/dilitiazem); centrally-acting antihypertensives; other beta-blockers (incl. eye drop ). Combi ation to be used with caution: Class III antiarrhythmic drugs; anaesthetics (volatile); insulin and other oral diabetic medicines; calcium antagonists (dihydropyridine type); catecholamine depleting agents; baclofen; amifostine; for other combinations requiring careful consideration, see full PI. ADVERSE EFFECTS: Headache, dizziness, tiredness, fatigue, paraesthesia, constipation, nausea, diarrhoea, cardiac failure aggravated, bradycardia, hypotension, dyspnoea, oedema, slowed AV conduction/AV-block, bronchospasm. Post-marketing reports of hypersensitivity, angioneurotic oedema, abnormal hepatic functio , cut pulmonary oedema, acute renal failure, myocardial infarction, others see full PI. DOSAGE AND ADMINISTRATION: Once d ily dosing, can be given with or without meals, consistent pproach is recommended. Hypertension: 5 mg daily. Renal insufficiency: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 65 years: recommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 75 years: caution must be exercised and these p tients monitored closely. Chronic Heart Failure: The initial up titrat should be d ne gradually at 1-2 wk in ervals ased on patient tolerability starting at 1.25 mg once daily, increased to 2.5 mg, then to 5 mg and then to 10 mg once daily. Initiation of therapy and every dose increase should be done under close supervision for at least 2 h. No dose adjustment is required in patients with mild to moderate renal insufficiency. Use in patients with severe renal insufficiency (serum creatinine ≥ 250 µ mol/L) is not recommended. Date prepared 17 December 2015. References: 1. Nebilet Approved Product Inform tion, 14 Dec mber 2015. 2. Flather MD et al. Eur Heart J 2005; 26: 215–25. Please revi w full Product Information b fore presc ibing. The Product Information can be accessed at www.menarini.com.au/pi A. Me arini Australia Pty Ltd. ABN 62 116 935 758, Level 8, 67 Albert Avenue, Chatswoo NSW 2067 Medical Information 1800 644 542 NEB-AU-0506 April 2016 • ALMIN.1.2 Nebilet ® (n bivolol hydrochlo ide) tablets 1.25 mg, 5 mg, 10 mg. INDICATIONS: Essential hypertension. Stable chronic heart failure (CHF) as an djunct o standard therapies n pat ents 70 years or ol . CONTRAINDICATIONS: Hypersensitivity to the active or any of the excipi nts; liver insufficiency o liver function impair ent; acute heart failure; ca iogenic shock or episodes f heart failur decompensatio requiring IV inotropic therapy; sick sinus yndrome, includ g sino-atrial block; second and third deg ee heart block (without a pacem k r); history of b onchospasm (e.g. includ g COPD) and/or asthm ; untreated phaeoc romocytoma; metabolic acidosis; bradycar ia (HR < 60 bpm prior to starting therapy); hypotensi n ( ystolic BP < 100 mmHg); severe peripheral circu atory disturbances. PRECAUTIONS: Avoid abrupt cessation unless c arly indicate – r uce dosage gr dually over 1-2 wks; refer to full PI. If it mus be withdrawn abruptly, close ob rvation is required. Anaesthesia; untreated congestive heart failure, unl ss stabili ed; bradycar ia; peripheral circu atory disorders (e.g. Raynaud’s disease, intermit nt claudi tion); first degree h art block; Prinzmetal’s or variant angina; lipid and c rbohydr te metabolism – does n t affect glu ose level in diabetic pa ents, bu may ask sympto sofhyp gl caemia.Hyperth roidism;COPD/asthm ;phaeoc romocytoma; various skin rashes; conjunctival xerosis; culomuc cutaneous syndrome; psoriasis; ncreased sensitivity to allergens and everity of anaphyl ctic reactions; galactose intol ranc , Lapp-lactase deficiency or glucose-galactose malabsorption; driving vehicles or operating machines. Pregnancy (Cat C). Lactation. Children and adolescent . Renal and hepatic insufficiency – see Dosage and Administration. INTERACTIONS: Combination not rec mmended: Class I ntiarrhythmics; calcium channel a tagonists (verapamil/dilitiazem); centrally-acting antihypertensives; other beta- lockers (incl. eye drops). Combination to be used with cau ion: Class III antiarrhythmic drugs; anaesthetics (volatile); insulin and other oral diabetic medicin s; calcium antagonists (dihydrop ridine type); catecholamine depleting agents; baclofen; amifostine; for other combinations requiring careful considerat on, see full PI. ADVERSE FFECTS: Headache, dizziness, tiredness, fatigue, paraesthesia, constipation, nausea, di rrhoe , cardia f ilure aggravated, bradycar ia, hypotensi n, dyspnoea, oedema, slowed AV condu tion/AV-block, bronchosp sm. Post-marketing reports f hypersensitivity, angioneurotic dema, abnormal hepatic fun tion, acute p lmonary oedema, acute renal failure, myocardial infarction, o hers se full PI. DOSAGE AND ADMINISTRATION: Once daily dosing, ca be given with or without meals,con iste t appro ch is recommended. Hypertension: 5 mg daily. Renal insufficiency: re ommended starting dose is 2.5 mg daily, can be increased to 5 mg if needed. Patients > 65 years: r commended starting dose is 2.5 mg daily, c n be incr ased to 5 mg if needed. Patients > 75 years: c ution must be exercised and these patients monitored closely. Chronic Heart Failure: The initial up titration should be don gradually at 1-2 wk intervals based on patient tol rability starting t 1.25 mg once daily, increased to 2.5 mg, then to 5 mg and the to 10 mg once daily. Init ation of therapy and every dose incr ase should be don und r close supervision for at least 2 h. No dose adjustment is required in pat ents with mild to moderate renal insufficiency. Use in patients with severe renal insufficiency (serum creatinine ≥ 250 µ mol/L) is no rec mmended. Date prepared 17 December 2015. Referenc s: 1. Nebilet Approved Product Information, 14 December 2015. 2. Flather MD et al. Eur Heart J 2005; 26: 215– 5. PBS Information: Rest icted b nefit. Moderat to sev r heart f ilu e. Refer o PBS Schedul for full restricted b nefit in ormation. Please review full Product Information b fore p scribing. The Pro uct Information can be accessed at ww .menarini.com.au/pi PBS Information: Restricted benefit. Moderate to severe heart failure. Refer to PBS Schedule for full restricted benefit information. PBS Information: Restricted benefit. Moderate to severe heart failure. Refer to PBS Schedule for full restricted benefit information. A. Menarini Australia Pty Ltd. ABN 62 116 935 758, Level 8, 67 Albert Avenue, Chatswood NSW 2067 Medical Information 1800 644 542 NEB-AU-0506 April 2016 • ALMIN.1.2

nebivolol hydrochloride

NEBILET: Age proven in elderly ( ≥ 70 years) CHF patients 1,2 *vs placebo P= 0.039; patients ≥ 70 years regardless of age, gender or left ventricular ejection fraction NEBILET: Age proven in elderly ( ≥ 70 years) CHF patients 1,2 NEBILET reduced the risk of all cause mortality or cardiovascular hospital s tion i a broad range of eld rly CHF patients *1,2 *vs placebo P= 0.039; patien s ≥ 70 years regardless of age, nd r or left ventricular ejection fraction Elderly ( ≥ 70 years) CHF patients deserve an age proven blocker 1,2 NEBILET reduced the risk of all cause mortality or cardiovascular hospitalisation in a broad range of elderly CHF patients *1,2 *vs placebo P= 0.039; patients ≥ 70 years regardless of age, gender or left ventricular ejection fraction Elderly ( ≥ 70 y ars) CHF patients deserve an age proven blocker 1,2 NEBILET reduced the risk of all cause mortality or cardiovascular hospitalisation in a broad range of elderly CHF patients *1,2 Elderly ( ≥ 70 years) CHF patients deserve an g prov n blocker 1,2 NEBILET reduced the risk of all cause mortality or cardiovascular hospitalisation in a broad range of elderly CHF patients *1,2 *vs placebo P= 0.039; patients ≥ 70 years regardless of age, gender or left ventricular ejection fracti n Elderly ( ≥ 70 years) CHF patients d serve an age proven blocke 1,2

NEBILET: Age proven in eld rly ( ≥ 70 years) CHF patients 1,2

NEBILET: Age proven in elderly ( ≥ 70 years) CHF patients 1,2

CHF= Chronic Heart Failure

CHF= Chronic Heart Failure

A. Menarini Australia P y Ltd. ABN 62 116 935 758, Level 8, 67 Albert Avenue, Chatswood NSW 2067 Medical Informati n 1800 644 542 NEB-AU-0506 April 2016 • ALMIN.1.2

A. Menarini Australia Pty Ltd. ABN 62 116 935 758, Level 8, 67 Albert Avenue, Chatswood NSW 2067 Medical Information 1800 644 542 NEB-AU-0506 April 2016 • ALMIN.1.2

CHF= hronic Heart Failure

CHF= Chronic Heart Failure

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© ESC Congress 2017 – European Society of Cardiology

CONTENTS

4

12

4 The Interleukin-1 β Inhibitor Canakinumab Cuts Cardiovascular Disease and Lung Cancer Risk by Reducing Inflammation – CANTOS Trial 6 Ibuprofen Is Associated with a Rise in Blood Pressure in Patients with Arthritis and Cardiovascular Risk – PRECISION-ABPM Trial 7 Ablation of Atrial Fibrillation Improves Quality of Life More than Drugs – CAPTAF Trial 8 Renal Denervation Lowers Blood Pressure in Hypertensive Patients Not Taking Antihypertensive Medication – SPYRAL HTN-OFF MED Trial 8 Oxygen Therapy Does Not Improve Survival in Patients With Symptoms of MI – DETO2X-AMI 10 Catheter Ablation Improves Outcomes in Patients With Heart Failure and Atrial Fibrillation – CASTLE-AF Trial 11 Apixaban Lowers Stroke Risk in Patients Undergoing Cardioversion for Atrial Fibrillation – EMANATE Trial

12 Two Results of the PURE Study May Be Game Changers in Heart Disease Prevention 14 Risk Factor-Driven Upstream Atrial Fibrillation Therapy Improves Sinus Rhythm Maintenance 14 Women Are Less Likely Than Men to Receive Recommended Statin Doses 16 Underweight is Associated with Highest Mortality and Costs After Cardiac Catheterization 18 Rivaroxaban + Aspirin Is Shown to Improve Outcomes in Patients With Stable Cardiovascular Disease – COMPASS Trial 19 The Gender Gap in Death from Acute Myocardial Infarction is Closing, Particularly in Women Younger than Age 60 20 Screening for Vascular Disease Saves More Lives at Lower Cost than Cancer Screening – VIVA Trial 22 Anacetrapib Reduces Risk of Serious Cardiovascular Events in High-Risk Patients on Statins – REVEAL Trial

ELSEVIER AUSTRALIA ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 Printed in Australia. EMC081701

ESC Congress 2017 • PRACTICEUPDATE CONFERENCE SERIES 3

The Interleukin-1 β Inhibitor Canakinumab Cuts Cardiovascular Disease and Lung Cancer Risk by Reducing Inflammation – CANTOS Trial

The interleukin-1 β inhibitor canakinumab lowered risk of cardiovascular disease and lung cancer risk by reducing inflammation. This conclusion, based on results of the Canakinumab ANti-inflammatory Thrombosis Outcomes Study (CANTOS) trial, conducted in 39 countries, was presented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30.

P aul M. Ridker, MD, of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, Massachusetts, said, “These findings represent the end game of more than two decades of research, stemming from a critical observation that half of heart attacks occur in people who do not have high cholesterol.” He continued, “For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovas- cular risk. This has far-reaching implications. By leveraging an entirely new way to treat patients – targeting inflammation – we may be able to improve outcomes significantly for certain very high risk populations.” The CANTOS trial aimed to determine whether reducing inflammation in patients who had a prior heart attack can lower risk of another cardiovas- cular event. The evaluated drug was canakinumab, a human monoclonal antibody that neutralizes interleukin-1β signaling, thereby suppressing inflammation. It is used to treat rare inherited conditions associated with overproduction of interleukin-1β. Interleukin-β is known to play “multiple roles in the development of atherothrombotic plaque,” the investigators noted. These roles include inducing procoagulant activity, promoting monocyte and leukocyte adhesion to vascular endothelial cells, and promoting the growth of vascular smooth- muscle cells.

The study included 10,061 patients who had pre- viously suffered a heart attack and had persistent, elevated levels of high-sensitivity C-reactive pro- tein, a marker of inflammation. All patients received aggressive standard care, which included high doses of cholesterol-lowering statins. In addition, participants were randomized to 50, 150, or 300 mg of canakinumab, or placebo, administered sub- cutaneously once every 3 months. Patients were followed for up to 4 years. The primary endpoint was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the first occurrence of any of the above, or of hospitalization for unstable angina requiring urgent revascularization. Canakinumab at doses of 150 or 300 mg reduced the risk of a cardiovascular event (the primary end- point) by 15% and 14%, respectively. Hazard ratios for the primary endpoint in the 50, 150, and 300 mg groups were 0.93 (95% confidence interval 0.80–1.07; P = .30), 0.85 (95% confidence interval 0.74–0.98; P = .021); and 0.86 (95% confidence interval 0.75–0.99; P = .031), respectively. The secondary endpoint was reduced by 17% in groups taking 150 or 300 mg of canakinumab. Corresponding hazard ratios in the 50, 150, and 300 mg groups were 0.90 (95% confidence inter- val 0.78–1.03; P = .12); 0.83 (95% confidence interval 0.73–0.95, P = .005); and 0.83 (95% confidence interval 0.72–0.94; P = .004), respectively.

Dr. Paul M. Ridker

PRACTICEUPDATE CONFERENCE SERIES • ESC Congress 2017 4

the progression of certain cancers, but these are exploratory findings that need replication.” “Maybe we don’t want everybody on this drug,” Dr. Ridker explained, speculating on how treatment might be managed for the still investigational canakinumab. “Maybe we give patients the first dose for free to see if they respond? If they respond, with a 25% or 30% risk reduction, that’s pretty good. If they do not respond, we don’t want you exposed to the toxicity, and we want you to stay away from the drug. It’s a different way of thinking about care.” “This is the first time in 40 years where we have something that’s not about lipid-lowering. We had no change in LDL cholesterol – there was a 30% to 40% reduction in interleukin-6 and C-reactive protein. Yet we had an event rate identical to what you’d get from being treated with a PCSK9 inhibitor.” “This is about personalized medicine,” he continued. “It’s saying not all second- ary-prevention patients are the same. If your problem is because your inflam- matory response has not been inhibited enough, that your C-reactive protein is high, that’s residual inflammatory risk.” He added, “Now we have something to offer those patients. If your LDL choles- terol is high after a myocardial infarction, then you can think about a PCSK9 inhibi- tor. You’re not going to give both drugs to patients. We’re trying to figure out how to give the right drug to the right patient.” " The data on cancer rates point to the possibility of slowing the progression of certain cancers, but these are exploratory findings that need replication. Paul M Ridker, MD

In contrast, cancer mortality was signif- icantly lower in patients treated with canakinumab than those treated with placebo, which Dr. Ridker said was “remarkable.” Treatment with canakinumab 150 mg and 300 mg reduced the risk of death from any cancer by 22% and 51%, respectively. The reduction was driven primarily by a reduction in the risk of lung cancer. In addition, treatment with canak- inumab resulted in a reduction in the risk of arthritis, osteoarthritis, and gout. Dr. Ridker said, “We found that in high risk patients, a drug that lowers inflam- mation but exerts no effect on cholesterol reduced the risk of major adverse cardio- vascular events. In my lifetime, I’ve seen three broad eras of preventative cardiol- ogy. First, we recognized the importance of diet, exercise, and smoking cessation. Then we saw the tremendous value of lipid-lowering drugs such as statins. Now we’re cracking the door open on the third era. This is very exciting.” “As an inflammatory biologist and car- diologist, my primary interest is heart disease but CANTOS was a good set- ting to explore a previously observed link between cancer and inflammation,” said Dr. Ridker. “The data on cancer rates point to the possibility of slowing

Due to multiplicity testing, only the 150-mg dose met statistical significance for both the primary and secondary endpoints. The benefit of the 150-mg dose was driven by a significant, 24% reduced risk of nonfatal stroke or cardiovascular death observed. Treatment with canakinumab did reduce the risk of hospitalization for unstable angina leading to urgent revascularization (odds ratio 0.64; 95% confidence interval 0.44–0.94) and the need for any coronary revascularization (odds ratio 0.68;95% confidence interval 0.58–0.81). Dr. Ridker explained that the relative reduction in clinical events ranged from 5% to 30%, depending on C-reactive pro- tein and interleukin-6 levels. Overall, the drug was found to be safe, but approximately one in every 1000 patients suffered a potentially fatal infec- tion. A small but significantly increased risk of death caused by infection or sepsis was observed when all three treatment arms were combined and compared with events in the placebo arm (0.31 vs 0.18 events per 100 patient years; P = .02). Neutropenia and thrombocytopenia were more common in patients treated with canakinumab.

PracticeUpdate Editorial Team

ESC Congress 2017 • PRACTICEUPDATE CONFERENCE SERIES 5

Ibuprofen Is Associated with a Rise in Blood Pressure in Patients with Arthritis and Cardiovascular Risk – PRECISION-ABPM Trial

The results supported and extended the findings of the PRECISION trial, inasmuch as they demonstrated noninferiority of the primary cardiovascular outcomes with moderate doses of celecoxib vs naproxen or ibuprofen. The findings may hold the greatest clinical significance in the elderly, who suffer a high prevalence of arthritis and hypertension. “The findings suggested that the elevated cardiovascular risk with NSAIDs may be partly due to drug-specific increases in blood pressure, challenging the widely cited hypothesis that adverse effects of NSAIDs relate directly to their effects on platelets and endothelial cells," Dr. Ruschitzka said. He added, “Since decreasing systolic blood pressure by just 2 mmHg lowers stroke mortality by 10% and ischemic heart dis- ease mortality by 7%, increases in systolic blood pressure associated with NSAIDs as observed in PRECISION-ABPM should be considered clinically relevant.”

In patients with osteoarthritis or rheumatoid arthritis, ibuprofen was associated with increased blood pressure and hypertension compared with celecoxib as well as an increased risk of cardiovascular disease. This conclusion, based on results of the double-blind noninferiority cardiovascular safety trial called Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement (PRECISION- ABPM), was presented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30.

Dr. Frank Ruschitzka

F rank Ruschitzka, MD, of the University Heart Centre, Zurich, Switzerland, explained that nonsteroidal anti-inflammatory drugs (NSAIDs), both nonselective and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely prescribed drugs worldwide, though they are linked with increased blood pressure and adverse cardiovascular events. One-fourth of the world’s population aged over 35 years has arthritis, and of these, almost half have or are at high risk of cardiovascular disease, particularly hyper- tension,” Dr. Ruschitzka said during his presentation. “Clinicians need to weigh the potential hazards of worsening blood pressure control and its clinical sequelae against the arthritis-mitigating benefits associated with the use of NSAIDs, par- ticularly ibuprofen. The landmark PRECISION study was a prospective, long-term noninferiority trial of 24,081 patients. It was designed to assess the cardiovascular safety of cel- ecoxib vs prescription-strength doses of ibuprofen and naproxen in patients with chronic pain from osteoarthritis or rheu- matoid arthritis. It was conducted at 60 sites in the US and included 444 patients, of whom 408 (92%) had osteoarthritis and 36 (8%) had rheu- matoid arthritis. All patients had evidence of, or were at increased risk for, coronary artery disease. PRECISION-ABPM, a prespecified 4-month substudy of the PRECISION trial, was designed to determine the blood pressure effects of the selective COX-2 inhibitor celecoxib compared to

the non-selective NSAIDs naproxen and ibuprofen. Patients were randomized 1:1:1 to celecoxib (100–200 mg twice a day), ibu- profen (600–800 mg three times a day), or naproxen (375–500 mg twice a day) or placebo. The primary endpoint was change from baseline in 24-h ambulatory blood pressure after 4 months. Celecoxib decreased average systolic blood pressure measured over 24 h by –0.3 mmHg. Ibuprofen and naproxen increased it by 3.7 and 1.6 mm Hg, respectively. The resulting difference of –3.9 mmHg between celecoxib and ibu- profen was significant (P = .009). According to Dr. Ruschitzka the PRECISION-ABPM showed differential blood pressure effects between the dif- ferent NSAIDs, ibuprofen and naproxen, and the COX-2 inhibitor celecoxib. While celecoxib and naproxen produced either a slight decrease (celecoxib) or a rela- tively small increase (naproxen) in blood pressure, ibuprofen was associated with a significant increase in ambulatory systolic blood pressure of more than 3 mmHg. An additional analysis showed that the percentage of patients with normal baseline blood pressure who developed hypertension (n=5) was 23.2% for ibu- profen, 19.0% for naproxen, and 10.3% for celecoxib (odds ratio 0.39, P = .004; and 0.49, P = .03 for celecoxib vs ibuprofen and naproxen, respectively). “Patients receiving ibuprofen experienced a 61% higher incidence of de novo hyper- tension vs those receiving celecoxib,” Dr. Ruschitzka said.

PracticeUpdate Editorial Team

PRACTICEUPDATE CONFERENCE SERIES • ESC Congress 2017 6

Ablation of Atrial Fibrillation Improves Quality of Life More than Drugs – CAPTAF Trial Ablation of atrial fibrillation has been shown to improve quality of life more than drugs, even though the reduction in atrial fibrillation burden did not differ significantly between treatments. This conclusion, based on results of the multicenter, prospective, randomized Catheter Ablation compared with optimized Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial, was presented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30.

C arina Blomström-Lundqvist, MD, PhD, of the University of Uppsala, Sweden, explained that previous randomized trials have reported that pulmonary vein isolation is more effective in preventing atrial fibrillation than antiarrhythmic drugs. None of these trials, however, employed continuous cardiac rhythm monitoring, so effects on the burden of atrial fibrillation could not be assessed reliably. Until now, no trial of ablation of atrial fibrillation has employed quality of life as the primary endpoint even though the main indication for ablation of atrial fibrillation is symptom relief. “Instead,” Dr. Blomström- Lundqvist said, “30-s recurrences of atrial fibrillation have been used as the primary endpoint, hardly a relevant measure of successful therapy.” The main purpose of the CAPTAF trial was to compare the treatment effects of ablation of atrial fibrillation and antiarrhythmic drugs using quality of life as the primary endpoint and an implanta- ble cardiac monitor to assess the burden of atrial fibrillation. CAPTAF included 155 patients with symptomatic atrial fibrillation who had failed one drug for either rate or rhythm control. Patients suffered at least one episode of atrial fibrillation documented on electrocardiography in the previous 12 months. At least one symptomatic paroxysmal episode had occurred in the previous 2 months, or at least two symptomatic episodes of persistent atrial fibrilla- tion necessitating cardioversion in the previous 12 months. Patients received an implantable cardiac monitor for a 2-month run-in period, then were randomized to ablation with pulmonary vein isolation or anti- arrhythmic drug therapy with adequate dosages according to guidelines. The primary endpoint was the change in general health, as measured by the Short Form 36-item health survey, from baseline to 12 months. Secondary endpoints included quality of life (by Short Form 36 and EuroQol 5 Dimensions), symptoms, European Heart Rhythm Association Symptom Classification, burden of atrial fibrillation, and safety. “We measured the burden of atrial fibrillation before randomization so we got a good idea of burden at baseline,” Dr. Blomström-Lundqvist said. The main secondary endpoints were morbidity and mortality as composite outcome, cardiovascular

hospitalization, symptoms, heart failure, left atrial and ventricular function and diameters, exercise capacity, health care economics, rhythm, atrial fibrillation burden, successful vs failed treatment, safety, and "cross-overs" over time. “We tried to record silent atrial fibrillation via a patient log book. We got a record for the first year but in the second year, patients were reluctant to record these episodes. We haven’t analyzed these data yet.” After 12 months of follow-up, the primary endpoint of general health score had improved significantly more in the ablation group (mean change 11.0; 95% confidence interval 6.7–15.2) than in the drug group (mean change 3.1; 95% confidence interval –0.9–7.1), P = .0084. Furthermore, all quality-of-life Short Form 36 subscales except for bodily pain and social functioning had improved significantly more in the ablation group than in the drug group. European Heart Rhythm Association symptom score improved significantly more from baseline to 12 months in the ablation group (from mean 3.0 ± 0.7 to 1.6 ± 0.8) than in the drug group (from mean 2.9 ± 0.7 to 2.1 ± 1.1; P = .0079). Reduction of burden in atrial fibrillation (that is, the proportion of time in atrial fibrillation), obtained from the implantable cardiac monitor, was numer- ically larger in the ablation than in the drug group, but change from baseline did not reach statistical significance between treatment groups. The com- plication rate was comparable between treatment groups. Dr. Blomström-Lundqvist concluded, “Quality of life should be the primary endpoint in future tri- als since the main indication for rhythm control is improvement.” She continued, “The lack of a statistically signifi- cant difference between treatment groups in the reduction in burden of atrial fibrillation suggests that other mechanisms may explain the better improvement of quality of life and symptoms achieved with pulmonary vein isolation compared to antiarrhythmic drugs.” She added, “We confirmed that quality of life improved greatly with ablation vs antiarrhythmic drugs. We think it’s because of side effects of anti- arrhythmic drugs, but we have not determined this definitively.”

Dr. Carina Blomström- Lundqvist

PracticeUpdate Editorial Team

© ESC Congress 2017 – European Society of Cardiology

ESC Congress 2017 • PRACTICEUPDATE CONFERENCE SERIES 7

Renal DenervationLowers BloodPressure in Hypertensive Patients Not Taking Antihypertensive Medication – SPYRALHTN-OFFMEDTrial Renal denervation has been shown to lower blood pressure in hypertensive patients not taking antihypertensive medication. This outcome of the international, multicenter, prospective, randomized, sham-controlled SPYRAL HTN-OFF MED trial was reported at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30.

M ichael Boehm, MD, PhD, of the University of Saarland, Homburg/Saar, Germany, explained that renal denervation is a min- imally invasive catheter-based procedure that delivers energy to the nerves in the kidneys. It was developed to treat resistant hypertension. Coinvestigator David Kandzari, MD, of the Piedmont Heart Institute, Atlanta, Georgia, said, “After SYMPLICITY HTN-3, we learned a lot about the procedure itself, medication adherence, and which patients may have less response to the renal denervation procedure – these insights have been incorporated into the revised clinical approach in the SPYRAL HTN program.” He continued, “With this new approach and pro- tocol design, coupled with new technology that allows more consistent circumferential treatment and easier access into the distal anatomy, based on these compelling results we are confident that

we’ve addressed the issues of previous renal den- ervation trials appropriately.” SPYRAL HTN-OFF MED was designed to evaluate the safety and blood pressure-lowering efficacy of the multi-electrode Symplicity Spyral renal den- ervation system. The study included patients with uncontrolled hypertension who were drug-naïve or stopped taking antihypertensive medications at least 4 weeks prior to randomization. Uncontrolled hypertension was defined as an office systolic blood pressure 150–180 mmHg and diastolic blood pressure >90 mmHg, and a 24-h mean systolic blood pressure 140–170 mmHg. Patients were randomized to renal denervation in the main renal arteries and branches or to a sham procedure. Blood pressure was measured at baseline and 3 months, and compared within each treatment group.

Dr. Michael Boehm

OxygenTherapyDoes Not Improve Survival in PatientsWith Symptoms ofMI –DETO2X-AMI

diabetes, and those with previous heart disease, mortality was similar within 1 year. European Society of Cardiology (ESC) guidelines from 2012 on ST-segment elevation myocardial infarction (STEMI) recommended oxygen (by mask or nasal prongs) for patients who were breathless, hypoxic, or suffered from heart failure. They added that systematic oxygen use in patients without heart failure or dyspnea was “at best, uncertain.” “ESC guidelines have gradually shifted towards more restrictive use of oxygen,” said author Prof Stefan James, a cardi- ologist at Uppsala University, Uppsala, Sweden. “While the current recommen- dations were based on expert opinion only, we can now add substantial new data from our large clinical trial.” The ESC has updated its guidelines for the management of patients with acute myocardial infarction. In the new 2017

Oxygen therapy has been found not to improve survival in patients with symptoms of heart attack. This conclusion, based on results of the prospective, randomized, open-label DETermination of the role of OXygen in suspected Acute Myocardial Infarction (DETO2X-AMI), was presented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30.

Dr. Robin Hofmann

R obin Hofmann, MD, of the Karolinska Institutet at Södersjukhuset, Stockholm, Sweden, explained, “The DETO2X- AMI study questioned the practice of routine oxygen therapy for all patients with suspected myocardial infarction.” DETO2X-AMI enrolled 6229 patients with suspected heart attack from 35 hospitals across Sweden. Half were assigned to oxygen given through an open face mask and the other half to room air without a mask.

The primary outcome, mortality rate 1 year after randomization, did not differ statistically between the two groups (5.0% in the oxygen group vs 5.1% in the air group). Similarly, the two groups did not differ significantly in secondary end- points, including risk of a new heart attack or heart muscle injury as measured by blood markers. Even in patients at high risk, such as smokers, older patients, patients with

PRACTICEUPDATE CONFERENCE SERIES • ESC Congress 2017 8

guidelines, it recommends physicians provide supplemental oxygen only when arterial oxygen saturation drops below 90% (class I indication). A fear that oxygen therapy could be harm- ful arose after the multicenter, randomized, controlled Air Versus Oxygen In myocar- Dial infarction (AVOID) trial, in 2015, which reported a larger infarct size in patients receiving oxygen therapy. “Routine oxy- gen therapy seems unnecessary in this patient group, but fortunately our data do not give any indication of increased risk for patients on oxygen,” said Dr. James. “So all of us who have used oxygen for decades can rest assured.” The DETO2X-AMI trial was the first large- scale randomized trial of oxygen therapy in patients with suspected myocardial infarction that was large enough to reveal meaningful findings on mortality and morbidity. The study enrolled six times more patients than all previous randomized trials of this therapy combined, and included a much broader range of patients, rendering the results relevant to everyday clinical practice. Dr. Boehm presented 3-month results of the first 80 patients, 38 of whom received renal denervation and 42 the sham proce- dure. Compared to baseline, at 3 months after the procedure, office-based systolic and diastolic blood pressure had declined by 10.0 mmHg (P < .001) and 5.3 mmHg (P = .008) in the renal denervation arm, respectively, vs declines of 2.3 and 0.3 mmHg (neither significant) in the sham arm, respectively. Regarding 24-h ambulatory blood pres- sure vs baseline, systolic and diastolic blood pressure of patients undergo- ing renal denervation decreased by 5.5 mmHg (P = .04) and 4.8 mmHg (P < .001), respectively. In the sham control arm, systolic and diastolic blood pressure decreased by 0.5 and 0.4 mmHg, respec- tively (neither significant). Decreases in systolic and diastolic office and 24-h blood pressure were confirmed by directly comparing between the renal denervation and sham groups. No major safety events were reported in either arm, even with the revised proce- dural approach. The latter increased the total number of ablations and included denervation in the branch arteries. Dr. Boehm explained that the results – published simultaneously online in The

highly focused ultrasound), not only to support these preliminary results but also to investigate whether an escape phenomenon might occur in hyperten- sion in the long term (reports exist of renal nerve regrowth after catheter-based renal denervation in animal models) and the unknown risk of de-novo renal artery stenoses associated with the new cathe- ters.”

Lancet – provided biological proof of prin- ciple of the efficacy of renal denervation and will inform the design of a larger, more definitive trial of the approach. Dr. Boehm concluded, “The effective- ness of renal denervation in this study may have been due to the new proce- dural approach, which aimed to achieve complete denervation, and the fact that patients were not taking antihypertensive medications, which may have confounded the results of previous studies.”

PracticeUpdate Editorial Team

He added, “With consistent and significant drops across ambulatory and office-based blood pressure – including both systolic and diastolic measurements – we are con- fident to be moving forward with a pivotal trial so that doc- tors and patients may have an alternative approach to lowering blood pressure.” In a recent editorial about the study in The Lancet , Michel Azizi, MD, PhD, with the Paris Descartes University, France, noted that “More studies are needed with the Spyral and other catheters and using different technologies (e.g.,

© ESC Congress 2017 – European Society of Cardiology

know if oxygen is beneficial and that’s why we have to do this [study] – they could accept that,” he said. “Now we have good data, with many patients, and I think practice will change.” “We saw that myocardial infarction meas- ured by very sensitive biomarkers was virtually identical between the groups, which is good for us because we’ve been using this stuff for ages,” said Dr. Hofmann. “Can you imagine if we had harmed our patients? It would have been terrible.” In an accompanying editorial in the New England Journal of Medicine , Joseph Loscalzo, MD, PhD, of Brigham and Women’s Hospital, Boston, wrote that while themechanisms underlying the adaptation to myocardial ischemia are complicated, the results of DETO2X-AMI were straight- forward and indisputable: “supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia – it is clearly time for clinical practice to change to reflect this definitive evidence.”

The study’s registry-based randomized clinical trial protocol employed national registries including SWEDEHEART for randomization, case record forms, and follow-up. Dr. Hofmann said, “Using this design, we could enroll 6629 patients with high-quality data in less than 3 years and keep overall costs to a fraction of a conventional randomized trial.” Dr. Hofmann noted that for the general patient with suspected myocardial infarc- tion, widespread use of supplemental oxygen is no longer warranted, despite being a firmly entrenched among physi- cians and emergency providers who treat patients with acute coronary syndrome. Dr. Hofmann explained that when they began the trial there was resistance, with physicians arguing that oxygen shouldn’t be taken away from patients with acute coronary syndrome. He and colleagues argued that there was simply no evidence to support supplemental oxygen, that it was simply “one of those things” that had always been done. “When it came down to it, and you explained it to physicians – that we don’t

PracticeUpdate Editorial Team

ESC Congress 2017 • PRACTICEUPDATE CONFERENCE SERIES 9