FEBRUARY 2019 I 1

CARDIOVASCULAR DISEASE

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healthcare professionals CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASESpecial report from the World Congress of Internal Medicine, Cape Town, October 2018

Non-communicable diseases (NCDs), driven by the cardiovascular epidemic, account for 70% of deaths in developing countries. At the 2018 World Congress of Internal Medicine, hosted in Cape Town from 18 to 21 October, risk factors of lifestyle and environment proved a common thread in all fields of medicine. These factors play a role in cardiovascular disease (CVD) and the metabolic syndrome, as well as inflammatory illness; they also affect the interplay between these disorders. Expert presentations shared insights into and current opinion on the management of heart failure, cardiometabolic comorbidities in inflammatory and rheumatoid illness, CVD prevention and lifestyle interventions.

Heart failure managementWhere are we at with heart failure management in 2018?

KEY MESSAGES

• Great strides have been made in recent decades in respect of treating heart failure (HF)

• Angiotensin-converting enzyme inhibitors (ACE-Is) are the cornerstone of treatment for HF with reduced systolic function

• There is no treatment that convincingly reduces morbidity and mortality in HF with preserved ejection fraction (HF-PEF)

• The increasing number of elderly patients with multiple comorbidities requires an increasing focus on the latter and a multidisciplinary approach

• Regular aerobic exercise improves functional capacity and symptoms in stable patients.

This report was made possible by an unrestricted educational grant from Novartis. The content of the report is independent of the sponsor.

NP4 Number #: ZA1812936849

Disclaimer: The views expressed in this publication by the editors or authors do not necessarily reflect those of the sponsor or publishers. It is not the intention of this publication to provide specific medical advice or to substitute the advice of a health care practitioner, but rather to provide readers with information to understand health disorders. Readers are advised to consult with their health care practitioner for clinical advice and/or recommendations regarding the management of personal health matters. Novartis shall bear no responsibility and also disclaims all liability for any claim, loss, cost and expense (including attorneys’ fees and disbursements), damage or other liability, either directly or indirectly, arising from the use or misuse of the information provided in this publication. Novartis makes no warranties or representations of any kind as to the accuracy, currency, or completeness of any information contained in such publications and shall have no liability for any damages or injuries of any kind arising from such content or information. Novartis does not support the use of products for off label indications, nor for dosing which falls outside the approved label recommendations.

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

“We have come a long way with regard to survival rates in HF-REF. The one-year mortality rate in clinical trials is now 8%.”

Professor McDonagh observed that chronic HF is a big subject and that she would focus primarily on HF with reduced systolic function (HF-REF) as opposed to HF-PEF. HF-REF is classi-fied as an EF <40%.

“We’ve come a long way but it’s taken a long time,” she said. Disease-modifying treatments only started to become avail-able in the 1980s. Drugs include diuretics, ACE-Is, angiotensin II receptor blockers (ARBs), beta-blockers, digoxin, ivabra-dine, sacubutril-valsartan and aldoster-one antagonists. “Diuretics are still used as first-line therapy because they improve symptoms. However, we no longer use them in industrial-strength doses; we now use the smallest doses so as not to acti-vate the renin-angiotensin-aldosterone system. While we can’t say they improve mortality, all other drugs are used against a background of loop diuretics and may not work in their absence.” The goal of therapy is to improve symptoms at the minimum dose to reduce congestion and achieve dry weight.

ACE-Is are the cornerstone of treat-ment for HF-REF, convincingly reducing morbidity, mortality and hospitalisation, while improving symptoms and cardiac function. Concordant results have been obtained in both HF and post-myocar-dial infarction trials. For the ACE-I-intolerant, ARBs have a smaller place.

Beta-blockers are established as second-line therapy. Once a patient is on an ACE-I plus beta-blocker and carefully titrated, spironolactone can be added, as it has been shown to reduce all-cause mortality and hospitalisation.

There is class 1A evidence in any guide-line for ACE-Is/ARBs, beta-blockers and mineralocorticoid receptor antagonists (MRAs). If patients get symptomatically worse, despite the use of these agents, ivabradine can be introduced in those patients with heart rates >70.

The combination of an ARB (valsar-tan) and neprilysin inhibitor (sacubutril) (ARNI) is a relatively new treatment for HF. An ARNI is indicated in patients with ambulatory symptomatic HF-REF, a left ventricular ejection fraction (LVEF) ≤35%, elevated plasma natriuretic pep-tide levels and an estimated glomerular

filtration rate (eGFR) ≥30ml/min/1.73m2. Professor McDonagh cautioned, how-ever, that there are some safety issues that need to be borne in mind when initiating this drug in clinical practice.

What about digoxin, the ‘original HF treatment’? It is neutral in respect of all-cause mortality but does reduce hospi-talisation. However, there are challenges associated with its therapeutic range.

Turning to devices, Professor McDonagh observed that cardiac resyn-chronisation therapy is a life-saving treatment in patients with a wide QRS complex, but may be harmful in those without.1 The use of implantable cardio-verter defibrillators is recommended as secondary prevention to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a ventricular arrhythmia and are expected to survive for one year with good func-tional status. Their use should be limited to those with an EF <35% and avoided in patients with serious comorbidities such as cancer.

Where HF-PEF is concerned, there is no treatment that convincingly reduces morbidity and mortality. The findings of large trials have been disappointing. Diuretics are advised for symptomatic relief.

A bigger problem is the increasing number of older HF patients with multi-ple comorbidities; the mean age at pres-entation has increased to 77 years and the mean number of comorbidities, including chronic kidney disease (CKD), chronic obstructive pulmonary disease and dia-betes, is 5.4. “All of these impact mortal-ity and we need an increasing focus on these comorbidities,” observed Professor McDonagh.

“We have come a long way with regard to survival rates in HF-REF. The one-year mortality rate in clinical trials is now 8%. Enrolment in multidisciplinary care man-agement programmes is recommended to ensure that patients see the right profes-sional to get the right diagnosis and the right management plan. Regular aerobic exercise should be encouraged to improve functional capacity and symptoms,” she concluded.

Professor Theresa McDonaghProfessor of Heart Failure and Consultant CardiologistKing’s College HospitalLondon, UK

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

Optimising diuretic therapy in HF

KEY MESSAGES

• Diuretics improve the symptoms of HF, despite having no prognostic benefit

• Loop diuretics are most commonly used in HF

• They should not be given until perfusion and blood pressure (BP) are adequate

• Fluid and salt restriction are important

• If pharmacokinetic problems occur, increase the dose or consider intravenous (IV) therapy. If there are pharmacodynamic issues, increase the frequency and add a thiazide diuretic.

Diuretic resistance occurs when the diu-retic response is diminished before the therapeutic goal of relief from congestion has been reached. “It is important to rec-ognise congestion in order to relieve it and to ascertain whether perfusion is good or low. The latter is easy to determine, but congestion may not be obvious and is dif-ficult to diagnose,” said Dr Klug.

Renal blood flow is similarly of para-mount importance, as is the need for ultrasound of the chest to detect pulmo-nary oedema.2 Diuretics should not be given until adequate perfusion is estab-lished and BP is controlled. The goal of diuresis should be a minimum reduction of 5-10% of body weight. An increase in the creatinine level may be required to adequately relieve congestion.

Venous congestion plays an impor-tant role in worsening renal function and a central venous pressure (CVP) higher than 24 predicts worsening kidney func-tion, regardless of systolic BP. There is also a link between inadequate perfusion and central venous congestion; and when both are present, they are associated with worse renal function. Patients with HF tend to have high levels of thirst. Fluid intake should nonetheless be restricted and excess fluid should not be given intra-venously while in hospital.

There are three major types of diu-retic: loop diuretics, thiazide diuretics and MRAs (potassium-sparing diuretics). The loop diuretics furosemide, bumetanide and torasemide are most commonly used in the treatment of HF. They have a veno-dilator action that precedes their diuretic effect. This is beneficial in congestive HF. “When treating critical illness, it’s impor-tant not to do harm, and as yet we have no good randomised trials on diuretic use

in HF,” cautioned Dr Klug.Diuretics do have symptomatic bene-

fits - diminishing congestion, lowering left ventricular filling pressure and alle-viating oedema and dyspnoea. However, their effectiveness is reduced by excess salt intake, underlying CKD, renal adap-tation to diuretics and neurohormonal activation.

Patients who respond do better, and patients with persistent congestion have poorer outcomes. Dr Klug pointed out, however, that high doses of furose- mide may worsen outcomes and increase mortality.

Diuretics act on the tubular surface of the cell, not the vascular surface. They are absorbed in the gastrointestinal tract and their bioavailability differs from the IV dose: 50% for furosemide, 90-100% for the other two. Diuretics are important organic acids and bind strongly to albu-min. Many other drugs (aspirin, NSAIDs) compete with them for delivery to the tubular lumen, and it may be necessary to increase the oral dose to compensate for this. Switching to IV therapy is another way to overcome diuretic resistance.

Chronic therapy may lead to adapta-tion, with a diminished response over time (the ‘breaking phenomenon’) and distal convoluted tubule hypertrophy. Adding a thiazide to chronic loop diuretic therapy may bring about a synergistic response.

In principle always use the lowest dose, and adjust as the patient improves, given that increased doses and combination therapy can worsen renal function.

Concluding, Dr Klug reiterated that loop diuretics are the ones most com-monly used in HF and are highly effec-tive for addressing symptoms, despite no evidence of prognostic benefit. The

Dr Eric KlugCardiologist in Private PracticeSunninghill, Sunward Park and Charlotte Maxeke Johannesburg Hospitals

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

subcutaneous administration of a novel buffered furosemide formulation is fea-sible and safe, and achieves diuresis equivalent to conventional IV furosem-ide. Subcutaneous furosemide may offer a new therapeutic modality for outpatient use with equivalent diuresis to hospi-tal- or emergency room–administered IV diuretics.

If pharmacokinetic problems occur, increase the dose or consider alternative routes of administration. If there are pharmacodynamic issues, increase the frequency and add a thiazide or an MRA (spironolactone). Fluid and salt restric-tion are important. Remain mindful of competing drugs.

The management of anaemia in HF

KEY MESSAGES

• Anaemia increases the workload of the failing heart and is an important risk factor for morbidity (including kidney disease) and mortality

• IV iron is currently the best treatment for anaemia in HF.

Anaemia (a loss of red cell blood mass) in the presence of HF indicates a poor prognosis. If found to be present, it is important to consider nutritional defi-ciencies, erythropoietin, inflammation, occult bleeding, bone marrow failure and idiopathic anaemia of ageing. “Hepcidin, a protein that is a key regulator of the entry of iron into the circulation, plays a central role. Hepcidin blocks the absorp-tion of iron, so if we can reduce it, we can release more iron.”

HF is characterised by decreased myo-cardial function, abnormal loading and arrhythmia. In HF-REF, inflammatory markers that block the release of iron are important. These include tumour necrosis factor alpha (TNF-α), interleukins (ILs) and C-reactive protein (CRP). Anaemia increases the workload of the already

failing heart and is an independent risk factor for morbidity and mortality.

Thirty-seven percent of HF patients have anaemia, putting them at risk for CKD. Fifty percent will have iron defi-ciency without anaemia and may present with fatigue long before they develop overt anaemia.

Blood transfusions are not advisable. Erythropoietin is also of questionable value as bone marrow is resistant to it and it has no effect on the inflammatory response. “All studies show that the best outcomes are achieved with IV iron, even in iron-deficient patients without anae-mia.3 Trials of anti-hepcidin therapy are ongoing, and the targeting of an anti-hepcidin pathway may be an alternative treatment in the future.”

Dr Piet WesselsHaematologist in Private PracticeGroenkloof Hospital, Pretoria

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

Inflammatory and rheumatic diseaseCardiometabolic comorbidities in inflammatory and rheumatic diseases

KEY MESSAGES

• Cardiometabolic comorbidities are of concern in inflammatory arthritis

• Comorbidities differ between and within inflammatory disease and require different solutions

• The mainstay of treatment is to control inflammation and CVD risk factors

• Management must include lifestyle interventions.

CVD

The pathogenesis and pathophysiology of CVD differ between rheumatoid arthri-tis (RA) and spondyloarthritis (SpA). Increased cardiovascular mortality risk associated with RA has been ascribed to its carrying a higher inflammatory burden than SpA conditions. People with RA, psoriatic arthritis (PsA) and psoriasis are at increased risk of cardiovascular events.

The greatest increase in risk of RA-associated cardiovascular mortal-ity is at a young age; with older age, risk reduces to almost normal population levels.4,5 Traditional risk factors such as lipid levels can be misleading and very hard to interpret in the face of inflamma-tion, as cardiovascular risk factors may behave differently in RA (e.g. as CRP lev-els increase with increased inflammatory burden, circulating lipid levels decrease).6

While real-life data show no difference in rates of myocardial infarction between those on TNF inhibitors compared to those on disease-modifying antirheumatic drugs (DMARDs), this is confounded by selection bias. Myocardial infarction risk in those who respond to TNF inhibi-tion by six months is markedly reduced (66%) compared to non-responders.7 The CANTOS study8 has shown reduced

CVD events using IL-1 inhibition with canakinumab; with the fall in CRP after a single dose of canakinumab the best pre-dictor of benefit, confirming the causal link between inflammation and CVD, even in the general population.9

In PsA, 80% of people have multimor-bidity and 60% have at least two other conditions. All PsA outcomes worsen as the number of comorbidities increases, and patients are less likely to respond to biologics and other therapies.10,11

The cardiovascular risk factors of hypertension, type 2 diabetes (T2DM) and obesity are all increased in PsA compared to psoriasis; and in psoriasis compared to the general population.12 Compared to RA, PsA shows only a slightly increased CVD risk, despite a far greater risk burden.

Increased risk of cerebrovascular events features across the SpA spectrum, prob-ably related to increased hypertension in this group. There is a higher risk of hyper-tension with mild psoriasis compared to the general population and patients with severe psoriasis have a yet greater risk. PsA has the highest stroke risk in the pso-riatic disease spectrum.13

Metabolic syndromeIn psoriatic disease, risk for T2DM and metabolic syndrome increases in correla-tion to severity of disease. Risk for T2DM

and obesity is almost doubled with psori-asis compared to the general population. Two-thirds of patients with PsA have

Dr Stefan Siebert Institute of Infection, Immunity and Inflammation University of Glasgow United Kingdom

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

metabolic syndrome by some definition, whereas only one-quarter to one-third of RA patients have metabolic syndrome.14,15

Of note is that obesity itself is a risk factor for psoriatic disease. For every standard deviation increase in BMI, the risk of psoriasis increases by 20%. This dose response extends to risk of develop-ing PsA, where a female with BMI >35 has a six-fold increased risk. Fat distribu-tion is more predictive of cardiovascular risk than BMI; visceral fat, being more metabolically active, is of greater concern and waist circumference can be a useful surrogate measurement. Again, there is a dose response between weight and the likelihood of achieving minimal disease activity, with obese patients less likely to respond as well to therapy.16-18

Patients with psoriasis are at greater risk of fatty liver disease (as part of the metabolic syndrome) than RA, with risk doubling further in PsA compared to psoriasis. As a consequence, methotrexate therapy in this group carries a far higher risk of liver impairment and is often not tolerated.19

The complexity of PsA extends beyond the cardiovascular element. Other than inflammation, there is a metabolic drive that Dr Siebert considers to be part of the disease. He predicts that future therapies will be using metabolic drugs in tandem with immune-modulating agents.

Dr Siebert’s recommendations for best management of cardiovascular risk in inflammatory arthritis are to:• Treat the inflammatory disease

aggressively• Measure BP• Stop smoking• Adjust CVD risk for RA and inflam-

matory arthritis using a risk calculator (QRISK-2, SCORE)

• Remember the lipid paradox (treat inflammation before worrying about lipids)

• Check for diabetes (particularly in PsA)

• Promote physical activity and healthy diet

• Implement weight management pro-grammes for obese patients.

Approach to spondyloarthritis

KEY MESSAGES

• SpA comprises a heterogeneous group of non-rheumatoid, phenotypically related conditions

• Effects of therapeutic agents differ between RA and SpA

• Effects of therapeutic agents differ within the SpA spectrum.

SpA comprises a group of phenotypically related (but heterogeneous) conditions with musculoskeletal and extra-articular features that are very different from those of RA.

The effects of some targeted therapeu-tic agents on RA and SpA conditions differ. Many agents ‘adopted’ from RA have worked well in treatment of non-rheumatoid conditions. Some DMARDs are effective for peripheral disease in the seronegative spectrum, but not for the spi-nal disease or enthesitis that often charac-terise the SpA conditions. TNF-inhibitors are largely effective across the board: psoriasis, PsA, uveitis, axial SpA, enter-opathic arthropathy and inflammatory

bowel disease (IBD). RA treatments that have been unsuccessful in SpA include rituximab, tocilizumab and sarilumab (no significant clinical benefit in ankylos-ing spondylitis (AS) despite reduction in CRP); and abatacept (modest response in PsA).

SpA conditions share common genetic and pathogenic features but differ in clini-cal response to specific immune-targeted interventions. Human trials targeting different cytokines suggest the existence of hierarchical networks of cytokines that define groups of chronic inflamma-tory diseases rather differently from the homogenous molecular disease pattern previously assumed.20

Dr Stefan Siebert Institute of Infection, Immunity and Inflammation University of Glasgow United Kingdom

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

IL-12/-23/-17A inhibitors

SpA conditions have shared (IL-23/-17, innate immunity) and disease-specific pathogenic pathways. Evidence from human studies indicates that IL-17 is a key cytokine in psoriasis. The IL-23/-17 pathway is key in PsA, AS and IBD.21,22

TNFα-inhibitors themselves reduce IL-17 activity. IL-23 has two sub-units, p19 and p40. The p40 sub-unit is shared with IL-12, so targeting p40 can inhibit both IL-12 and IL-23, although it is unclear whether or not this is better than inhibiting just IL-23 via p19. In RA, IL-23/-17A inhibition has no clear clini-cal efficacy. The response to therapeutic inhibition of these key cytokines differs across the SpA spectrum (Table 1).20

In psoriasis and PsA, IL-23 inhibitors

(ustekinumab, guselkumab, adalimumab, risankizumab) and IL-17A inhibitors (secukinumab, ixekizumab) show good clinical efficacy, particularly in the skin where many patients achieve 95-100% skin clearance.

In AS, the IL-17A inhibitor secuki-numab works well in both TNF-naïve and TNF-exposed patients; however, IL-12/-23 inhibition has failed to demonstrate a clinical effect in the spine.

In contrast, in Crohn’s disease, the opposite holds true. Inhibiting IL-23 with ustekinumab is effective in TNF-inhibitor non-responders and TNF-naïve patients; whereas inhibiting IL-17 appeared to aggravate the condition.

Table 1. Therapeutic cytokine inhibition in the RA and SpA spectrumAdapted from Schett, 201320

TNF IL-6R IL-1 IL-12/23 IL-17A

Rheumatoid arthritis

Good clinical efficacy

Good clinical efficacy

Moderate clinical efficacy, or preliminary data

Insufficient, or no clinical efficacy, or aggravating effect

Insufficient, or no clinical efficacy, or aggravating effect

Crohn’s disease

Good clinical efficacy

No data No data Good clinical efficacy

Insufficient, or no clinical efficacy, or aggravating effect

Psoriasis Good clinical efficacy

Insufficient, or no clinical efficacy, or aggravating effect

No data Good clinical efficacy

Good clinical efficacy

Psoriatic arthritis

Good clinical efficacy

Insufficient, or no clinical efficacy, or aggravating effect

No data Good clinical efficacy

Good clinical efficacy

Ankylosing spondylitis

Good clinical efficacy

Insufficient, or no clinical efficacy, or aggravating effect

No data Insufficient, or no clinical efficacy, or aggravating effect

Good clinical efficacy

“These drugs are telling us some really interesting things about our diseases…”

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

What lessons have we learned from IL-17 inhibition trials?

Even within the same patient there are tis-sue differences in response to therapies, implying functional cytokine hierarchi-cal roles within different tissues. Figure 1 highlights cytokine pathways with demon-strable therapeutic effects in each discrete tissue based on responses in clinical trials. These comparisons are potential, rather

than proven.23 Dr Siebert believes that in future there

will increasingly be a move towards treat-ing the molecular signature of the patient, rather than just the phenotype, with more head-to-head studies required in order to determine the best strategies.

Skin

Joint

Axial skeleton

IL-17, IL-23p19IL-12/23p40, TNF

TNF, IL-17, IL-23p19, IL-12/23p40

IL-17, IL-12/23p40 TNF, IL-23p19

TNF IL-12/23p40, IL-23p19

IL-17, TNF

Enthesis

Gut

Figure 1. Proposed notional emerging tissue cytokine hierarchy based on current clinical trial data23

Focus on CVD preventionHypertension management update

KEY MESSAGES

• Hypertension is the single biggest contributor to disease burden and mortality worldwide

• Awareness, treatment and control are worse in low-income countries

• Controlling BP with medication is the most cost-effective treatment strategy to prevent cardiovascular events

• Most patients will need two or more agents to achieve BP control

• Single pill combinations improve compliance.

Raised BP is the primary contributor to the global burden of disease and mortal-ity. “It is the single biggest killer and the numbers are increasing year by year,” said Professor Poulter. “CVD affects one-third of adults worldwide, making it the largest

epidemic known to mankind.”Half the attributable CVD burden

occurs at BP levels below what is classi-fied as hypertension (≥140/90mmHg), and hence population-based strategies are required for prevention, not necessarily

Professor Neil PoulterProfessor of Preventive Cardiovascular MedicineImperial College LondonUnited Kingdom

…we can’t just rely on phenotype for the way we treat our patients…”

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

“All patients should also be on a statin regardless of their cholesterol level, as this is about reducing overall cardiovascular risk.”

pharmacological interventions. Risk fac-tors include age, alcohol use, high salt and saturated fat intake, lack of exercise and being overweight.

The PURE study,24 which looked at hypertension around the world, found that treatment and awareness rates get progressively worse as one moves from high- to low-income countries. “Globally, 46% of hypertensives don’t know that they have the condition, so greater aware-ness is critical.”

In the first ‘May Measurement Month’ campaign in 2017, an initiative of the International Society of Hypertension, 1.2 million individuals were screened. Over 250  000 had raised BP, of whom 100  000 were inadequately treated. In 2018, 1.5 million were screened; 220 000 were found to have untreated hyper-tension and 110  000 had inadequately treated hypertension. The two campaigns together identified and advised 580  000 people with raised BP and offered a unique opportunity to undertake global analyses.

“Controlling BP with medication is the most cost-effective treatment strategy to prevent cardiovascular events. Most people get treated once they know they’re hypertensive, but only one-third achieve

control. Monotherapy is seldom sufficient, and most patients will require at least two drugs – but which two? Guidelines differ around the world, recommending either A+C (ACE-I/ARB plus calcium channel blocker), A+D (ACE-I/ARB plus diu-retic) or C+D (calcium channel blocker plus diuretic).” Data are lacking as to which combination is optimal in differ-ent ethnic groups. Current US guide-lines define hypertension as beginning at 130/80mmHg, while European guidelines have retained 140/90mmHg.

If two drugs prove inadequate to con-trol BP, a third can be added for a com-bination of A+C+D. If that still proves inadequate, there is sufficient evidence to support the use of spironolactone as a fourth-line option.

Use of single pill combinations of two drug classes improves compliance and if compliance improves, BP improves. They’re also more cost-effective. “In addi-tion, all patients should also be on a statin regardless of their cholesterol level, as this is about reducing overall cardiovascular risk. To prevent CVD effectively, we need to look at patients holistically and not at BP in isolation,” concluded Professor Poulter.

Residual cardiovascular risk – does it exist?

KEY MESSAGES

• Dyslipidaemia, especially LDL-cholesterol, plays a pivotal role in CVD

• There are some promising new treatments for cholesterol, namely the PCSK9 inhibitors and the ANGPTL3 inhibitors

• An LDL-cholesterol level of 1.8 mmol/l is the cut off-value for regression of atherosclerosis

• When treating dyslipidaemia, always bear inflammation and thrombotic risk in mind and treat concomitantly

• Early treatment is critical to minimise residual risk.

Despite major advances in the treat-ment of CVD, it remains a major killer responsible for 17 million deaths per annum. Hypertension, diabetes, smok-ing, obesity and dyslipidaemia all con- tribute, but the role of the latter, especially LDL-cholesterol, is pivotal. The sta-tin trials, involving 170 000 people, have shown that for every 1mmol/l reduction

in LDL-cholesterol, cardiovascular events are reduced by 29%. But ‘residual risk’ remains and tailored therapy is required to target cholesterol, inflammation and thrombotic risk.

“Statins and ezetimibe are effective and can bring about a 55-70% reduction in LDL-cholesterol, but those with familial hypercholesterolaemia are not reaching

Professor Derick RaalDirector: Carbohydrate and Lipid Metabolism Research UnitProfessor and Head: Division of Endocrinology and MetabolismFaculty of Health Sciences, University of the Witwatersrand

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

target levels,” said Professor Raal. Newer drugs showing great promise are the PCSK9 inhibitors,25 whose journey from laboratory to clinical use has been rapid, and the ANGPTL3 inhibitors, currently under development. The PCSK9 inhibi-tor, alirocumab, has been shown to reduce LDL-cholesterol from baseline by almost 60%. The addition of evolocumab to sta-tin treatment was shown to enhance the latter’s effects, further reducing atheroma volume.26

Inflammation plays a key role in ath-erosclerosis, which is a chronic inflam-matory process that in excess leads to a disease state. Experimental and clinical data suggest that reducing inflammation, even without affecting lipid levels, may reduce the risk of CVD. The CANTOS trial, using the monoclonal antibody

canakinumab, dramatically reduced the inflammatory marker CRP, despite no change in LDL-cholesterol.8

While lipids play a central role, it’s important always to bear inflammation and thrombotic risk in mind when treat-ing dyslipidaemia. The combination of aspirin and a novel anticoagulant has been shown to reduce thrombotic risk by 25% in stable coronary artery disease.

Professor Raal concluded by under-scoring that LDL-cholesterol is essential for the development of atherosclerosis, and that if we can remove this ‘ultimate cause’ we can effectively treat or even prevent the latter. Early treatment is very important, as treating the residual risk may well constitute doing ‘too little too late’.

How can we reduce premature CVD by 50% in a generation?

KEY MESSAGES

• Eighty percent of CVD and 90% of deaths are due to modifiable risk factors

• Eighty percent of deaths occur in low- and middle-income countries

• A polypill can reduce risk by >65%

• A combination of lifestyle measures and low-cost drugs, along with improved health systems, better vital statistics and greater involvement of non-physician health workers, will contribute to the halving of CVD within a generation.

Eighty percent of CVD deaths occur in low- and middle-income countries.27 In 1990, the figure was 12.7 million, and had risen to 17.3 million by 2013. While the age-specific death rate has in fact declined, the increase can be attributed to an increase in the size of the population and to ageing.

Several facts about CVD preven-tion are clear and irrefutable. Tobacco avoidance, lowering LDL-cholesterol by 1mmol/l (regardless of level) and low-ering systolic BP by 10mmHg together reduce disease by 75%. Professor Yusuf cautions that tobacco usage is not a thing of the past, despite the worldwide decline in smoking and smoking-related deaths in recent decades; and that tobacco use will still kill one billion people in the course of this century. “Smoking cessation is there-fore critical,” he said. “When it comes to

BP, meta-analyses have shown that the higher the BP, the greater the benefits of reduction.”

Low- and middle-income countries generally have weaker health systems, and access to and affordability of treat-ment are often poor. Non-severe dis-ease is picked up and treated earlier in wealthy countries, so fatalities are lower. It’s because treatment is poorer in poor countries that death rates are higher, not because of risk factors.

BP is easy to control, but at least two drugs are usually needed, and affordabil-ity is a major stumbling block. “The key is to make these drugs more affordable and available.” Eighty percent of hyperten-sives in India cannot afford the medica-tions they need. “Guidelines are written for academics in rich countries and have limited value in poor countries.”

Professor Salim YusufDivision of CardiologyMcMaster University Medical SchoolCanada

“Early treatment is very important, as treating the residual risk may well constitute doing ‘too little too late’.”

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

“It’s because treatment is poorer in poor countries that death rates are higher, not because of risk factors.”

A polypill, comprising BP/cholesterol agents and aspirin, can reduce cardiovas-cular risk by >65%. But having the drugs isn’t enough. “We also need to deliver.” Professor Yusuf underscored the impor-tant role that non-physician health work-ers can play, as well as the importance of support from friends and family.

Addressing CVD is not only about medication. Lifestyle modification should entail tobacco avoidance, increased physi-cal activity, reduced salt and alcohol intake, as well as dietary measures. “Diet is never a straight line and the data are not always clear. However, the Mediterranean diet does appear to lower cardiovascular

risk, and high-fat diets also appear to be more beneficial than high-carbohy-drate ones.” High carbohydrate intake is a major problem in low- and middle-income countries.

Professor Yusuf feels that investing in education, more than any other policy, is key to improving global health. “Eighty percent of CVD and 90% of deaths are due to modifiable risk factors. A combination of lifestyle measures and low-cost drugs, along with improved health systems, bet-ter vital statistics and greater involvement of non-physician health workers will go a long way towards halving CVD within a generation,” he concluded.

Exercise is the best medicine!

KEY MESSAGES

• In South Africa, NCD deaths outnumber combined deaths from communicable diseases and injury/violent death.

• Physical inactivity is the modifiable risk factor associated with the biggest risk reduction for all-cause mortality and chronic disease

• Risk of primary cardiac arrest transiently increases during vigorous exercise, although habitual vigorous exercise is associated with an overall decreased risk

• Medical clearance is appropriate in the presence of existing CVD, symptoms of CVD, pregnancy, chronic disease and in the presence of any acute illness.

In 2018, more than 65% of deaths glob-ally were due to NCDs, with this figure expected to rise exponentially in the coming decade. CVD, cancer, chronic lung disease and diabetes comprise 82% of all NCD deaths. In Africa, there is a 21% probability of dying of one of these four main NCDs; in South Africa, NCD deaths outnumber combined deaths from communicable diseases and injury/violent death.

Professor Schwellnus refers to the ‘eight deadly sins’ of NCDs, broadly cat-egorising them as daily choice risk fac-tors (tobacco, harmful use of alcohol, unhealthy diet, physical inactivity) and metabolic or physiological risk factors (obesity, elevations in BP, blood sugar and certain types of blood fats). Adherence to healthy lifestyle behaviours could reduce

the risk for death from all causes. Specific combinations of lifestyle risk behaviours may be more harmful than others, sug-gesting synergistic relationships among risk factors.28 The greater the number of risk factors that can be reduced, the more substantial the reduction in risk of dying, even in the presence of pre-existing dis-ease or older age.

Physical inactivity is the modifiable risk factor associated with the biggest risk reduction for all-cause mortality and chronic disease (Figure 2). Risk reduction for all-cause mortality is 32% with physi-cal activity vs 14% with statins; 33% vs 25%, respectively, for CVD mortality; and risk reduction for transition from pre-diabetes to diabetes is 58% with physical activity vs 31% with metformin.29

Professor Martin SchwellnusSport, Exercise Medicine and Lifestyle Institute (SEMLI)University of PretoriaSouth Africa

“The sickest people benefit the most from an exercise programme.”

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

Figure 2. Risk reduction for all-cause mortality and chronic disease seen in physically active subjects30

45.0

40.0

35.0

30.0

25.0

20.0

15.0

10.0

5.0

0.0

Mea

n ri

sk r

educ

tion

(%)

Physical activity

Statins Physical activity

Statins Stroke Hyper-tension

Colon cancer

Breast cancer

Diabetes (type 2)

All-cause mortality: Cardiovascular disease:

How does physical activity affect health? A dose response to amount of exercise is associated with longer life expectancy across a range of activity levels and BMI groups. Individuals who are regularly physically active have a 30-45% lower risk of early death. Additional health benefits include a lowered risk of up to:• 35% for coronary heart disease and

stroke

• 50% for T2DM• 50% for colon cancer• 20% for breast cancer• 83% for osteoarthritis• 68% for hip fracture• 30% for falls among older adults• 30% for depression• 30% for dementia.

How much physical activity is recommended? SEMLI guidelines recommend:1. One hundred and fifty minutes of

moderate- to high-intensity endurance physical training per week, with each

session lasting 30 minutes or longer.2. Strength and balance training 2-3

times per week.

Exercise in patients with existing diseaseReducing risk of injury is part of respon-sible promotion of physical exercise (Table 2). There is the risk of a medical complication occurring during an exer-cise session. Life-threatening and minor medical complications are associated with high-intensity exercise; and the ‘unmask-ing’ of a pre-existing underlying disease may occur. “The exercise prescription should match the patient profile,” advises Professor Schwellnus.

During moderate- to high-intensity training, many organ systems are chal-lenged by the physiological response to exercise. An incorrect exercise prescrip-tion may, for example, precipitate a car-diac arrest or sudden death. This exercise paradox has risk of primary cardiac arrest transiently increased during vig-orous exercise, although habitual vigor-ous exercise is associated with an overall

“The exercise prescription should match the patient profile.”

Table 2. Preventing exercise-related injuries.

• If injured already, get expert help

• Start training slowly, progress gradually

• Perform an adequate warm-up/stretching

• Develop normal muscle strength, balance and optimal neuromuscular control

• Use the correct sports equipment

• Be aware of correct exercise technique (biomechanics)

• Use protection (strapping, bracing) if appropriate

• Realise the value of optimal nutrition

• Psychological status is linked to injury risk

• Consider lifestyle/habits (e.g. smoking).

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CLINICAL ISSUES: CARDIOVASCULAR DISEASE IN HEART FAILURE AND RHEUMATOID DISEASE

decreased risk of primary cardiac arrest.31

For moderate- to high-intensity exer-cise, Professor Schwellnus recommends medical clearance in males older than 45 years and females older than 55 years with more than one risk factor for CVD. Medical clearance is also appropriate in the presence of any existing CVD, any

symptoms of CVD (chest pain, dizzi-ness, shortness of breath), pregnancy, use of prescription medication for chronic disease, known underlying chronic dis-ease, development of symptoms during exercise, concerns about the safety of the exercise and in the presence of any acute illness.

References1. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac-

resynchronization therapy in heart failure with a narrow

QRS complex. N Engl J Med 2013; 369: 1395-1405.

2. Ellison DH, Felker GM. Diuretic treatment in heart failure.

N Engl J Med 2017; 377: 1964-1975.

3. Capellini MD, Comin-Colet J, de Francisco A, et

al. Iron deficiency across inflammatory conditions:

International expert opinion on definition, diagnosis, and

management. Am J Hematol 2017; 92: 1068-1078.

4. Ogdie A, Yu Y, Haynes K, et al. Risk of major

cardiovascular events in patients with psoriatic arthritis,

psoriasis and rheumatoid arthritis: a population-based

cohort study. Ann Rheum Dis 2015; 74(2): 326-332.

5. Jafri K, Bartels CM, Shin D, et al. Incidence and

management of cardiovascular risk factors in psoriatic

arthritis and rheumatoid arthritis: A population-based

study. Arthritis Care Res 2017; 69(1): 51-57.

6. Choy E, Sattar N. Interpreting lipid levels in the context

of high-grade inflammatory states with a focus on

rheumatoid arthritis: a challenge to conventional

cardiovascular risk actions. Ann Rheum Dis 2009; 68(4):

460-469.

7. Dixon WG, Watson KD, Lunt M, et al. Reduction in

the incidence of myocardial infarction in patients with

rheumatoid arthritis who respond to anti-tumor necrosis

factor alpha therapy: results from the British Society for

Rheumatology Biologics Register. Arthritis Rheum 2007;

56(9): 2905-2912.

8. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory

therapy with canakinumab for atherosclerotic disease. N

Engl J Med 2017; 377: 1119-1131.

9. Ridker PM, MacFadyen JG, Everett BM, et al.

Relationship of C-reactive protein reduction to

cardiovascular event reduction following treatment with

canakinumab: a secondary analysis from the CANTOS

randomized controlled trial. Lancet 2018; 391: 319-328.

10. Ballegaard C, Hojgaard P, Dreyer L, et al. Impact of

comorbidities on tumor necrosis factor inhibitor therapy

in psoriatic arthritis: A population-based cohort study.

Arthritis Car Res 2018; 70(4): 592-599.

11. Mrowietz U, Steinz K, Gerdes S. Psoriasis: to treat or to

manage? Exp Dermatol 2014: 23(10): 705-709.

12. Charlton R, Green A, Shaddick G, et al. Risk of type 2

diabetes and cardiovascular disease in an incident cohort

of people with psoriatic arthritis: a population-based

cohort study. Rheumatology 2018; Sep 6. DOI: https://

doi.org/10.1093/rheumatology/key286

13. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis

and metabolic syndrome: a systematic review and meta-

analysis of observational studies. J Am Acad Dermatol

2013; 68(4): 654-662.

14. Dubreuil M, Rho YH, Man A, et al. Diabetes incidence

in psoriatic arthritis, psoriasis and rheumatoid arthritis: a

UK population-based cohort study. Rheumatology 2014;

53(2): 346-352.

15. Labitigan M, Bahce-Altuntas A, Kremer JM, et al. Higher

rates and clustering of abnormal lipids, obesity, and

diabetes mellitus in psoriatic arthritis compared with

rheumatoid arthritis. Arthritis Care Res 2014: 66(4):

600-607.

16. Snekvik I, Smith CH, Nilsen TIL, et al. Obesity, waist

circumference, weight change, and risk of incident

psoriasis: Prospective data from the HUNT Study. J Invest

Dermatol 2017; 137(12): 2484-2490.

17. Love TJ, Zhu Y, Zhang Y, et al. Obesity and the risk of

psoriatic arthritis: a population-based study. Ann Rheum

Dis 2012; 71: 1273-1277.

18. Eder L, Thavaneswaran A, Chandran V, et al. Obesity

is associated with a lower probability of achieving

sustained minimal disease activity state among patients

with psoriatic arthritis. Ann Rheum Dis 2015; 74(5):

813-817.

19. Ogdie A, Grewal SK, Noe MJ, et al. Risk of incident liver

disease in patients with psoriasis, psoriatic arthritis, and

rheumatoid arthritis: A population-based study. J Invest

Dermatol 2018; 138(4): 760-767.

20. Schett G, Elewaut D, McInnes IB, et al. How cytokine

networks fuel inflammation: Toward a cytokine-based

disease taxonomy. Nat Med 2013; 19(7): 822-824.

21. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23

induces spondyloarthropathy by acting on ROR-

γt+CD3+CD4-CD8- entheseal resident T cells. Nat Med

2012; 18(7): 1069-1076.

22. Johansen C, Usher PA, Kjellerup RB, et al.

Characterization of the interleukin-17 isoforms and

receptors in lesional psoriatic skin. Br J Dermatol 2009;

160(20): 319-324.

23. Siebert S, Millar NL, McInnes IB. Why did IL-23p19

inhibition fail in AS: a tale of tissues, trials or translation?

Ann Rheum Dis 2018; DOI: https://doi.org/10.1136/

annrheumdis-2018-213654

24. Chow CK, Teo KK, Rangarajan S, et al. Prevalence,

awareness, treatment, and control of hypertension in

rural and urban communities in high-, middle-, and low-

income countries. JAMA 2013: 310: 959-968.

25. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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monoclonal antibody to PCSK9 on LDL cholesterol. N

Engl J Med 2012; 366: 1108-1118.

26. Nicholls SJ, Puri R, Anderson T, et al. Effect of

evolocumab on progression of coronary disease in statin-

treated patients: The GLAGOV randomized clinical trial.

JAMA 2016; 316: 2373-2384.

27. Roth GA, Forouzanfar MH, Moran AE, et al.

Demographic and epidemiologic drivers of global

cardiovascular mortality. N Engl J Med 2015; 372: 1333-

1341.

28. Ding D, Rogers K, van der Ploeg H, et al. Traditional

and emerging lifestyle risk behaviours and all-cause

mortality in middle-aged and older adults: Evidence

from a large population-based Australian cohort. PLOS

Med Dec 8, 2015. DOI: https://doi.org/10.1371/journal.

pmed.1001917.

29. McKinney J, Lithwick DJ, Morrison BN, et al. The health

benefits of physical activity and cardiorespiratory fitness.

BCMJ 2016; 58(3): 131-137.

30. Moore SC, Patel AV, Matthews CE, et al. Leisure time

physical activity of moderate to vigorous intensity and

mortality: A large pooled cohort analysis. PLOS Med

Nov 6, 2012. DOI: https://doi.org/10.1371/journal.

pmed.1001335.

31. Siscovick DS, Weiss NS, Fletcher RH, et al. The incidence

of primary cardiac arrest during vigorous exercise. N Engl

J Med 1984; 311: 874-877.