Case discussionPractical challenges in CV risk

management: Managing patents with

comorbidities

Professor Konradi A.O., PhD, FESCAlmazov Federal North-West Medical

Research Centre, St.Petersburgkonradi@almazovcentre.ru

Comorbidity – the growing importance in 21st century?

• Patients have multiple diseases and risk factors

• Risk stratification and risk reduction in comorbidity is unclear

• The is an uncertainty in different guidelines

• Evidence-based medicine is a poor tool, because lack of good evidence in comorbidity

• Goal-oriented care is very important

Causes of growing burden of comorbidity

• Aging population

• Better medical care – better survival in many conditions

• Medicines that can accelerate atherosclerosis (cancer, antipsychotics, etc)

http://www.un.org/esa/socdev/ageing/agewpop1.htm (2002).

Percentage of population in age 60 or over by region, 2000-2050

Perc

en

tag

e o

f p

op

ula

tio

n

ag

e 6

0 a

nd

over

25

20

15

10

5

0

35

30

Worldtotal

Africa Asia Europe LatinAmerica & Caribbean

NorthernAmerica

Oceania

2000 2050

Ageing

Proportion of subjects over 70 years in Russia

7,5

8

8,5

9

9,5

10

10,5

2005 2006 2007 2008 2009 2010 2011 2012

Rosstat, official website

%

Number of chronic disorders by age-group

Karen Barnett, Stewart W Mercer, Michael Norbury, Graham Watt, Sally Wyke, Bruce Guthrie

Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study

null,

Volume 380, Issue 9836, 2012, 37–

43

Selected comorbidities in people with four common, important disorders

in the most affluent and most deprived deciles

Karen Barnett, Stewart W Mercer, Michael Norbury, Graham Watt, Sally Wyke, Bruce Guthrie

Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study

null, Volume 380, Issue 9836, 2012, 37–43

Deaths attributed to major cardiometabolic risk factors

The Lancet Diabetes & Endocrinology 2014 2, 634-647

Risk of specific deaths according to different risk-factors

The Lancet Diabetes & Endocrinology 2014 2, 634-647

Cardiac, renal and brain comorbidity

Heart

Brain

Kidney

RCT and real-life

• Mostly selected patients less that 75 years

• Predominately males

• Comorbidities are usually excludes, especially cancer

• Reflects less that 50% of population

• Included selected clinics and selected specialists

Paradigm of medicine

Pre-evidence-based empiric medicine

Evidence-based medicine

Medicine-based evidence

Case 1. An obese lady with diabetes

Female 55 yrs

• Hypertension for 10 years, no medication

• Preeclampsia during last pregnancy

• Farther – MI at the age of 60, sister – stroke at the age of 55

• Smoking for 20 years

• BMI 32 kg/m2, WC 98 cm

• Sedentary lifestyle

• Atypical chest pain after exercise or emotional stress

Examination

• Blood pressure 160/90 mmHg, HR 70 min -1

• Plasma glucose 7,6 mmol/l repeated

• HgA1C 7,2%, GFR 70 mL/min/1,73 m2

• Total cholesterol 6,5, LDL 4,3, HDL 1,0 mmol/l

• ECG – LVH

Questions

• What is the risk of the patients and which scale to use?

• What is the target BP level?

• Which preferable drugs?

• What is the target LDL level?

• Do we need to perform an exercise test to confirm CAD?

• Do we need to perform Echo?

• Options to treat DM

The patients is unique – factors that can affect management

• Gender – she is a female with specific risk factor

• Comorbidities – obesity, diabetes, metabolic syndrome

• Family history

• More than 1 CVD risk factor and TOD

Female-specific risk factors of CVD

Risk factor CVD CGD HTN STROKE DM

PSOS * * ***

POI ** **

PIH ** * *** * **

Preeclampsia ** ** *** ** **

GDM ** ** *** ***

Parity **

Miscarriage **

Preterm birth ** * * ** **

SGA ** ** **

Stillbirth **

Adapted from Appelman Y. et al. Atherosclerosis 2015; 241:211-218

Pre-eclampsia increases CVD risk by 1.5-2.5

Who should not use SCORE for risk assessment

• There are subjects, who can be considered at high risk for starting interventions (already enough)

• Established atherosclerotic CVD

• Hypertension stage 2 or more with TOD

• DM

• Renal dysfunction

• Familial hyperlipidemia

• People over 75 yrs (especially hypertensive and smoking)

Why Is Echocardiography Useful In Hypertensive Patients?

“No other biological variable (except advancing age) predicts cardiac risk better

than left ventricular hypertrophy”.

(De Simone et al, J Hypertens 12;1129, 1994)

LVH is associated with a 2.5-fold increase in

the relative risk of all-cause mortality

Vakili et al. Am Heart J 2001;141:334–341

Levy (m)‡BIRNH†

Kahn†

Levy (w)‡

Parfrey‡#*Koren‡*Ghali -CAD‡

Ghali CAD‡

Mensah‡*Liao (m)‡

Liao (w)‡

Foley‡

Larsen†#*Sullivan†*SPRINT†*Dunn (w)†

Dunn (m)†

Boden†*Kannel (w)†*Kannel (m)†*CDP†#*Sokolow†*All Studies

Relative risk

†Electrocardiographic LVH; ‡Echocardiographic LVH; #unadjusted; (m) men; (w) women; CAD=coronary artery disease; *P<0.05

0 1 2 3 4 5 6 7 8 9

0 1 2 3 4 5 6 7 8 9

Left ventricular remodeling patterns (Ganau et al.,1992)

LVH - LVH +

Normal geometry Eccentric LVH

Concentric remodelling

Concentric LVH

RWT<0,45

RWT>0,45RISK

increased

CAD and diabetes

Do we need to perform exercise test to check for CAD?

• There are data that suggest exercise tests less informative in diabetic patients and having lower prognostic value (Daddy trial)

Eur J Internal Med 2015; 26:417-426

Prognostic value of stress-echocadiography in diabetic and non-

diabetic patients

JACC 2006; 47:606-610

Case 1. Examination results

• Echocardiography – concentric LVH, LVMI 145 g/m2, diastolic dysfunction, no other structural abnormalities

• ECG stress test – negative according to both symptoms and ECG criteria

LDL target

Risk Recommended intervention

LDL-C goals

VERY HIGH RISKEstablished CVDDM type 2 (> 40 yrs with 1 or more risk factors or TOD)SCORE>10%

Lifestyle and drug initiation <1,8 mmol/l or >50% reduction

HIGH RISKSCORE 5-10%

Lifestyle and drug initiation <2,5 mmol/l

MODERATE RISKSCORE>1%, <5%

Lifestyle and drug initiationif no control

<3 mmol/l

EHJ 2011;32: 1769-1818

Case 1. Treatment

• Hypertension. ACE inhibitors. Combinations if necessary. Goal 140/85 mmHg. Enalapril 40 mg, CCB or D or ARB

• Lipids – statins for target – 1,8 mmol/l

Atorvastatin 40-80 mg

• Antithrombotic. Aspirin 100 mg

• Diabetes – metformin 1000 mg for target HbA1c <7,0%

A problem of multiple goals

BP

LDL

BMI

HbA1c

Lifestyle interventions are crucial– smoking cessation, diet, weight reduction, exercising

Look-AHEAD study5145 patients, DM+obesity

lifestyle interventions for risk reduction

Alas…Combined end point– CV death+MI+stroke+hospitalization

No outcome benefit

Life is so disappointing

Predictors of statin failure (resistance)

• Under-dosing

• Low compliance

• Other risk factors and multiple gals

• ACVD events

• Internet

2 years later

• Poor compliance with lifestyle

• Smoking, BMI 31kg/m2

• HbA1c – never re-checked

• BP more or less controlled, taking AH drugs

• Atorvastatin stopped 3 months after prescription (saving lever from side effects)

• Only one visit o cardiologist, no aspirin

• Non-fatal MI at the age of 57

Optimal therapy is therapy that is taken by the patient

Case 2Female patient with non-fatal stroke

A cornerstone in cardiology

• A non-fatal MI is an inconvenience

• A non-fatal stroke is a catastrophe

Background – the burden of stroke

• In the European Union stroke is the second cause of mortality (10.9%) immediately after coronary heart disease (18.1%), accounting for approximately 200,000 deaths yearly.

• Stroke accounts for 5.27% of the total burden of illness, but because of aging of the population it has been calculated that, by the year 2020, stroke will account for 6.2% of the total illness burden.

• Among patients above the age of 65 years and surviving a stroke, 50% have some residual hemiparesis, 30% are unable to walk without assistance, 26% are dependent on others for help with daily living, 19% have aphasia, 35% depressive symptoms and 26% are being cared for in a nursing home.

Special attention to stroke in females

• About 425 000 cases of stroke in females annually

• Women have higher lifetime risk of stroke and higher rates of mortality

• Female stroke patients have higher prevalence of hypertension compared to male

• Even prehypertension increases risk of stroke in females up to 2 times.

• Women have a high risk of stroke in peripartum period

• Women have higher risk of intracranial hemorrhage

• Females after stroke are more likely to be disabled

Secondary prevention

• Stroke recurrences account for 15-20% of all strokes.

• Transient ischemic attack (TIA) often heralds occurrence of a stroke, and it has recently been reported that up to 40% (average 20%) of strokes are actually preceded by a TIA.

• Therefore, the population of patients with a history of stroke or TIA is large, and secondary prevention of stroke is of the greatest importance.

Clinical case 2

Female, 76 years old, obese, hypertensive

(untreated)

Paroxysmal atrial fibrillation (aspirin only)

admitted to the hospital 1 hour 10 minutes

from the symptom onset:

• Acute weakness of the right hand and leg

• Disorientation

• Conscious, no seizures

Physical examination:Vital Signs:

Blood Pressure 200/100 mm Hg. Pulse 80 bpm, regular (sinus

rhythm on ECG). Respirations 20 per minute. Temperature 37

degrees. Weight 130 kg. Height 189 cm. BMI 36.39 kg/m2.

General:

Alert, disoriented, uncooperative.

Neurological status:

• Mixed aphasia

• Face: right-sided hemianopia, central type paresis

• Limbs: decreased muscle tone, right hemiplegia

• NIHSS -15

CT scan

In the left temporal zone there is poor differentiation of white and grey brain tissue, decreased tissue density, increased density of left medial brain artery

Should and can we perform thrombolytic therapy?

1. No indications

2. Yes, immediately

3. Yes, after appropriate BP reduction

Ischemic stroke, hypertension and reperfusion: drug therapy

• Patient otherwise eligible for acute reperfusion therapy except that BP is >185/110 mm Hg:

• If BP is not maintained at or below 185/110 mm Hg, do not administer rtPA

• Management of BP during and after rtPA or other acute reperfusion therapy to maintain BP at or below 180/105 mm Hg:

• Monitor BP every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic BP >180–230 mm Hg or diastolic BP >105–120 mm Hg:

AHA/ASA 2013, Stroke 2013

Voting slideWhich drug to use

1. Labetalol

2. Nimodipin (oral)

3. Nitrendipine

4. Nitroprusside

5. Nitroglicerine

6. Enalaprilat i.v.

AH medication in acute strokeWhat do the guidelines say?

• A single optimal medication to lower the blood pressure in all patients with acute stroke has not been determined, and an individualized approach is the best

• Oral drugs are less predictable and swallowing is often impaired

• AHA 2013 – IV labetalol, IV enalapriat, IV Nitrendipine, avoid venodilators

Case 2- treatment

• Enalaprilat i.v. 10mg in 30 minutes.

• BP 180/90 mm Hg

• Neurologic status – no changes

45 minutes after admission (2 hours after symptom onset) - systemic thrombolysis (Actilyse).

Neurological status after rtPA

• Mild mixed aphasia, dysarthria

• Face: mild right-sided central type paresis

• Limbs. Paresis score: right hand-4, right

leg-4

• NIHSS decreased from 15 to 3

Dynamics of BP

0

20

40

60

80

100

120

140

160

180

200

15min

30min

1 h 2 h 3h 4h 6h 12h 24h 2d 3d 7d 14d

SBP

DBP

CT scan 15 day

Contrast MSCT –hypodense zone in the left hemisphere, in temporal zone and basal nucleus from14х19 mm to 46х2 mm.

Voting slideWhat is the target BP for this patient?

1. 130/80

2. 140/90

3. 140-150/90

Summary: secondary stroke prevention in randomized trials

What do the guidelines say?

The 2013 ESH-ESC hypertension guidelines reserve antihypertensive treatment to those

patients with a previous stroke or TIA with SBP > 140 mmHg or DBP > 90 mmHg, recommend a

SBP target < 140 mmHg acknowledging there is no direct evidence supporting how far below 140 mmHg the optimal target should be, and

recommend that this missing evidence is searched for by an adequate trial.

Hypertension Recommendations1. Initiation of BP therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established BP <140 mm Hg systolic or <90 mm Hg diastolic (Class I; Level of Evidence B). Initiation of therapy for patients with BP <140 mm Hg systolic and <90 mm Hg diastolic is of uncertain benefit (Class IIb; Level of Evidence C).

2. Resumption of BP therapy is indicated for previously treated patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events in those who have had an ischemic stroke or TIA and are beyond the first several days (Class I; Level of Evidence A).

3. Goals for target BP level or reduction from pretreatment baseline are uncertain and should be individualized, but it is reasonable to achieve a systolic pressure <140 mm Hg and a diastolic pressure <90 mm Hg (Class IIa; Level of Evidence B). For patients with a recent lacunar stroke, it might be reasonable to target an SBP of <130 mm Hg (Class IIb; Level of Evidence B).

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the AHA/ASA, 2014

Discharge

• Residual neurological deficit

• MMSE 27

• BP 144/86 mm Hg

• Therapy

– Apixiban 2,5 mg

– Atorvastatin 40 mg

– Bisoprolol 5mg

– Enalapril 20 mg

The major goals of hypertension treatment in specific population:

post-stroke

• Stroke recurrence prevention

• BP lowering tolerability, including hypotension and cognitive dysfunction

• Maintenance of quality of life and general health

• Cardiovascular complications and total mortality

Secondary Prevention of Small Subcortical Strokes (SPS3) trial

(2013)• Patients with recent, symptomatic, MRI-

confirmed lacunar stroke: two target ranges of systolic blood pressure: 130–149 mm Hg or less than 130 mm Hg

• 81 centres in North America, Latin America, and Spain

• Open-label treatment

• March, 2003- April, 2011.

• Patients 30 years or older

Lancet 2013; 382: 507–15

Systolic blood pressure by treatment group

Lancet 2013; 382: 507–15

Probability of patients experiencing a primary event by time after randomization

events: recurrent stroke, MI, death

Lancet 2013; 382: 507–15

4. Several lifestyle modifications have been associated with BP reductions and are a reasonable part of a comprehensive antihypertensive therapy (Class IIa; Level of Evidence C). These modifications include salt restriction; weight loss; the consumption of a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption.5. The optimal drug regimen to achieve the recommended level of reductions is uncertain because direct comparisons between regimens are limited.The available data indicate that diuretics or the combination of diuretics and an angiotensin-converting enzyme inhibitor is useful (Class I; Level ofEvidence A). 6. The choice of specific drugs and targets should be individualized on the basis of pharmacological properties, mechanism of action, and consideration of specific patient characteristics for which specific agents are probably indicated (eg, extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, and DM) (Class IIa; Level of Evidence B).

AHA/ASA 2014 Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

ESH-CHL-SHOT• Multinational, randomized trial with a 3 × 2 factorial design comparing:

three different SBP targets

– <145-135;

– <135-125;

– <125 mmHg); • two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l).

• 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization.

• Antihypertensive treatments initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP windows.

• All patients will be followed up every 3 months for BP. Ambulatory BP will be measured yearly.

• Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia.

• Almazov Centre – national coordinator in Russia

The vicious circle of comorbidities

Multiple risk factors

Comorbidity

Polypharmacy

Drug interactions

Poor compliance

Multiple health

providers

Multiple goals

Multiple mistakes

Multiple complications