L4 CVD Flashcards Preview

5043 > L4 CVD > Flashcards

Flashcards in L4 CVD Deck (72):

Therapeutic outcomes

–  When using drugs in practice, either for treatment or prevention, we want a “result”

–  This result is often referred to as an “outcome”

–  As well as being a key aspect of therapeutics, outcomes are

also fundamental to healthcare research

–  There are two types of outcome, understanding the difference between these is important

–  The two types of outcomes are: Surrogate (or proxy) outcomes (or markers)

e.g. blood pressure control Clinical (or hard) outcomes

e.g. stroke

–  Clinical outcomes are the ones that are really most important

– These can considered as outcomes that are the most patient-orientated

– Surrogate outcomes (or markers) are those considered to predict clinical outcomes

– Using the example of blood pressure and stroke:
– We know that sustained high blood pressure (BP) is a major

risk factor (i.e. predictor) for stroke

– However other factors impact on the likelihood of a person having a stroke

–  A reduction in BP may be a good surrogate marker for a reduced risk of stroke, but...

–  It would be more meaningful to assess the actual occurrence of stroke (where possible)

–  Clinical practice and research often rely heavily on surrogate markers (e.g. BP reduction) rather than hard outcomes

–  The key point is that (where we can) we should ideally use drugs that have been shown to favourably impact clinical outcomes

–  Drugs that have only been shown to impact on surrogate outcomes may not always deliver the clinical outcomes we want


Outcomes – Surrogate or clinical?

A image thumb

why focus on CVD risk

A image thumb

CVD is an umbrella term for:

– Coronary heart disease

angina, myocardial infarction (MI i.e. ‘heart attack’) – Cerebrovascular disease

stroke, transient ischaemic attack (TIA i.e. ‘mini-stroke’) – Other vascular disease

peripheral artery (vascular) disease (PAD or PVD)


CVD Risk

–  For example David and Anna are both 67 years old and have the same BP (SBP 155mmHg)

–  However their CVD risk scores are very different – David’s risk is 30%
– Anna’s risk of 5%

–  When considering the management of a person with risk factors for CVD, knowing their absolute risk of CVD is fundamentally important

–  A particular intervention may be associated with a certain level of relative risk reduction

–  For example, let’s say this relative risk reduction is 20% and apply this to David and Anna:

David’s 30% risk falls to 24%

Anna’s 5% risk falls to 4%

–  This illustrates how interventions tend to have the biggest impact on those at higher risk

–  Absolute CVD risk assessment therefore looks at a person holistically

–  Assessing absolute CVD risk and making interventions based on such assessments is also something considered at a strategic or ‘public health’ level

–  When we refer to a person’s absolute CVD risk as a % we are referring to this level of risk over a given time period, typically 5 years

–  Absolute CVD risk assessment and the consequent management of risk is all about trying to prevent adverse CV health outcomes in the future

–  An assessment of absolute CVD risk is not required to inform treatment decisions in people who already have established CVD

–  As well as people with established CVD and DM aged >60 years, Australian recommendations also exclude other groups from risk assessment

–  These other groups are people with:

Diabetes with microalbuminuria (at any age)

Moderate to severe chronic kidney disease (CKD)

Previous diagnosis of familial hypercholesterolemia

Severe hypertension (SBP ≥180 or DBP ≥110 mmHg)

Severe hypercholesterolemia (TC ≥7.5 mmol/L)

–  People in these categories are again automatically assumed to have high risk of CVD

–  There are several CVD risk assessment tools

–  One of the best known of these is the Framingham Heart Study

(FHS) www.framinghamheartstudy.org

–  Risk calculators are now available in many formats, including

on-line versions

–  Irrespective of the tool used, the ‘levels’ of 5-year risk are consistent:

Low < 10%

Moderate 10-15%

High > 15%

–  Note: the risk is of developing CVD, not dying

–  But sadly many people do die as a result of MI/stroke

–  As noted with regard to FHS, there are some deficiencies with the tools related to known (and possibly unknown) CVD risk factors that are not taken into account

–  Examples of these are:


family history


social deprivation


CVD Risk Summary

– Irrespective of which tool is used, they share the theme of considering a range of risk factors to guide patient management

– It is widely considered that ‘absolute CVD risk assessment’ scoring is valuable and widely accepted

– However, it is important to remember that we are only estimating a person’s risk

A smoker with hypertension and dyslipidaemia has a high probability of developing CVD, but may live to 90!

Conversely someone with no major risk factors may suffer a heart attack tomorrow!

– Use of risk assessment tools does mean increased use of preventative drug therapy and in some patients, their outcome may be no different

This costs a lot and they may suffer ADRs!



–  Sustained elevation of blood pressure (chronic hypertension) is one of the most common medical conditions affecting society today

–  It is consequently one of the most frequent reasons that people visit a health professional and are prescribed long-term medication, both in Australia and many countries overseas

–  Most people with hypertension experience no signs or symptoms (S&S), especially when their BP is only modestly elevated

–  The ‘silent’ or asymptomatic nature of hypertension creates many significant challenges when it comes to both diagnosis and management

–  In some cases, events such as MI or stroke may ‘unmask’ years of asymptomatic hypertension



Pathophysiology of Hypertension

– Essentially BP is determined by the interplay of:
– Cardiac output
– Peripheral resistance

– Although many factors are involved in BP control, two systems are particularly important:

– Renin-Angiotensin-Aldosterone System (RAAS)

– Sympathetic nervous system (SNS)


classification of HT

– Hypertension may be classified as: – Primary (‘essential’) hypertension

• Accounts for >90% of cases and is where no specific underlying cause is identifiable

– Secondary hypertension
• Where another condition causes

BP to be elevated
• Many potential causes of

secondary hypertension


Blood Pressure Measurement & Diagnosis

– Diagnosis not based on just one BP measurement
– Blood pressure varies and multiple BP measurements

are needed, typically:

– Over several clinic appointments (days/weeks apart)

– Within each clinic appointment – Factors affecting BP levels include:

– Time of day

– Effect of recent smoking/caffeine
– Results of BP measurements should be recorded

accurately and communicated to patients


BP measurement

– Blood pressure measurement involves: – systolic blood pressure (SBP)

• pressure during heart contraction (higher) – diastolic blood pressure (DBP)

• pressure between contractions (lower)
– Convention is to report BP as SBP/DBP and in units of

mmHg e.g. 160/95 mmHg

– The difference between the SBP and DBP is known as the ‘pulse pressure’

– in the case above, it would be 65 mmHg

– this pulse pressure tends to increase with age



– Aims:
– prevention of complications arising from end-organ

damage i.e. stroke, CKD etc
– reduction of symptoms (if they exist !)

– These are achieved with a step-wise approach:

–  Step 1: Lifestyle modifications

–  Step 2: Review use of drugs that may cause or exacerbate hypertension

–  Step 3: Initiate drug therapy whilst maintaining lifestyle modifications



Step 1: Lifestyle Modifications

A image thumb

Step 2: Review other drugs

–  Formulation of medicines can also be an issue e.g. soluble tablets, intravenous antibiotics

–  Some of these contain sodium as part of the formulation to promote dissolution or the drug may be formulated as a sodium salt

–  Whilst use of these may in many cases be short term and therefore of less concern, research* does suggest that soluble tablets may be associated with increased risk of CV events


stage 2 review other drug

–  Formulation of medicines can also be an issue e.g. soluble tablets, intravenous antibiotics

–  Some of these contain sodium as part of the formulation to promote dissolution or the drug may be formulated as a sodium salt

–  Whilst use of these may in many cases be short term and therefore of less concern, research* does suggest that soluble tablets may be associated with increased risk of CV events


stage 3 commence other drug

– The decision to initiate pharmacological treatment for a person requires consideration of several factors:

– the degree of elevation of blood pressure – the presence of target organ damage
– their absolute CVD risk
– their willingness to commence treatment

– A useful summary of recommendations is provided in the NHF Hypertension Guidelines


drug therapy

– The four main classes of antihypertensive drug used in Australia today are:

Angiotensin converting enzyme inhibitors (ACEI)

Angiotensin receptor antagonists/blockers (ARAs,


Calcium channel blockers (CCBs)

Thiazide (and thiazide-like) diuretics

– Less commonly used antihypertensives include: • Beta-blockers e.g. atenolol
• Alpha-blockers e.g. prazosin

• Centrally acting drugs e.g. moxonidine

– Guideline recommendations need to be individualised to each patient

– Choice of drug class/specific agent should be influenced by:

– patient factors e.g. • co-morbidities

–compelling indications or contraindications • age

– effectiveness
– adverse effects – cost

– availability


drug therapy effectiveness

–  Most antihypertensive drugs lower blood pressure by similar amounts when used at equivalent doses

–  But this may not always tell the whole story

–  What is more meaningful is their effectiveness at preventing adverse clinical outcomes such as stroke, MI, heart failure, chronic kidney disease (CKD) etc.

– For example, in the major ALLHAT trial ...
– all the four classes of drugs studied (ACEI, CCB, diuretic and

α-blocker) controlled BP similarly

– however treatment with the α-blocker doxazosin (not available in Australia but widely used in the US and Europe) was associated with worse outcomes


starting drug therapy

Guidelines recommend starting with one drug

If target BP is not reached with this, check compliance and if it is good, continue 1st drug and add 2nd drug etc

If significant adverse effect occurs with a drug, stop it and replace with an alternative


overview of drug therapy options - ACEI "pril"

–  Evidence for ACE inhibitors in hypertension is good

–  Most widely used ACE inhibitors in Australia are:

• Ramipril, perindopril

–  But there are many others including:

• captopril, enalapril, fosinopril, lisinopril, quinapril and Trandolapril

–  Summary of ACE inhibitor mode of action:

Inhibit conversion of Angiotensin I > II (vasoconstrictor)

Reduce aldosterone mediated Na+ / H2O retention

Inhibit breakdown of vasodilatory bradykinins

–  Other indications:

Heart failure


Cardiovascular protection

Chronic kidney disease (CKD)

–  In people with hypertension and these co-existing conditions, an ACEI is a particularly good choice



– Adverse effects:
– Hypotension, which may present as dizziness – Persistent dry cough
– Hyperkalaemia
– Decreasedrenalfunction
– Angioedema,uncommon

– Key practice points for ACEIs:
– Baseline/periodic monitoring of K+ and creatinine needed – Initiate at low/medium dose
– More caution in the elderly and those fluid depleted
– Generallyavoidotherpotassiumsparingdrugs



– Most widely used Angiotensin receptor blockers (ARBs) in Australia are:

• Candesartan • Irbesartan
• Telmisartan

• Others include:
• olmesartan, valsartan, eprosartan, losartan

– Summary of ARB mode of action:

Block effect of the potent vasoconstrictor Angiotensin II

Reduces aldosterone mediated Na+ / H2O retention

– Otherindications:

Chronic kidney disease

Heart failure


• Key practice points for ARBs (note - same as ACEI):



– Dihydropyridine (DHP) CCBs are the most widely used type of CCBs in hypertension, in particular:

• Amlodipine
• Other DHP CCBs include felodipine, nifedipine, lercanidipine!

–  ‘Rate-limiting’CCBsaregenerallyonlyusedinhypertensionifalso indicated for a co-existing condition, such as angina or tachyarrhythmia:

Verapamil MR

Diltiazem MR

–  Summary mode of action

• Inhibit calcium inflow through L-type channels required for contraction of

smooth muscle

– OtherindicationsforCCBs

Angina (diltiazem/verapamil preferred)

Tachyarrhythmias (only verapamil or diltiazem)

Raynaud’s phenomena (DHPs especially nifedipine)

Cluster headaches (only verapamil)


CCB AE and practice point

– Adverse effects:
• Hypotension leading to dizziness (all)
• Flushing, headache, ankle oedema (mainly DHPs) • Bradycardia (diltiazem/verapamil)
• Gum hyperplasia (rare)

– Key practice points for CCBs:
• No routine laboratory (U&E) monitoring required
• Monitor heart rate for diltiazem or verapamil
• Initiate at low/medium dose
• Combine well with ACEI or AIIRA (or B-blocker if DHP) • Care as some CYP3A4 mediated interactions



–  Evidence for thiazides in hypertension is good

–  Long established class of antihypertensives, despite newer

drugs they still have an important role in therapy

–  Have more of an effect to lower SBP than DBP

–  Other indications – Heart failure

• Although thiazides of limited value as monotherapy in moderate- severe HF, usually the more potent loop diuretics e.g. frusemide are preferred

– Adverseeffects:
• Hypotension, which may present as dizziness • Hyponatraemia,Hypokalaemia
• Other adverse metabolic effects



–  Key practice points for thiazides and related drugs

Baseline/periodic monitoring of K+ & Na+ appropriate

Evidence of improved outcomes is strongest in older patients, so some guidelines recommend restricting use to those over a certain age e.g. > 65 years

Combine very well with either an ACEI or ARB

Think for a minute... why this might be ?

–  There has been some debate about the continued use of thiazides in recent years

–  Thisresultsfromevidenceshowingthiazidesappeartoincreaseonset of Type 2 diabetes, especially when combined with beta-blockers

–  TheriskofAEswithalltypesofantihypertensiveisdosedependent, but the metabolic AEs of thiazides are particularly dose dependent:

– electrolyte loss, especially Na+ and K+
– Loopdiureticsdolowerbloodpressure,butaregenerallynotused

for management of hypertension


b0block "lol"

– Of the beta-blockers, it is the beta-1 (‘cardioselective’) drugs that are most commonly used in hypertension

– Atenolol,Metoprolol

– Other beta-blockers are less often used for hypertension unless there is a co-existing condition for which they have proven benefits, for example in heart failure:

– Carvedilol – Bisoprolol

– Propranolol is now infrequently used in treatment of hypertension

– exception is for portal hypertension in people with liver disease – Mode of action:

– Multiple factors probably important including reduced cardiac output, decreased peripheral resistance and inhibition of renin release

– Other indications:
– Angina, Post-MI, Heart failure, Arrhythmias
– Non-CV indications: migraine prevention, tremor

– Adverse effects:
– Hypotension, Bradycardia, Bronchospasm, Cold extremities, Vivid


– Key practice points specific to beta-blockers:
– Baseline and periodic monitoring of heart rate required
– Caution if using other drugs prone to cause bradycardia
– Need to assess risk/benefit in people with airways disease
– Rarely justified in simple HTN, as other better options available – Avoid use with thiazides where possible


other options

–  Other established classes of antihypertensives (alpha-blockers, centrally acting drugs) tend to have niche roles for specific patients, e.g. those:

–  on maximal standard therapy but still not at target

–  with specific circumstances (Methyldopa in pregnancy, Alpha

blockers in BPH)

–  who have been taking for years and don’t want to change

–  Potential reasons for their limited role include:
– poorer evidence regarding desired clinical outcomes
– poorer adverse effect profile / tolerability
– some require multiple daily doses unhelpful for compliance

–  But you will come across these drugs in practice...


Antihypertensive drug therapy-Summary, potential SE

– As highlighted earlier, factors such as comorbidities and adverse effects are important to consider when making treatment decisions for individual people

A image thumb

Comorbidity & compelling indications

A image thumb

Comorbidity & compelling indications

A image thumb

Comorbidity & compelling indications

A image thumb

HT treatment target

A image thumb

Hypertension: Key Points

A image thumb

Dyslipidaemia: terminology

A image thumb

Dyslipidaemia: Lipid Profile

A image thumb

dyslipidaemia causes

– Lipoprotein metabolism, largely genetic
– Dietary fat intake
– Level of physical activity
– Can also occur secondary to medications or medical conditions, e.g. beta blockers, anabolic steroids


Dyslipidaemia: Manifestations

A image thumb

Dyslipidaemia: Management

–  Although a major risk factor for CVD important to consider other CVD risk factors

–  This is why we calculate absolute CVD risk in people without CVD

to inform treatment decisions

–  The balance between harmful (LDL-C) and protective (HDL-C) lipids is important

–  Many CVD risk tools use TC:HDL-C ratio

–  Management guidelines vary around the world, but decision to treat is
generally based on CV risk

–  Primary Prevention: based on CV risk tool

–  Secondary Prevention: high risk is assumed and therapy given irrespective of lipid levels


Dyslipidaemia: medication

A image thumb

Statins: Mode of Action

– Inhibit the enzyme 3-hydroxyl-3-methyl-glutaryl-CoA (HMG- CoA reductase)

– Major effects on LDL-C –hence reduces TC
– But also reduce TG and increase HDL-C modestly

– Five statins are currently available in Australia: – Fluvastatin (e.g. Lescol®)
– Pravastatin(e.g.Lipostat®)
– Simvastatin (e.g. Zocor®)

– Atorvastatin (e.g. Lipitor®) – Rosuvastatin (e.g. Crestor®)


Statins-Key points

–  For any one statin doubling the dose produces an average of 6% further reduction in cholesterol

–  Atorvastatinandrosuvastatinhave long half-life so can be given anytime

–  Allothernighttimeideal

–  People with CVD prescribed

irrespective of cholesterol levels

–  Generally well tolerated and safe

–  Most common side effect is myopathy

–  If levels of creatine kinase >10 Upper normal limit stop

–  LFTs need to be monitored as well (Stop if >3 ULN)

–  Several Interactions that can increase muscle side effects: erythromycin,

clarithromycin, diltiazem, verapamil, amiodarone, grapefruit juice

–  Interactionsdifferwithdifferentstatins

–  Severalstoriesreportedinthemedia:Diabetes,dementia



A image thumb


–  Mode of Action; Reduces dietary cholesterol absorption

–  Combination with statin reduces cholesterol to greater extent than high dose statin monotherapy without increase in side effects

–  Increasingly being used

–  However, no hard outcome data

–  Omega-3 Fatty Acids
– Including fish in diet is preferred
– Supplements may reduce TGs by 25-30% – But, dose required is 4g/day


Nicotinic acid;

– use very limited in Australia because of side effects – Also not PBS listed
– Reduces TG, LDL, increase HDL


– Bile acid binding resins

– Cholestyramine
– Cholestipol

• Binds to bile salts in the gut, increasing the need for cholesterol to replace the lost bile acids, stimulating expression of LDL-C receptors by hepatocytes and uptake of LDL from blood

• May increase TG

• Major Drawbacks: poor tolerability (GI side effects) and interactions with other drugs (need to give other drugs 1 hour before of 4-6 after the resin)


Dyslipidaemia - SUMMARY

A image thumb

Heart Failure (HF) + Oedema
= Congestive Cardiac Failure (CCF) = Congestive Heart Failure (CHF)



CHF definitions

– A pathophysiological state in which the heart is unable to deliver blood (and thus O2) at a rate sufficient to meet the needs of the body

– 5-year mortality rate approx. 50%
– HF deaths increased 109.8% from 1979 to 1993
– 2-5% of all hospital admissions
– most frequent cause of hospitalisation for people aged 65+



Pathophysiology: systolic HF

– mechanisms act to maintain cardiac output...

– BUT capacity limited and eventually the heart FAILS DECOMPENSATED HEART FAILURE

– NB. Definition based on ejection fraction (EF) < 40%

A image thumb

causes of systolic HF

A image thumb

CHF clinical manifestations

A image thumb

CHF symptoms and signs

A image thumb

diagnosis of HF

A image thumb

diagnosis of HF

A image thumb

diagnosis of HF

A image thumb

New York Heart Association (NYHA) classification of capacity

A image thumb

pharmacological prevention

A image thumb

General Management guidelines

A image thumb

 Drug Therapy for HF

A image thumb


A image thumb

And other vasodilators for HF

A image thumb

– β-Blockers (contd)

– evidence based agents:

– bisoprolol, carvedilol, metoprolol XL, nebivolol

– may cause initial exacerbation, bradycardia, hypotension - titrate slowly


– Cardiac glycosides- digoxin

– may be considered for symptom relief and to reduce hospitalisation in patients with advanced CHF... remains valuable therapy in CHF patients with AF”


– Diuretics- thiazide & loop diuretics

– should be used, if necessary, to achieve euvolaemia in fluid- overloaded patients... should never be used as monotherapy but should always be combined with an ACEI”

–  “should be used, if necessary, to achieve euvolaemia in fluid-overloaded patients... should never be used as monotherapy but should always be combined with an ACEI”

relieve signs and symptoms


consequences of excessive diuresis: (orthostatic) hypotension, electrolyte disturbances, pre-renal RF

–  thiazide diuretics may be effective in mild HF

–  loop diuretics: titrate according to symptoms

–  diuretic resistance”

• loss of effect of diuretic due to: delayed absorption (“soggy gut”)

• management: increase/split dose; or IV administration; or addition of another agent


Diuretics- aldosterone antagonists

A image thumb


–  ‘funny current inhibitor’ slows HR

–  “consider ivabradine for patients with systolic HF and a recent HF hospitalisation who are in sinus rhythm, where their heart rate remains 70 beats/min despite maximal tolerated β-blocker dosing”


– Sacubitril(ascombinationtherapyonly)

–  Novel mechanism - first-in-class

–  angiotensin receptor neprilysin inhibitor (ARNI)

–  boosts concentration of natriuretic peptides by inhibiting their degradation – leading to increased cGMP concentrations

–  Promoting vasodilation, natriuresis, diuresis, increased renal blood flow and inhibition of renin and aldosterone release

–  Licensed by the TGA this year in combination with Valsartan for heart failure NYHA class II to IV with reduced ejection fraction

–  Not PBS as yet - watch this space!


– polyunsaturated fatty acids (PUFAs)

A image thumb


– iron deficiency common in HF, usually associated with

– investigate and treat iron deficiency in patients with HF”


CHF –Management Summary

A image thumb

Treatment of HFPSF

A image thumb