L4 CVD Flashcards
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?
why focus on CVD risk
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:
ethnicity
family history
weight
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!
HT
– 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
treatment
– 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
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,
ARBs)
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
Post-MI
Cardiovascular protection
Chronic kidney disease (CKD)
– In people with hypertension and these co-existing conditions, an ACEI is a particularly good choice
ACEI
– 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
ARB
– 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
Post-MI
• Key practice points for ARBs (note - same as ACEI):
CCB
– 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
diuretics
– 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
diuretics
– 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
dreams
– 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
Comorbidity & compelling indications
Comorbidity & compelling indications
Comorbidity & compelling indications
HT treatment target
Hypertension: Key Points
Dyslipidaemia: terminology
Dyslipidaemia: Lipid Profile
Dyslipidaemia: Manifestations
Dyslipidaemia: medication
Fibrates
Dyslipidaemia - SUMMARY
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%
causes of systolic HF
CHF clinical manifestations
CHF symptoms and signs
diagnosis of HF
diagnosis of HF
diagnosis of HF
New York Heart Association (NYHA) classification of capacity
pharmacological prevention
General Management guidelines
Drug Therapy for HF
ACEIs/ARBs
And other vasodilators for HF
Diuretics- aldosterone antagonists
– polyunsaturated fatty acids (PUFAs)
CHF –Management Summary
Treatment of HFPSF
