Coronary Heart Disease Medication

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Coronary Heart Disease Medication

• Robert Hallworth
• Chair Greater Manchester Non-Medical
  Prescribing Network

Oldham Primary Care Trust
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CHD - so who do we mean and what should we look
at?

• Established - post MI, CABG, ischaemic stroke /
  TIA, angina, AF, PVD
• Heart failure
• Hypertension
• (Diabetes)
• Raised cholesterol, obesity, smokers
• Intervention review based on current status,
  risk factors, existing treatment
• Targets in the GMS contract

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CaseIt is a busy day in your practice and
you are sitting at your desk, legs up, leafing
through a recent issue of Diversion, The Magazine
for Physicians at Leisure. You come across an ad
for Plavix,TM which states that this medication
reduces the risk of cardiovascular events by 9
compared to aspirin. You wonder if you should be
switching all your patients to Plavix. TM
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Primary prevention statin therapy NICE 2008

• Offer statin therapy for adults who have a 20 or
  greater 10-year risk of developing CVD
• Initiate treatment with simvastatin 40 mg
• If simvastatin 40 mg is contraindicated, offer a
  lower dose or alternative preparation (such as
  pravastatin)
• A target for total or LDL cholesterol is not
• recommended

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Secondary prevention statin therapy NICE 2008

• Offer statin therapy to adults with clinical
  evidence of CVD
• Offer higher intensity statin to people with
  acute coronary syndrome, taking into account
• the patients informed preference
• comorbidities
• multiple drug therapy, and
• the benefits and risks of treatment

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Secondary prevention statin therapy continued

• Treatment should be initiated with simvastatin
  40 mg
• If simvastatin 40 mg is contraindicated, offer a
  lower dose or alternative preparation (such as
  pravastatin)
• If total cholesterol of lt 4 mmol/litre or LDL
• cholesterol of lt 2 mmol/litre is not attained
  consider simvastatin 80 mg (or similar)

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Targets for PCT Advisers

• Better Care Better Value
• Statins
• Generic Prescribing
• National Audit Office
• Proton Pump Inhibitors
• ACE inhibitors / Angiotensin 2 Receptor
  Antagonists
• Antiplatelets
• Other important cost areas
• Drugs used in diabetes
• Respiratory corticosteroids
• Analgesics
• Hypertension and Heart Failure

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What is our approach for primary and secondary
prevention?
Will this differ based on the age of our patient?
Will this differ if our patient has diabetes?
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A recent meta-analysisCholesterol Treatment
Trialists' (CTT) CollaboratorsLancet 2005 366
1267-1278.

• Statin therapy reduces the relative risk of major
  events by one fifth (20) for every 1mmol/L
  reduction in LDL cholesterol (but is there really
  a linear relationship?).
• This is largely irrespective of the initial lipid
  profile or other presenting characteristics.
• The absolute benefit relates chiefly to an
  individual's absolute risk of such events and to
  the absolute reduction in LDL cholesterol
  achieved.
• Statins at established doses (e.g. simvastatin
  40mg) can reduce LDL cholesterol by at least
  15mmol/L in many patients, and hence would be
  expected to reduce the incidence of major
  vascular events by about one third.
• The possibility that higher doses would result in
  clinically relevant adverse effects cannot be
  excluded.

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Summary of High-Dose POO Studies

• A-Z study (JAMA 2004 292 1307-1316)
  simvastatin 80mg vs. no statin/20mg simvastatin
  after AMI No significant benefit, problem with
  harms on higher dose myopathy and
  rhabdomyolysis
• PROVE-IT (N Engl J Med 2004 350 1495-1504)
  atorvastatin 80mg vs. pravastatin 40mg post ACS
  Significant benefit not much harm seen
• TNT (N Engl J Med 2005 352 1425-1435)
  atorvastatin 80mg vs. atorvastatin 10mg in stable
  CHD (but who responded well to atorvastatin in
  the run-in) Significant benefit but also
  significant harm
• IDEAL (JAMA 2005 294 2437-2445) atorvastin
  80mg vs. simvastatin 20mg in stable CHD No
  significant benefit, some harm
• SPARCL (N Engl J Med 2006 355 549-559)
  atorvastatin 80mg vs. placebo in stroke/TIA
  Significant benefit, some harm

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Use a statin in patients with ACS de Lemos JA, et
al. JAMA 2004 292 1307?16 Cannon CP, et al. N
Engl J Med 2004 350 1495?504 Pedersen TR, et
al. JAMA 2005 294 2437?45

• Phase Z of the A to Z trial showed no difference
  in event rates between simvastatin 40mg od for 1
  month followed by 80mg od compared to placebo for
  4 months followed by simvastatin 20mg od. There
  were 3 cases of rhabdomyolysis in patients
  receiving 80mg simvastatin.
• PROVE-IT compared pravastatin 40mg to
  atorvastatin 80mg. The primary endpoint was time
  to first of death, MI, re-hospitalisation for UA,
  revascularisation or stroke. 22.4 of patients in
  the atorvastatin arm had these events at 2 years
  compared to 26.3 in the pravastatin group.
• IDEAL showed no difference in the primary
  endpoint of time to first coronary death, MI or
  resuscitated cardiac arrest between simvastatin
  or atorvastatin

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Statins

• Baseline
• Serum cholesterol, LFTs, CK, UEs (rosuvastatin),
  TFT
• Routine
• Cholesterol
• Every 12 months
• CK
• Within 1-3 months when cholesterol checked,
  after dose increase or when given with a fibrate
• LFTs
• Within 1-3 months, then at 6 and 12 months or if
  hepatotoxicity suspected (greater risk with
  higher doses rosuvastatin 40mg / simvastatin
  80mg)

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Discontinuing statins

• Serum transaminases at 3 x upper limit of normal
• Beware higher doses
• If myopathy occurs (daily discomfort)
• CK gt 5 x upper limit of normal
• Liver disease is likely to be obstructive

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Cholesterol measurements in the first few years
of statin treatment may mislead

• Galsziou P et al. Monitoring cholesterol levels
  measurement error or true change? Ann Intern Med
  2008 148 656-61
• Health professionals should be wary of increasing
  a patients lipid-lowering treatment on the basis
  of a single cholesterol test if they are
  reasonably confident that the patient is taking
  the medication as prescribed.

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OTC Simvastatin

• Is an initial cholesterol test needed?
• How often do LFTs and CK need monitoring?

HPS suggests Up to 40mg simvastatin adverse
effects placebo
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SEAS and ezetimibe no benefits on CV endpoints,
questions raised over cancer risk

• Rossebo AB et al for the SEAS Investigators.
  Intensive lipid lowering with simvastatin and
  ezetimibe in aortic stenosis. N Engl J Med 2008
  359
• It would seem sensible to use ezetimibe only with
  caution as there is no published evidence of its
  benefit on clinically important outcomes such as
  cardiovascular events and its long-term safety is
  unknown

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Fibrates

• Baseline serum cholesterol, LFTs, CK
• Routine cholesterol (every 12 months), LFTs
  (every 3 months for 1 year), FBC (gemfibrozil
  every 3 months for 1 year)
• DISCONTINUE
• Serum transaminase 3 x ULN
• Myopathy symptoms or CK gt 10 x ULN

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Omacor

• Licensed for hypertriglyceridaemia (high dose)
  and secondary prevention of MI (low dose).
• Main data comes from Gissi-Prevenzione trial
• Is this representative of UK patients?

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Hypertension
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NICE CG 54 - Hypertension

• Offer drug therapy to patients with
• persistent high blood pressure of 160/100 mmHg or
  more
• persistent blood pressure above 140/90 mmHg and
  raised cardiovascular risk (10-year risk of
  cardiovascular disease of at least 20, existing
  cardiovascular disease or target organ damage).
• Aim to reduce blood pressure to 140/90 mmHg or
  less, adding more drugs as needed, until further
  treatment is inappropriate or declined.

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ALLHAT (JAMA 2002)

• The key message from ALLHAT is that what matters
  most is getting blood pressure controlled, and
  that this is overwhelmingly more important than
  the means. Combinations of several drugs will be
  required for most patients, and such an
  antihypertensive treatment cocktail should
  include a thiazide diuretic

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The Moral of the Tale

• As long as we reach the objective (130/80), it
  doesnt matter how we get there

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Comparing Interventions(Clinical Evidence)

• Primary prevention, to prevent CHD / CHD death
• Tight BP control NNT 14
• Tight BG control NNT 46
• Tight BG control, metformin NNT 16
• Statin NNT 27
• Aspirin NNT 16-39
• Ramipril NNT 22

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Hypertension in Diabetes NICE 2008

• First choice antihypertensive drug is a
  once-daily ACE inhibitor
• (Plus a diuretic and / or calcium channel blocker
  in people whose blood pressure is not controlled
  to target on monotherapy)
• A calcium channel blocker is recommended for
  women who may become pregnant

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ARBs as effective as ACE inhibitors in CV risk
reduction? Jury still out

• The TRANSCEND study reinforces the importance of
  only prescribing ARBs as an alternative to ACE
  inhibitors where there is clear intolerance to
  ACE inhibitors.
• Lancet 2008 372 1172-83.

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Angina - Treatment Options

• Immediate relief of symptoms
• GTN
• Long-term prevention of symptoms
• Beta-blocker
• Calcium channel blocker
• Nitrate
• Potassium channel activator

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Combination therapy

• With a maximal dose beta-blocker add
• Long acting dihydropyridine
• ISMN or nicorandil
• If a beta-blocker is contra-indicated use
• CCB add ISMN or nicorandil
• Nitrate add CCB or nicorandil
• There is no evidence that a third drug improves
  symptom control

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Adverse Effects

• Antiplatelets
• Beta-blockers
• Calcium-channel blockers
• Nitrates
• Nicorandil

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Myocardial Infarction NICE CG43 May 2007

• Give low dose aspirin (75mg daily) clopidogrel
  if allergy (NSTEMI / STEMI)
• Give beta-blockers ALL patients EARLY for at
  least 2-3 years
• Give ACE inhibitors ALL patients EARLY
• Provide advice and treatment to control BP
• Give statins of low acquisition cost ASAP to
  reduce cholesterol to target
• Tackle other risks such as blood glucose levels,
  smoking, physical activity, diet and weight

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Are the risk reductions relative or absolute?
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Risk (Rx) 8/100 8Risk (Pl) 12/100 12
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Relative Risk(RR) Risk (Rx)/ Risk (Pl)
.08/.12 .67 Relative Risk Reduction (RRR) 1
- RR 1- .67 .33 or 33
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Absolute Risk Reduction (ARR) Risk (Pl) - Risk
(Rx) .12 - .08 .04 or 4
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Number Needed to Treat (NNT) NNT 1/ARR

• Number of patients needed to treat to prevent one
  outcome

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NNT 1/ARR

• ARR 4NNT 1/.04 25

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Check-list

• Are the risks relative or absolute?

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Check-list

• Are the risks relative or absolute?
• Relative.
• Absolute 0.9

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant?

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Check-list

• Are the risks relative or absolute?
• Is the result statistically significant?
• Yes, marginally.
• P .045 95 CI (0.3 to 16.5)

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant?

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant?
• No
• NNT 1/ARR 1/.009 111 95CI (57 - 2500)

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant? No
• Does the size of the effect shown equal the size
  of the effect in the data?

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant? No
• Does the size of the effect shown equal the size
  of the effect in the data? No

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant? No
• Does the size of the effect shown equal the size
  of the effect in the data? No
• Are the references "real?

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Check-list

• Are the risks relative or absolute? Relative
• Is the result statistically significant? Yes
• Is the result clinically significant? No
• Does the size of the effect shown equal the size
  of the effect in the data? No
• Are the references "real?
• Yes, the CAPRIE study, The Lancet, Vol. 348,
  November 16,1996.

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Aspirin ineffective for primary prevention in
patients with diabetes

• Belch J et al. the prevention of the progression
  of arterial disease and diabetes (POPADAD) trial.
  BMJ 2008 337 a1840
• This trial found aspirin was ineffective for the
  primary prevention of cardiovascular (CV) events
  in patients with diabetes and asymptomatic
  peripheral arterial disease (a risk factor for CV
  disease).

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Heart failure treatmentNICE 2003
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ACE inhibitor dosageNICE 2003
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Initiation in Heart Failure

• 1. Withhold diuretics
• 2. Initiate in the evening (or morning and
  monitor BP)
• 3. Start with low dose build up to recommended
  or highest tolerated
• 4. Stop if RF deteriorates

• 5. Avoid K-sparing diuretics NSAIDs
• 6. What to do if BP falls
• 7. What to do if cough occurs
• 8. Rarely necessary to stop treatment beware
  clinical deterioration

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ACEI A2A monitoring

• Baseline
• BP, RF (urea / creatinine), electrolytes
  (especially K)
• Routine
• BP, RF, electrolytes (especially K)
• - 1 week after initiation
• - 1 week after dose increase
• - thereafter annually

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Modifying / Stopping ACEIs A2As
Serum creatinine increase by 50 or to
200µmol/l halve dose
Stop if Serum potassium 6mmol/l or more
Or Creatinine gt 350µmol/l
Or Creatinine increase by gt 100
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Using beta-blockersNICE 2003
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Beta blockers in Heart Failure

• 1. Should be on a background ACEI
• 2. Start low dose and titrate up to maintenance
• 3. Double dose every 2 weeks
• 4. Monitor heart rate, BP (UEs every 1-2 weeks
  and 1-2 weeks after final dose reached)

• 5. Worsening HF, hypotension and bradycardia can
  occur during titration
• 6. Adjust treatment, but consider dose increase
  when patient stable
• 7. Dont stop suddenly rebound myocardial
  ischaemia and arrhythmia

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Place of ARBs in HF therapy

• If truly ACEI intolerent ARB should be used
  (NICE)
• Adding ARB in addition to ACEI gains little. In
  Val-Heft it was harmful in people on ACEI and
  ?-blocker.
• And may increase drop out due to side effects
  Pfeffer MA, et al. NEJM 2003
• CHARM-Added showed some benefits but increased
  harms (in an RCT where ACEIs were said to be
  optimised but were low compared with UK targets)
• Adding ARB in diastolic failure not beneficial
  (most already on ACEI) CHARM-Preserved

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Using spironolactoneNICE 2003

• Dose 12.525mg daily (50mg only by specialist and
  no potassium problems)
• Check UE at 1, 4, 8 12 weeks 6, 9 12
  months 6 monthly thereafter

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Oral Anticoagulants - Uses

• Deep vein thrombosis / pulmonary embolism
• Atrial fibrillation
• Prosthetic heart valves

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Warfarin

• Baseline
• PT APTT
• Platelet count and LFT (if possible)
• Routine
• INR weekly until stable (daily for rapid
  anticoagulation)
• At intervals up to maximum of 3 months
• Increase frequency if response likely to change
  (liver disease, illness, drug interaction)

Do you record doses and INRs ?
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INRs

• INR 2 2.5 (DVT prophylaxis)
• INR 2.5 (treatment of DVT PE, AF,
  cardioversion, dilated cardiomyopathy, mural
  thrombus post-MI, rheumatic valve disease)
• INR 3.5 (recurrent DVT PE, prosthetic heart
  valves)

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Warfarin / Diet Interactions

• Vitamin E
• Vitamin K
• Fish oils
• Avocado
• Green vegetables

• Chromium
• Coenzyme Q10
• Cranberry juice
• Ice cream
• Soya bean products

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New Patients

• Loading doses
• Consider thrombophilia screening
• Standard 10mg for 2 days (reduced in some
  patient groups)
• Slow induction (AF) 2 or 3mg daily
• Maintenance doses
• 3 9mg

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New Patients

• LMWH Clexane
• If patient discharged and INR less than 2.0
  continue heparin until 2 consecutive readings
  above 2.0.
• Consider restarting heparin if INR ever falls
  significantly below 2.0.
• Treatment dose Clexane 1.5mg/kg/day.

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INR monitoring and dose adjustment

• Initially daily then increase frequency to a
  maximum of 8 week intervals for stable patients.
• INR reflect dose 48 hours ago.
• Same dose each day where possible.
• Avoid halving tablets.

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Fluctuating INRs

• Dont overreact!
• Look for obvious causes.
• Raised INR.
• E.g. diarrhoea,exacerbation of HF, LF,
  hyperthroidism, weight loss, alcohol (acute),
  overdose, drug interactions.
• Omit 1doses as appropriate
• Usually only change maintenance dose if 2nd
  episode of raised INR
• Consider checking LFTs if 3rd episode

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Fluctuating INRs

• Reduced INRs
• E.g. hypothyroidism,diet (Vitamin K), weight
  gain, missed doses, drug interactions, poor
  compliance
• Booster dose, double maintenance dose
• Usually only change maintenance dose on 2nd
  episode

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Overanticoagulation- Patients at risk of bleeding

• Age over 75 years
• History of uncontrolled hypertension
• Liver disease, increased alcohol intake
• Poor drug compliance or clinic attendance
• Bleeding lesions especially GI
• Bleeding tendency (inc coagulation defects,
  thrombocytopenia) or concomitant NSAIDs
• New patients, INRs greater than 4.0

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Overanticoagulation - Management

• See BNF for details
• Avoid use of vitamin K in valve replacements
• Vitamin K may be used orally
• For partial reversal give 0.5 2mg orally
• Deranged clotting factors for several days with
  high doses
• Control of haemorrhage using vitamin k
• 1 3 hours IV
• 4 6 hours oral
• INR change lags 12 24 hours

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Discontinuing Treatment

• Stop treatment abruptly no need to tail off
• Baseline blood test after six weeks
• Counsel regarding future high risk situations
• Operations, prolonged bedrest
• Pregnancy
• Long distance travel
• Patient Information sheet

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Dental Treatment

• Dental treatment continue as long as INR 4.0.
  Check blood 72 hours before treatment.

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Amiodarone
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Amiodarone

• Antiarrhythmic secondary care initiation
• Beware interactions with warfarin, beta-blockers,
  calcium channel blockers, digoxin

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Amiodarone - monitoring

• Baseline
• LFTs, TFTs (TSH, T3, T4)
• Chest x-ray, lung function (BNF)
• Serum K and ECG (SPC)
• Routine
• TFTs
• Every 6 months and for some months after
  discontinuation (possibly 12 months)
• Hyperthyroidism discontinue (often refractory).
  Hypothyroidism weigh risk / benefit (can use
  thyroxine)

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Amiodarone monitoring 2

• Routine
• LFTs
• Every 6 months
• Initial rise in serum transaminases usually
  resolves within 6 months (may need dose decrease)
• Increase after more than 6 months treatment or
  hepatomegaly indicates chronic liver disease
• Eye examination
• Every 12 months
• Recommended by SPC to detect corneal
  microdeposits. These are untreatable and
  reversible
• Beware optic neuritis and neuropathy

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Amiodarone monitoring 3

• Routine
• Chest x-ray and lung function tests
• If toxicity suspected
• Observe for dyspnoea, cough, pleuritic pain
• Aim to prevent pneumonitis (which can be fatal)
• Periodic ECGs
• Neurological symptoms
• Use of sunscreens

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Digoxin

• Baseline
• Serum creatinine (TFTs, K)
• Routine
• If on diuretic monitor K periodically (lt4mmol/l
  give K-sparing diuretic)
• Digoxin level (only if toxicity suspected or 1
  week after adding or stopping interacting drug)
• Discontinue if toxicity (usually gt3ng/ml)
• Also check potassium if toxicity suspected

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Frequency of and risk factors for preventable
medication-related hospital admissions

• Leendertse AJ et al. Arch Intern Med. 2008 168
  1890-1896
• Medicines most frequently associated with the
  potentially preventable admissions included those
  affecting blood coagulation, NSAIDs, and
  antidiabetic drugs, with a total of 509
  medication errors being identified in the 332
  potentially preventable medicines-related
  admissions.

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Questions?

• Thank you
• Robert.Hallworth_at_nhs.net