Download Coronary Heart Disease Medication

Coronary Heart Disease
Medication
Robert Hallworth
Chair – Greater Manchester
Non-Medical Prescribing
Network
Oldham
Primary Care Trust
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
Case
It 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, 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
TM
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
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 patient’s informed preference
comorbidities
multiple drug therapy, and
the benefits and risks of treatment
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 < 4 mmol/litre or LDL
cholesterol of < 2 mmol/litre is not attained
consider simvastatin 80 mg (or similar)
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
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?
A recent meta-analysis
Cholesterol Treatment Trialists' (CTT) Collaborators
Lancet 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 1·5mmol/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.
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
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
Statins
• Baseline
– Serum cholesterol, LFTs, CK, U&Es (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)
Discontinuing statins
• Serum transaminases at 3 x upper limit of
normal
• Beware higher doses
• If myopathy occurs (daily discomfort)
• CK > 5 x upper limit of normal
• Liver disease is likely to be obstructive
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 patient’s 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.
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
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
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 > 10 x ULN
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?
Hypertension
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 (10year 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.
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”
The Moral of the Tale
• As long as we
reach the objective
(130/80), it doesn’t
matter how we get
there
Comparing Interventions
(Clinical Evidence)
• Primary prevention, to prevent CHD / CHD
death:
– Tight BP control
– Tight BG control
– Tight BG control, metformin
– Statin
– Aspirin
– Ramipril
NNT 14
NNT 46
NNT 16
NNT 27
NNT 16-39
NNT 22
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
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.
Angina - Treatment Options
• Immediate relief of
symptoms
– GTN
• Long-term prevention
of symptoms
– Beta-blocker
– Calcium channel
blocker
– Nitrate
– Potassium channel
activator
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
Adverse Effects
•
•
•
•
•
Antiplatelets
Beta-blockers
Calcium-channel blockers
Nitrates
Nicorandil
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
Are the risk reductions relative
or absolute?
Dead Alive
Therapy
8
92
100
Placebo
12
88
100
Dead Alive
Therapy
8
92
100
Placebo
12
88
100
Risk (Rx) = 8/100 = 8%
Risk (Pl) = 12/100 =12%
Dead Alive
Therapy
8
92
100
Placebo
12
88
100
Relative Risk(RR) = Risk (Rx)/ Risk (Pl) = .08/.12 =
.67
Relative Risk Reduction (RRR) = 1 - RR = 1- .67 =
.33 or 33%
Dead Alive
Therapy
8
92
100
Placebo
12
88
100
Absolute Risk Reduction (ARR) = Risk (Pl) - Risk
(Rx) = .12 - .08 = .04 or 4%
Number Needed to
Treat (NNT):
Number of patients needed
to treat to prevent one
outcome
NNT = 1/ARR
NNT = 1/ARR
ARR = 4%
NNT = 1/.04 = 25
Check-list
• Are the risks relative or absolute?
Check-list
• Are the risks relative or absolute?
Relative.
Absolute = 0.9%
Check-list
• Are the risks relative or absolute?
Relative
• Is the result statistically significant?
Check-list
• Are the risks relative or absolute?
• Is the result statistically significant?
Yes, marginally.
P = .045
95% CI (0.3% to 16.5%)
Check-list
• Are the risks relative or absolute?
Relative
• Is the result statistically significant?
Yes
• Is the result clinically significant?
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
95%CI (57 - 2500)
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?
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
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?”
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.
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).
Heart failure – treatment
NICE 2003
ACE inhibitor dosage
NICE 2003
Licensed
Starting dose
ACEI (with
large outcome
RCT)
Target dose
Captopril
6.25mg tid
50–100mg tid
Enalapril
2.5mg bd
10–20mg bd
Lisinopril
2.5–5.0mg od
30–35mg od
Ramipril
2.5mg od
5mg bd or
10mg od
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
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
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
increase by >
100%
Or:
Creatinine >
350µmol/l
Using beta-blockers
NICE 2003
Bisoprolol
Carvedilol
Starting
dose
1.25mg od
3.125mg bd
Target
dose
10mg od
25 – 50mg
bd
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
(U&Es 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. Don’t stop suddenly –
rebound myocardial
ischaemia and arrhythmia
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
Using spironolactone
NICE 2003
• Dose 12.5–25mg daily (50mg only by
specialist and no potassium problems)
• Check U&E at 1, 4, 8 & 12 weeks; 6, 9 &
12 months; 6 monthly thereafter
Oral Anticoagulants - Uses
• Deep vein thrombosis / pulmonary
embolism
• Atrial fibrillation
• Prosthetic heart valves
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 ?
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)
Warfarin / Diet Interactions
•
•
•
•
•
Vitamin E
Vitamin K
Fish oils
Avocado
Green vegetables
•
•
•
•
•
Chromium
Coenzyme Q10
Cranberry juice
Ice cream
Soya bean
products
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
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.
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.
Fluctuating INRs
• Don’t 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
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
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
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
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
Dental Treatment
• Dental treatment – continue as long as
INR ≤ 4.0. Check blood ≤ 72 hours before
treatment.
Amiodarone
Amiodarone
• Antiarrhythmic – secondary care initiation
• Beware interactions with warfarin, betablockers, calcium channel blockers,
digoxin
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)
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
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
Digoxin
• Baseline
– Serum creatinine (TFTs, K)
• Routine
– If on diuretic monitor K periodically (<4mmol/l give Ksparing diuretic)
– Digoxin level (only if toxicity suspected or 1 week
after adding or stopping interacting drug)
• Discontinue if toxicity (usually >3ng/ml)
• Also check potassium if toxicity suspected
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.
Questions?
Thank you
[email protected]