Drugs for the Heart
Antiplatelet agents
Antiplatelet agents are used to reduce the risk of arterial thrombus formation by preventing platelet activation and aggregation. Antiplatelet agents have a role in the primary and secondary prevention of cardiovascular (CV) disease.
Antiplatelet agents: aspirin
Mode of action
Aspirin blocks the thromboxane A2 pathway of platelet activation by irreversibly acetylating cyclo-oxygenase. The effect of aspirin persists for the lifespan of the platelet.
Clinical evidence
Secondary prevention: Data to support the use of aspirin in secondary prevention of CV disease have been accruing since the 1980s, following the publication of the landmark Second International Study of Infarct Survival (ISIS-2), where the use of aspirin 300 mg in acute myocardial infarction (AMI) reduced mortality by 23%. The Antithrombotic Trialists’ Collaboration, concludes that post AMI, aspirin reduces the risk of further CV events by 25% (number needed to treat (NNT) = 28 over 2 years).
Primary prevention: The role of aspirin in primary prevention is less clear, as the cardiovascular benefits must be balanced against the risk of adverse events, in particular, the risk of gastrointestinal (GI) bleeds. Aspirin should not be prescribed for primary prevention in low- or moderate-risk patients (i.e. those with a calculated CV risk less than 20% over 10 years).
For patients at high CV risk (>20% over 10 years), the decision to initiate aspirin is controversial, with most clinicians avoiding use even in this high-risk group. While low-dose aspirin will prevent approximately 10-15 vascular events for every 1000 patients treated for 2 years, it increases the risk of bleeding two to threefold. In hypertensive patients, there is an increased risk of intracranial haemorrhage during treatment with low-dose aspirin; therefore, blood pressure should be controlled to less than 150/90 mmHg if it is initiated for primary prevention.
Place in therapy
The benefit of aspirin in secondary prevention is evident for all presentations of CV disease, including myocardial infarction (MI), acute coronary syndromes, unstable angina, chronic stable angina, post-CABG (coronary artery bypass graft), ischaemic stroke, and peripheral vascular disease. Aspirin is no longer recommended for routine use for primary prevention, as the benefit to risk ratio is finely balanced.
Platelet aggregation
Platelet aggregation occurs as a result of the formation of fibrinogen bonds between glycoprotein IIb/IIIa receptors expressed on the surface of activated platelets. Platelets are activated by a number of pathways, with specific inhibitors (see Table. 2.1).
Indications for aspirin
Secondary prevention of CVD:
stroke—ischaemic
peripheral arterial disease (PAD)
Primary prevention of CVD: generally no longer routinely recommended
Atrial fibrillation (AF): doses of 75-300 mg may be used in those at moderate to high risk of thrombotic events, especially where warfarin is unsuitable or not tolerated.
Adverse effects of aspirin
Aspirin, even at low doses, can precipitate bronchospasm in up to 20% of asthmatic adults.
Gastric side-effects are common and range from a feeling of nausea in the hour or so after the dose to major GI bleeds. Aspirin is associated with a greater risk of bleeding from duodenal ulcers than gastric ulcers and occurs more commonly in the early days of treatment.
Resistance
The effectiveness of aspirin in clinical practice is affected by ‘aspirin resistance’. This occurs relatively commonly in up to 10% of patients treated. However, as the testing of platelet activity is not widely undertaken, this is rarely identified.
Contraindications and cautions
Contraindications: known allergy, active peptic ulceration, history of recent GI bleeding, history of recent intracranial bleeding, and bleeding disorders including haemophilia, von Willebrand’s disease, thrombocytopenia and severe liver disease.
Cautions: asthma, uncontrolled hypertension, previous peptic ulceration (risk of GI bleeding; PPIs or H2-receptor antagonists may be considered for prophylaxis).
Risk factors for GI bleeds with aspirin
Age: risk doubles with each decade of life above 55 years.
Men: risk is twice as high in men as in women.
History of GI ulcer, bleed, or perforation.
Concomitant medications, such as NSAIDs, anticoagulants, selective serotonin reuptake inhibitors (SSRIs).
Serious co-morbidities, such as CV disease, liver or kidney disease, diabetes.
Need for prolonged NSAID use—osteoarthritis, rheumatoid arthritis, chronic low back pain.
Presence of H. pylori.
Excess alcohol.
Heavy smoking.
Strategies to reduce GI bleeding risk with aspirin
Prescribe 75 mg daily, unless a higher dose is indicated.
Advise the patient to take the dose with or after food.
Do not use enteric coated preparations, these do not reduce the risk of GI events.
Review concurrent medications and stop or reduce the dose of any that might increase the risk of bleeds.
Advise sensible drinking.
Advise smokers to quit or reduce their smoking.
Consider co-prescribing a PPI for those with multiple risk factors.
Drug interactions with aspirin
Analgesics: avoid concomitant use with NSAIDs as this increases the risk of adverse effects.
Anticoagulants: increased risk of bleeding with warfarin and other anticoagulants. Avoid concomitant use unless there is a compelling indication for both.
Antidepressants: increased risk of bleeding with SSRIs and venlafaxine.
Cytotoxics: aspirin reduces the excretion of methotrexate; avoid concomitant use where possible, or ensure close monitoring of methotrexate dose.
Antiplatelet agents: thienopyridines
Mode of action
Thienopyridines irreversibly block the binding of ADP to platelet receptors, and hence prevent expression of the active glycoprotein IIb/IIIa receptor. The first agent in this class, ticlopidine, has been superseded in clinical practice by the use of clopidogrel which has fewer serious adverse effects. Prasugrel was launched in 2009, and 2010 saw the introduction of ticagrelor.
Antiplatelet agents: clopidogrel
Clinical trial data
In the CAPRIE (Clopidogrel versus Aspirin in Patients at risk of Ischemic Events) study (1997), clopidogrel demonstrated a small advantage over aspirin in terms of protecting patients from recurrent CV events. As the clinical advantage over aspirin for this indication is small and the relative cost is large, clopidogrel should only be employed for monotherapy in patients who are unable to tolerate aspirin first line. There is no evidence to support the use of clopidogrel for primary prevention of CV disease.
The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study (2000) compared aspirin monotherapy to clopidogrel and aspirin dual therapy in patients for up to 9 months post-NSTEMI (non- ST-segment elevation MI) and demonstrated a 2% reduction in major CV events with dual antiplatelet therapy. The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) study (2005) demonstrated that aspirin/clopidogrel dual therapy reduced death and CV events at four weeks following the acute event compared to aspirin alone.
Place in therapy
Clopidogrel monotherapy is licensed for the secondary prevention of cardiovascular events in patients post MI or stroke, or with peripheral vascular disease. Clopidogrel is also licensed for use in combination with aspirin for patients following acute coronary syndromes (ST-segment elevation MI (STEMI) and NSTEMI). Clopidogrel should not be used for the primary prevention of CV events. Clopidogrel may also be used for prevention of CV events following procedures such as intracoronary stent implantation (bare metal or drug-eluting) or patent foraman ovale (PFO) closure, or following transapical valve implantation.
Dosing
Clopidogrel is prescribed at a maintenance dose of 75 mg daily for most indications. In STEMI and NSTEMI, a loading dose of clopidogrel 300-600 mg should be given as early as possible following presentation, and 75 mg daily continued for up to one year; aspirin should be continued indefinitely. Recent data from CURRENT-OASIS7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Intervention) indicate that a higher clopidogrel dose of 150 mg daily may be useful in the first week of treatment following a STEMI especially post-PCI.
The dual-therapy aspirin/clopidogrel regimen is also used for up to one year following PCI, particularly where intracoronary stents have been deployed to reduce the risk of stent thrombosis.
Indications and dosing for clopidogrel
See Table 2.2.
Table 2.2 Indications and dosing for clopidogrel | ||||||||||||
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Contraindications and cautions
Contraindications: hypersensitivity to clopidogrel, severe hepatic impairment, active pathological bleeding
Cautions: patients at increased risk of bleeding, recent cerebrovascular accident (CVA), renal impairment
Usual initiation and maintenance dose
The usual dose is 300-600 mg loading in the acute setting or preprocedure, followed by 75 mg daily thereafter.
Early cessation of clopidogrel therapy post-stent insertion is the largest single risk factor for stent thrombosis, which is associated with significant mortality. Patients must be encouraged to persist with therapy, and alternative agents initiated if they are unable to tolerate clopidogrel due to adverse events.
Risk factors for stent thrombosis
See Table 2.3.
Table 2.3 Risk factors for stent thrombosis | |||||||||||||||||||||
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Adverse effects
The single most troubling adverse effect of clopidogrel is skin rash.
Care should be taken to distinguish self-limiting X-ray contrast-mediainduced skin rash, which occurs early (within one week of PCI), to avoid unnecessary cessation of clopidogrel. Minor rashes may be managed by use of antihistamines, but often alternative therapies such as prasugrel or ticlopidine will be required.
GI side-effects are reported relatively commonly, and include diarrhoea, abdominal pain, and dyspepsia.
Bleeding and bruising are common, particularly where aspirin and clopidogrel are used in combination. There is a small risk of haematological disorders including thrombocytopenia and neutropenia.
Antiplatelet agents: prasugrel
Mode of action
The pharmacological benefits of prasugrel over clopidogrel are an earlier onset of anti-aggregatory effects (significant antiplatelet effects are seen within half an hour of loading) and less inter-patient variability in terms of antiplatelet response.
Clinical evidence
The TRITON TIMI 38 (Trial to Access Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel -Thrombolysis in Myocardial Infarction) study compared prasugrel to clopidogrel (on a background of aspirin therapy) in patients with acute coronary syndrome (ACS) undergoing immediate or delayed PCI, and demonstrated signific-antly fewer major CV events in the prasugrel-treated group but at the expense of an increased risk of bleeding.
Place in therapy
Prasugrel, used in combination with aspirin, is licensed for the prevention of atherothrombotic events in patients with ACS (STEMI, NSTEMI, or unstable angina) undergoing primary or delayed PCI. Patients with a history of stroke or transient ischaemic attack (TIA) did worse on prasugrel than on clopidogrel, and as a result this is a contraindication to therapy. Low body weight and age above 75 years was also associated with no net clinical benefit and therefore the agent should be used cautiously in this group—a lower maintenance dose may be employed. Prasugrel is more effective than clopidogrel in patients with diabetes.
Dosing
Prasugrel 60 mg loading dose followed by 10 mg daily thereafter (maintenance dose should be reduced to 5 mg daily if used in patients over the age of 75 years or those of low body weight, <60 kg). Prasugrel should be continued for a period of one year after the acute event.
Drug interactions with prasugrel
Anticoagulants: concomitant use of clopidogrel with warfarin is not routinely recommended due to the increased risk of bleeding; however, in clinical practice the use of aspirin, clopidogrel, and warfarin is not uncommon, where patients have compelling indications for all three. This should be undertaken with extreme caution and close supervision.
Ulcer-healing drugs: the antiplatelet effect of clopidogrel may be reduced by concomitant use of PPIs. Many centres are recommending a H2 antagonist, such as ranitidine, first line in patients requiring an acid suppressant, except where the benefits of PPIs are considered to outweigh the potential risks, for example, patients undergoing active ulcer healing.
NICE indications for prasugrel (October 2009)
Prasugrel should be considered as an option in patients undergoing only when:
stent thrombosis has occurred during clopidogrel therapy, or
the patient has diabetes mellitus.
Contraindications and cautions
Contraindications: hypersensitivity, history of CVA or TIA, active bleeding disorder, severe hepatic impairment
Cautions: those at increased risk of bleeding—over 75 years and body weight <60 kg, renal impairment and moderate hepatic impairment, Asian patients (due to limited clinical experience), pregnancy, and lactation.
Usual initiation and maintenance dose
60 mg loading dose followed by 10 mg daily thereafter. Maintenance dose may be reduced to 5 mg in patients at high risk of bleeding.
Adverse effects of prasugrel
Bleeding occurs commonly and is particularly problematic in the elderly (>75 years) or patients of low body weight (<60 kg)—a lower maintenance dose may be considered in these groups.
Anaemia, epistaxis, GI haemorrhage, haematuria are all commonly reported.
Rashes.
Drug interactions with prasugrel
No significant drug interactions have been identified.
Intravenous antiplatelet agents
Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitors
Abciximab, a monoclonal antibody, is indicated for the prevention of ischaemic cardiac complications in patients undergoing PCI and for patients presenting with unstable angina who are scheduled to undergo PCI.
Recommendations for use of GPIIb/IIIa inhibitors
Adapted from the European Society of Cardiology (ESC) guidelines for the management of NSTE-ACS.
In patients with ACS at intermediate or high risk, particularly patients with elevated troponins, ST depression, or diabetes, either eptifibatide or tirofiban is recommended, in addition to oral antiplatelet agents, for initial early treatment.
Patients who received initial treatment with eptifibatide or tirofiban prior to angiography, should be maintained on the same drug during and after PCI.
In high-risk patients not pre-treated with GPIIb/IIIa inhibitors and proceeding to PCI, abciximab is recommended immediately following angiography.
GPIIb/IIIa inhibitors must be combined with an anticoagulant.
Bivalirudin may be used as an alternative to GPIIb/IIIa inhibitors plus unfractionated heparin/low molecular weight heparin (UFH/LMWH).
When coronary anatomy is known and PCI planned to be performed within 24 hours with use of GPIIb/IIIa inhibitors, the most secure evidence is for abciximab.
Angiotensin-converting enzyme inhibitors
(e.g. captopril, enalapril, lisinopril, ramipril, perindopril)
Mode of action
Angiotensin-converting enzyme inhibitors (ACE-Is) block the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and promotes the production of aldosterone, which increases sodium and water retention. ACE-Is therefore lead to vasodilatation and prevent the build up of fluid that would result from aldosterone release.
Clinical trial data
ACE-Is are supported by a wealth of clinical trials data across a range of indications including:
Hypertension: numerous clinical studies confirm the blood pressure lowering efficacy of ACE-I.
Heart failure (SAVE (Survival and Ventricular Enlargement) 1993, enalapril; SOLVD (Studies of Left ventricular Dysfunction) 1994, enalapril; ATLAS (Assessment of Treatment with Lisinopril and Survival) 1999, lisinopril). Meta-analyses concludes that ACE-Is reduce mortality in heart failure (HF) by approximately 25%, with a substantial reduction in the risk of hospitalization.
Post-MI secondary prevention (AIRE (Acute Infarction Ramipril Efficacy) 1994, ramipril; GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico) 1994, lisinopril; ISIS-4 1994, captopril). ACE-Is initiated within 24 hours of presentation reduce the risk of death by approximately 7% compared to placebo in the first four to six weeks post-MI. In the longer term, mortality is reduced by ˜13% in unselected patients, with greater benefits in those with post-MI heart failure. Long-term follow-up of the SOLVD study showed a significant reduction in all-cause mortality associated with ACE-I treatment, even at 12 years post index event.
CV risk reduction (HOPE (Heart Outcomes Prevention Evaluation) 1999, ramipril; EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) 2004, perindopril). ACE-Is have been shown to reduce the risk of CV events in patients who are at high risk of events, such as those with established atherosclerotic disease.
Choice of agent
Not all ACE-Is are licensed for use in all different cardiovascular indications. It is recommended that a licensed agent, with trial evidence to support its use, is chosen for the indication being managed.
Dose
For essential hypertension, the dose should be titrated until blood pressure control is achieved, bearing in mind that higher ACE-I doses confer better CV protection.
For other indications, particularly heart failure and for cardioprotection in those with or at risk of cardiovascular disease, the ACE-I MUST be titrated to the target dose or the maximal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dysfunction, etc.).
Compelling indications for ACE-I use
Hypertension: all non-black patients <55years old
Heart failure: all patients with any degree of left ventricular systolic function, initiated as soon as possible following diagnosis
Post-MI secondary prevention: all patients following an MI, initiated during the inpatient phase of treatment
Contraindications and cautions
Contrainidications:
aortic/mitral stenosis
angioedema (any cause)
hypersensitivity to ACE-Is
bilateral renal artery stenosis
pregnancy.
Cautions:
hypotension (systolic blood pressure <90 mmHg)
Patients on high-dose diuretics (i.e. furosemide >80 mg daily)
Breast-feeding
Moderate to severe renal impairment (i.e. creatinine >150 µmol/L or estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2)—seek specialist advice for initiation.
Initiation and target doses of commonly used ACE-Is
See Table 2.4.
Table 2.4 Indications and doses for commonly used ACE-Is | |||||||||||||||
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Monitoring
Obtain baseline BP and urea and electrolytes (U&Es) before initiation
Check BP and U&Es within two weeks of initiation or change of dose, then annually
If serum creatinine increases by more than 20% (or eGFR falls by more than 15%) after initiation, stop ACE-I and seek specialist advice.
ACE-I dose should only be increased if:
systolic blood pressure >90 mmHg
serum creatinine increases by less than 20% (or eGFR falls by less than 15%) on each dose titration
potassium <5.5 mmol/L.
Hyperkalaemia: advise low-potassium diet, ensure adequate fluid intake Reduce dose if K+ >5.5 mmol/L; withdraw ACE-I if K+ >6 mmol/L.
Dealing with adverse effects
First-dose hypotension: use a long-acting agent, avoid excessive diuresis prior to initiation. First dose may be given at night before bed to reduce the risk of hypotension and associated falls.
Dry cough: may dissipate over time if patient persists with therapy. If troublesome, withdraw agent and re-introduce the same or an alternative ACE-I. Consider an angiotensin receptor blocker (ARB) if cough recurs/persists.
Angioedema: a rare but potentially life-threatening adverse effect. ACE-I therapy should be stopped and specialist advice sought before re-initiation.
Key drug interactions with ACE-Is
Ciclosporin: increases risk of hyperkalaemia
Diuretics: enhances hypotensive effect
Lithium: increases lithium levels
Potassium supplements: increased risk of severe hyperkalaemia.
Angiotensin receptor blockers (ARBs, also referred to as angiotensin II receptor antagonists, AIIRAs)
(candesartan, irbesartan, losartan, telmisartan, valsartan)
Mode of action
Angiotensin receptor blockers (ARBs) bind to the angiotensin II receptors and therefore block the action of angiotensin II. Angiotensin II is a potent vasoconstrictor and promotes the production of aldosterone, which increases sodium and water retention. ACE-Is therefore lead to vasodilatation and prevent the build up of fluid that would result from aldosterone release. Unlike ACE-Is the ARBs do not inhibit the breakdown of bradykinin that is responsible for ACE-I-induced cough.
Clinical trial data
ARBs are supported by fewer clinical trials than ACE-Is, but do have data across a range of indications including:
Hypertension: numerous clinical studies confirm the blood-pressurelowering efficacy of ARBs.
Heart failure: conflicting data emerged from early studies, but CHARM (Candesartan in Heart Failure—Assessment of Mortality and Morbidity) confirmed that candesartan reduced the risk of CV mortality or CV hospitalization in patients with HF, alone or in addition to ACE-I therapy, and with or without concurrent β-blocker therapy. (ELITE-II (Evaluation of Losartan in the Elderly, 2000, losartan; ValHeFT (Valsartan Heart Failure Trial), 2001, valsartan; CHARM, 2006, candesartan)
Post-MI heart failure: valsartan 160 mg bd was non-inferior to captopril in protecting against death and CV event in patients with post MI heart failure (VALIANT (Valsartan in Acute Myocardial Infarction Trial), 2003)*
Choice of agent
Not all ARBs are licensed for use in all the cardiovascular indications. It is recommended that a licensed agent, with trial evidence to support its use, is chosen for the indication being managed.
Dose
For essential hypertension, the dose should be titrated until BP control is achieved
For other indications, particularly heart failure and for cardioprotection in those with or at risk of cardiovascular disease, the ARB MUST be titrated to the target dose or the maximal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dysfunction etc.).
Compelling indications for ARB use
Hypertension: second line to ACE-I (i.e. ACE-I-intolerant patients) for non-black patients aged <55 years
Heart failure: second line to ACE-I (i.e. ACE-I-intolerant patients) in all patients with any degree of left ventricular systolic function, initiated as early as possible following diagnosis
Candesartan may also be considered in addition to ACE-I for inpatients remaining symptomatic despite optimal ACE treatment, if they are unable to tolerate spironolactone
Post-MI heart failure: second line to ACE-I (i.e. ACE-I-intolerant patients); valsartan may be considered for patients with post-MI heart failure
Contraindications and cautions
Contraindications:
hypersensitivity to ARBs
pregnancy
breast-feeding
Cautions:
bilateral renal artery stenosis
aortic or mitral valve stenosis
hypertrophic cardiomyopathy
prior angioedema of any cause
hypotension (systolic blood pressure <90 mmHg)
patients on high-dose diuretics (i.e. furosemide >80 mg daily)
moderate to severe renal impairment (i.e. creatinine >150 µmol/L or eGFR<60 mL/min/1.73 m2)—seek specialist advice for initiation.
Initiation and target doses of commonly used ARBs
See Table 2.5.
Table 2.5 Indications and doses for commonly used ARBs | ||||||||||||||||||
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Monitoring
Obtain baseline BP and U&Es before initiation
Check BP and U&Es within two weeks of initiation or change of dose, then annually
If serum creatinine increases by more than 20% (or eGFR falls by more than 15%) after initiation, stop ARB and seek specialist advice
ARB dose should only be increased if:
systolic blood pressure >90 mmHg
serum creatinine increases by less than 20% (or eGFR falls by less than 15%) on each dose titration
potassium is <5.5 mmol/L.
Hyperkalaemia: advise low-potassium diet, ensure adequate fluid intake. Reduce dose if K+ >5.5 mmol/L; withdraw ARB if K+>6 mmol/L.
Adverse effects of ARBs
Symptomatic hypotension: rare but may occur, particularly if there is intravascular volume depletion. Avoid excessive diuretic doses.
Angioedema: has been reported rarely with ARBs. Particular caution should be taken when initiating an ARB in a patient with a history of angioedema of any cause.
Key ARB drug interactions
Ciclosporin: increases risk of hyperkalaemia
Diuretics: enhance hypotensive effect
Lithium: increases lithium levels
Potassium supplements: increased risk of severe hyperkalaemia.
Aldosterone antagonists
(eplerenone, spironolactone)
Mode of action
The aldosterone antagonists are steroids that are structurally similar to aldosterone, a hormone that binds to mineralocorticoid receptors to promote sodium and water retention. Aldosterone increases blood pressure, promotes magnesium and potassium loss, potentiates the effects of the sympathetic nervous system, impairs the function of baroreceptors and endothelial function, and stimulates vascular fibrosis.
The aldosterone antagonists competitively bind to the aldosterone receptor to reduce sodium reabsorption and potassium excretion at the distal tubule and antagonize the effects of aldosterone listed above.
Clinical evidence
The landmark trial RALES (Randomized Aldactone Evaluation Study, 1999), secured the place of spironolactone in the management of severe heart failure (NYHA (New York Heart Association) class IV or class III with recent class IV exacerbation; ejection fraction (EF)<35%), by demonstrating a 30% reduction in mortality and a 35% reduction in hospitalizations for heart failure, compared to placebo. In the EPHESUS (2003) study, eplerenone, initiated in patients with post-MI left ventricular dysfunction (EF<40%) within 3-14 days of the acute event, demonstrated a 15% reduction in the risk of death over the course of one year.
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