Phase-contrast \202 ow velocity mapping can enable determination of peak \202 ow veloci ties, estimation of valve gradients, and relatively accurate quanti \201 cation of regurgi tant fractions. Through-plane \202 ow maps are used to characterize \202 ow jets and fa cilitate accurate positioning for in-plane measurements of \202 ow velocity. Measurements can be taken in a single breath hold. The ability of CMR to accurately and directly quantify ventricular volumes allows the separ ate estimation of stroke volume and the calculation of interventricular stroke volume diffe rence, which is particularly useful for MR, where the combination of annular through- plane motion and the altering geometry of the valve plane itself make the accurate use of phase- contrast \202 ow velocity mapping dif \201 cult. CMR can be used to planimeter the aortic valve, allowing direct estimation of aortic valve area. In addition, root dimensions and aortic, iliac, and femora l arterial anatomy can be assessed, providing useful information where percutaneous aortic valve replacement is being considered. The multiplanar capability of CMR allows a stack of images to be taken through the mitral v alve to disclose the mechanism of MR and assess the suitability of lea \202 ets for repair . CMR allows the pulmonary valve and right ventricle to be imaged in exquisite detail and is invaluable for the precise evaluation of pulmonary regurgitation as well as pulmonary arter y anatomy in patients with tetralogy of Fallot and other congenital heart diseases with sig ni \201 cant right ventricular involvement. It also allows ready estimation of shunt fract ions, and thereby facilitates the evaluation of both intra- and extra-cardiac shunts. CMR FOR CONGENITAL HEART DISEASE 77 CMR for congenital heart disease \200 The lack of ionizing radiation (a particular concer n where serial evaluation is required in adolescents or young adults), a wide \201 eld of view, and the versatile multiplanar 2D and 3D imaging capability afforded by CMR make it the modality of choice for the evaluation and follow-up of patients with congenital heart disease. This is particularly true in those with complex anatomy, e.g. Fontan circulation, or after repeated surgical repairs where scar tissue can give rise to poor ECHO windows. The wide \201 eld of view allows visceroatrial situs and cardiac position to be readily assessed. Atrioventricular and ventriculoarterial concordance can also be eva luated. Accurate assessment of pulmonary and aortic \202 ows allows shunt ratios (Qp/Qs) to be readily calculated. Detailed visualization and \202 ow mapping of th e atrium and interatrial septum can enable assessment of ASD for percutaneous or surgical c losure, and ready identi \201 cation of anomalous pulmonary venous drainage. Assessment of the effects of lesions on RV volumes and function may be critical for determining the natu re and timing of any surgical intervention. The origin and proximal course of coronary arteries can be delineated with whole-heart coro nary imaging sequences, allowing identi \201 cation of anomalous coronary arteries and de \201 nition of their course with respect to the aorta and pulmonary arteries. This can fac ilitate identi \201 cation of malignant courses and planning for surgical repair. CMR can also be used to assess the integrity of the proximal coronaries after Bentall repair for ao rtic root disease, the Ross procedure, and the arterial switch operation for transposition of the great arteries (TGA). This can also be combined with MR perfusion imaging to assess functional consequences. CMR is particularly adept at imaging the aorta and other great vessels. Patent ductus arter iosus (PDA) and associated anomalies are readily de \201 ned. Aortic coarctation can be co mprehensively assessed, including lesion severity and suitability for percutaneous treatmen t, or evaluation of re-coarctation or aneurysm formation following surgical repair. \200 The unrivaled clarity with which CMR images the RV, together with the functional informatio n it provides, makes it the ideal means for following up pulmonary regurgitation and RV fun ction in repaired tetralogy of Fallot. In recent years, the detection of right ventricular late gadolinium enhancement, signifying \201 brosis, has emerged as potentially prognostically important in patients with system ic right ventricles, e.g. transposition of great vessels treated by atrial redirection surg ery. CMR can therefore provide comprehensive evaluation of anatomy, ventricular function, v alve function, perfusion, and tissue characteristics in one non-invasive study. 78 CHAPTER 1 Cardiac investigations CMR for pericardial disease The ability of CMR to image in any plane with high spatial reso lution, and its tissue-characterizing ability, makes it the modality of choice for the asse ss- ment of pericardial disease. CMR can allow a detailed assessment of the pericardial ana tomy, detect the presence of active in \202 ammation, identify and often characterize peri cardial tumors and cysts, and help de \201 ne the haemodynamic consequences of pericardial disease. Pericarditis and pericardial effusions \200 In acute pericarditis, CMR with T 2 -STIR seq uences can often uniquely delineate areas of high signal in the pericardium, re \202 ectin g acute in \202 ammation. CMR can also reveal pericardial thickening, and the use of appro priate pre-pulses can facilitate the delineation of pericardium from surrounding fat or \202 uid. CMR is a particularly sensitive technique for the assessment of pericardial effusions. This can be readily accomplished with echocardiography; however, CMR can be helpful in the setting of loculated pericardial effusions; detecting pericardial haematoma; in those with poor ECHO windows; and in patients where neoplasia is suspected a nd information is required about surrounding tissues. CMR can be used to assess the sequelae of acute pericarditis. The administration of gadolinium can help to identify myocardial involvement, i.e. myoperic arditis, and, in the late phase, CMR can be used to diagnose constrictive pericarditis and to assess for surgery. Constrictive pericarditis \200 The pericardium is thickened and often low signal due to t he presence of \201 brotic tissue and calcium, which has poor water content. A pericardial t hickness > 4 mm should raise the index of suspicion for constriction. However, normal peric ardial thickness, i.e. 2 mm or less, does not exclude the condition. Other features that ma y be present include bi-atrial dilatation, engorgement of the IVC and hepatic veins, pleura l effusions, narrowing of the RV cavity, and reduction in the size of the AV groove. RV lon g-axis function, however, is often preserved in distinction to the situation with a restric tive cardiomyopathy. CMR tagging techniques can be used to identify \201 brous continuity between visceral and parietal pericardium. Real-time free-breathing cine sequences can be used to detect the haemodynamic effects of p ericardial constriction. The RV normally starts to \201 ll earlier than the LV. The const ricting pericardium prevents expansion of the RV that would normally accommodate this \201 lling. As a result, the interventricular septum is pushed from right to left in early diastole ( \200\230early septal bounce \200\231). Inspiration, by increasing RV \201 llin g, exacerbates the situation increasing left-ward septal movement in early diastole, partic ularly after the \201 rst heart beat following inspiration. These changes are not seen in restrictive cardiomyopathy. CMR FOR PERICARDIAL DISEASE 79 Pericardial defects \200 There may be partial or complete absence of the pericardium. Mos t commonly, the left side of the pericardium is involved. There is usually marked displacemen t of the heart, and interposition of a tongue of lung parenchyma between the aorta and pulm onary artery and between the inferior surface of the heart and the diaphragm. CMR can also be used to identify associated conditions such as a PDA, tetralogy of Fallot, ASD, and congenital mitral stenosis. Partial pericardial defects may be complicated by card iac herniation, particularly of the left atrial appendage. The latter can become strangulat ed and undergo infarction. Pericardial cysts \200 These are congenital, usually unilocular, cystic structures arisin g from the pericardium. They appear high signal on T 2 -weighted images because of their wa ter content and do not enhance with gadolinium as they have no direct blood supply. CMR the refore allows them to be readily differentiated from other potential cystic structures or n eoplasms. 80 CHAPTER 1 Cardiac investigations CMR evaluation of cardiac masses \200 The wide \201 eld of view offered by CMR, and its ability to image in any plane and to non-invasively characterize tissue makes CMR the modality of choice for ev aluating cardiac masses. Intracardiac thrombus is readily identi \201 ed by imaging in the early washout phase foll owing gadolinium administration. Thrombus is avascular, does not take up contrast, and appe ars dark. Imaging in the late phase can identify areas of late myocardial gadolinium uptake , revealing sites of infarction, which can constitute the substrate for mural thrombosis an d further highlight low-signal thrombus. Primary cardiac tumors are rare. The majority that occur ( > 75 % ) are benign. The commonest benign lesion by far is the myxoma (50 % of lesions). Lipomas, pa pillary \201 broelastomas, and, in the pediatric population, rhabdomyomas, and \201 bro mas are comparatively rarer. \200 The most common primary malignant tumors are sarcomas, followed by primary lymphomas. Angiosarcomas are the most common form of cardiac sarcoma an d predominantly involve the right atrium ( 75 % ). Metastatic lesions are over 20 times more common than primary tumors. The heart may be involved via haematogenous spread (e.g. melanoma, lymphoma), lymph ogenous spread (e.g. lymphoma), direct extension (e.g. breast, lung), or via the venous sys tem (e.g. renal cell carcinoma). CMR allows the location of lesions to be assessed (i.e. intramural versus intracavity) and identi \201 cation of multiple (metastatic) deposits. It can also identify pleural and pericardial effusions, which can raise the index of suspicion for mali gnant disease. The CMR evaluation of any suspected cardiac mass involves T 1 - and T 2 -weighted spin ECHO sequences; dynamic evaluation with gradient- ECHO-based cines; assessing the presence of c ontrast enhancement; and perfusion imaging with gadolinium; as well as late-enhancement ima ging. The technique of tagging \200\224 marking structures with intersecting tags to form a grid \200\224 can be used to assess the deformation of masses with cardiac contraction, and thereby reveal their continuity or relationship with cardiac muscle. CMR can also facilitate imaging of vascular structures and surrounding anatomy as part of planning a surgical approach. Differential diagnosis is approached by considering the location, appearance, and signal characteristics of tumors, and integrating these with the wider clin ical picture. 81 Chapter 2 Drugs for the heart Antiplatelet agents 82 Antiplatelet agents: aspirin 84 Antiplatelet agents: thienopyridines 88 Antiplatelet agents: clopidogrel 90 Antiplatelet agents: prasugrel 94 Intravenous antip latelet agents 96 Angiotensin-converting enzyme inhibitors 98 Angiotensin receptor blockers (ARBs, also referred to as angiotensin II receptor antagonists, AIIRAs) 102 Aldosterone antagonists 106 Beta-adrenoceptor blockers ( B -blockers) 110 Calcium-channel b lockers (CCBs) 114 Lipid-lowering therapies 118 Lipid-lowering agents: statins (HMG-CoA red uctase inhibitors) 120 Other lipid-lowering agents 126 Nitrates 132 Potassium-channel activators 136 Ivabradine 13 8 Ranolazine 140 82 CHAPTER 2 Drugs for the heart Antiplatelet agents Antiplatelet agents are used to reduce the risk of arterial thrombus fo rma- tion by preventing platelet activation and aggregation. Antiplatelet agents have a rol e in the primary and secondary prevention of cardiovascular (CV) disease. This page intentionally left blank 84 CHAPTER 2 Drugs for the heart Antiplatelet agents: aspirin Mode of action Aspirin blocks the thromboxane A 2 pathway of p latelet activation by irre- versibly acetylating cyclo-oxygenase. The effect of aspirin per sists for the lifespan of the platelet. Clinical evidence Secondary prevention: Data to support the use of aspirin in secondary pre vention 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 inf- arction (AMI) reduced mortality by 23 % . The Antithromboti c Trialists \200\231 Collaboration, concludes that post AMI, aspirin reduces the risk of fu rther 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 cardiov ascular bene \201 ts must be balanced against the risk of adverse events, in particular, t he risk of gastrointestinal (GI) bleeds. Aspirin should not be prescribed for primary preve ntion 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 c ontroversial, with most clinicians avoiding use even in this high-risk group. While low-dos e aspirin will prevent approximately 10 \200\22315 vascular events for every 1000 patients treated for 2 years, it increases the risk of bleeding two to threefold. In hypertensive pa tients, there is an increased risk of intracranial hemorrhage during treatment with low-dos e aspirin; therefore, blood pressure should be controlled to less than 150/90 mmHg if it is initiated for primary prevention. Place in therapy The bene \201 t of aspirin in secondary prevention is evident for all pre senta- tions of CV disease, including myocardial infarction (MI), acute coronary syndromes, unstable angina, chronic stable angina, post-CABG (coronary artery bypass graft), ischaemi c stroke, and peripheral vascular disease. Aspirin is no longer recommended for routine use for primary prevention, as the bene \201 t to risk ratio is \201 nely balanced. Platelet aggregation Platelet aggregation occurs as a result of the formation of \201 bri nogen bonds between glycoprotein IIb/IIIa receptors expressed on the surface of activated p latelets. Platelets are activated by a number of pathways, with speci \201 c inhibitors (s ee Table. 2.1 ). ANTIPLATELET AGENTS: ASPIRIN 85 Table 2.1 Platelet activation pathways and drug inhibitors Pathway Drug inhibitors Thromboxane A 2 Aspirin ADP mediated Clopidogrel Prasugrel Ticlopidine Ticagrelor Thrombin Heparin (weak) Bivalirudin Glycoprotein IIb/IIIa receptors Abciximab Epti \201 batide Tiro \201 ban ADP = adenosine diphosphate. Indications for aspirin \200 Secondary prevention of CVD : cardiac \200\224 angina, post PCI (percutaneous coronary intervention) or CABG, post MI \200 stroke \200\224 ischaemic \200 peripheral arterial disease (PAD) Primary prevention of CVD : generally no longer routinely recommended \200 Atrial \201 brillation (AF): doses of 75 \200\223300 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 \200 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 duo denal ulcers than gastric ulcers and occurs more commonly in the early days of treatment. Risk factors for bleeding, which should be assessed, include previous GI events, older age, and use of anticoagulants, corticosteroids, and non- steroidal anti-in \202 ammatory drug s (NSAIDs). Prophylaxis with a proton pump inhibitor (PPI) should be considered in patients with multiple risk factors. Resistance \200 The effectiveness of aspirin in clinical practice is affected by \200 \230aspirin resistance \200\231. This occurs relatively commonly in up to 10 % of patients treated. However, as the testing of platelet activity is not widely undertaken, this is rar ely identi \201 ed. 86 CHAPTER 2 Drugs for the heart Contraindications and cautions \200 Contraindications : known allergy, active peptic ulce ration, history of recent GI bleeding, history of recent intracranial bleeding, and bleedin g disorders including hemophilia, von Willebrand \200\231s disease, thrombocytopenia and se vere liver disease. Cautions : asthma, uncontrolled hypertension, previous peptic ulceration (risk of GI bleedi ng; PPIs or H 2 -receptor antagonists may be considered for prophylaxis). Risk factors for GI bleeds with aspirin \200 Age: risk doubles with each decade of life a bove 55 years. \200 Men: risk is twice as high in men as in women. \200 History of GI u lcer, bleed, or perforation. \200 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 \200\224 osteoarthritis, rheumatoid arthritis, chronic low back pain. \200 Presence of H. pylori. \200 Excess alcohol. \200 Heavy sm oking. Strategies to reduce GI bleeding risk with aspirin \200 Prescribe 75 mg daily, unless a h igher dose is indicated. \200 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. \200 Advise smokers to quit or reduce their smoking. \200 Con sider co-prescribing a PPI for those with multiple risk factors. Drug interactions with aspirin \200 Analgesics : avoid concomitant use with NSAIDs as thi s 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. \200 Cytotoxics : aspirin reduces the excretion of methotrexate; avoid concomitant use where possible, or e nsure close monitoring of methotrexate dose. This page intentionally left blank 88 CHAPTER 2 Drugs for the heart Antiplatelet agents: thienopyridines Mode of action Thienopyridines irreversibly block the binding of ADP to platelet recep- tors, and hence prevent expression of the active glycopro tein IIb/IIIa receptor. The \201 rst agent in this class, ticlopidine, has been supersede d in clinical practice by the use of clopidogrel which has fewer serious adverse effects. P rasugrel was launched in 2009, and 2010 saw the introduction of ticagrelor. This page intentionally left blank 90 CHAPTER 2 Drugs for the heart Antiplatelet agents: clopidogrel Clinical trial data In the CAPRIE (Clopidogrel versus Aspi rin 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 cli nical advantage over aspirin for this indication is small and the relative cost is large, c lopidogrel should only be employed for monotherapy in patients who are unable to tolerate a spirin \201 rst 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 ev ents with dual antiplatelet therapy. The COMMIT (Clopidogrel and Metoprolol in Myocardial I nfarction Trial) study (2005) demonstrated that aspirin/clopidogrel dual therapy reduced de ath 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 cardio vascular events in patients post MI or stroke, or with peripheral vascular disease. Clopido grel is also licensed for use in combination with aspirin for patients following acute coro nary 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-e luting) 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 \200\223600 mg should be given as e arly as possible following presentation, and 75 mg daily continued for up to one year; aspi rin should be continued inde \201 nitely. Recent data from CURRENT-OASIS7 (Clopidogrel Opt imal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interv ention) indicate that a higher clopidogrel dose of 150 mg daily may be useful in the \201 rst week of treatment following a STEMI espe- cially 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 thr ombosis. Indications and dosing for clopidogrel See Table 2.2 . ANTIPLATELET AGENTS: CLOPIDOGREL 91 Table 2.2 Indications and dosing for clopidogrel Indications Dosing Clopidogrel monotherapy; 75 mg daily Secondary prevention of CV events in patients post-MI or stroke, or in patients with PAD Usually only in patients unable tolerate aspirin \201 rst line STEMI Use in combination with aspirin \200\224 300 \200\223600 mg at presentation then 75 mg dai ly. Continue for at least 4 weeks post-event (NICE) NSTEMI Use in combination with aspirin \200\224 300 \200\223600 mg at presentation then 75 mg dai ly. Continue for at least one year post-event Post-PCI with stent insertion Use in combination with aspirin \200\224 300 \200\223600 mg as early as possible prior to procedure, then 75 mg daily. Continue for at least: \200 4 weeks post bare metal stent in sertion \200 1 year post drug-eluting stent insertion NICE = National Institute for Health and Clinical Excellence. Contraindications and cautions \200 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 \200\223600 mg loading in the a cute setting or pre- procedure, followed by 75 mg daily thereafter. Early cessation of clopidogrel therapy post-stent insertion is the largest single risk fact or for stent thrombosis, which is associated with signi \201 cant 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 . 92 CHAPTER 2 Drugs for the heart Table 2.3 Risk factors for stent thrombosis Risk factor Hazard ratio P Premature cessation of antiplatelet therapy 89.78 <0.001 Renal failure 6.49 <0.001 Bifurcation lesion 6.43 <0.001 Diabetes 3.71 <0.001 Reduction in LV function by 10 % 1.09 <0.001 Iakovou I, Schmidt T, Bonizzoni E, et al. (2005). Incidence, predictors, and outcome of thr ombosis after successful implantation of drug-eluting stents. JAMA 293 : 2126 \200\22330. Adverse effects \200 The single most troubling adverse effect of clopidogrel is skin rash . Care should be taken to distinguish self-limiting X-ray contrast-media- induced 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 diarrhea, abdominal pain, and dyspepsia. Bleeding and bruising are common, particularly where aspirin and clopidogrel are used in combination. There is a small risk of hematological disorders i ncluding thrombocytopenia and neutropenia. This page intentionally left blank 94 CHAPTER 2 Drugs for the heart Antiplatelet agents: prasugrel Mode of action The pharmacological bene \201 ts of prasugre l over clopidogrel are an earlier onset of anti-aggregatory effects (signi \201 cant antip latelet 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 b y Optimizing Platelet Inhibition with Prasugrel \200\223Thrombolysis in Myocardial Infarct ion) study compared prasugrel to clopidogrel (on a background of aspirin therapy) in patien ts with acute coronary syndrome (ACS) undergoing immediate or delayed PCI, and demonstrated signi \201 - cantly fewer major CV events in the prasugrel-treated group but at the expen se of an increased risk of bleeding. Place in therapy Prasugrel, used in combination with aspirin, is licensed for the preven- t ion of atherothrombotic events in patients with ACS (STEMI, NSTEMI, or unstable angina) und ergoing primary or delayed PCI. Patients with a history of stroke or transient ischaemic at tack (TIA) did worse on prasugrel than on clopidogrel, and as a result this is a contraindi cation to therapy. Low body weight and age above 75 years was also associ- ated with no net clinical bene \201 t and therefore the agent should be used cautiously in this group \200\224 a lower maintenance dose may be employed. Prasugrel is more effective than clopido grel in patients with diabetes. Dosing Prasugrel 60 mg loading dose followed by 10 mg daily thereafter (mainte- nance dose should be reduced to 5 mg daily if used in patients over the age of 75 years or those of lo w body weight, <60 kg). Prasugrel should be continued for a period of one year after the ac ute event. Drug interactions with prasugrel \200 Anticoagulants : concomitant use of clopidogrel wit h warfarin is not routinely recommended due to the increased risk of bleeding; however, in clinical pract ice the use of aspirin, clopidogrel, and warfarin is not uncommon, where patients have comp elling 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 centers are recommending a H 2 antagonist, such as ranitidine, \201 rst line in patients requiring an acid suppressant, except where the be ne \201 ts of PPIs are considered to outweigh the potential risks, for example, patients u ndergoing active ulcer healing. ANTIPLATELET AGENTS: PRASUGREL 95 NICE indications for prasugrel (October 2009) Prasugrel should be considered as an option i n patients undergoing only when: \200 immediate primary PCI for STEMI is planned, or \200 stent thrombosis has occurred during clopidogrel therapy, or \200 the patient has d iabetes mellitus. Contraindications and cautions \200 Contraindications : hypersensitivity, history of CVA or TIA, active bleeding disorder, severe hepatic impairment Cautions : those at increased risk of bleeding \200\224 over 75 years and body weight <60 kg, renal impairment and moderate hepatic impairment, Asian patients (due to limited clinic al 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 \200 Bleeding occurs commonly and is particularly problemati c in the elderly ( > 75 years) or patients of low body weight (<60 kg) \200\224 a lower maintenance dose may be considered in these groups. Anemia, epistaxis, GI hemorrhage, haematuria are all commonly reported. Rashes. Drug interactions with prasugrel No signi \201 cant drug interactions have been identi \201 ed. 96 CHAPTER 2 Drugs for the heart Intravenous antiplatelet agents Glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitors Abci ximab, a monoclonal antibody, is indicated for the prevention of ischaemic cardiac complica tions in patients undergoing PCI and for patients presenting with unstable angina who are s cheduled to undergo PCI. Small-molecule GPIIb/IIIa receptor inhibitors, epti \201 batide or tiro \201 ban are indi cated for the prevention of early MI in patients presenting with STEMI or unstable angina. Recommendations for use of GPIIb/IIIa inhibitors Adapted from the European Society of Cardi ology (ESC) guidelines for the management of NSTE-ACS. \200 In patients with ACS at inter mediate or high risk, particularly patients with elevated troponins, ST depression, or diab etes, either epti \201 batide or tiro \201 ban is recommended, in addition to oral antipl atelet agents, for initial early treatment. Patients who received initial treatment with epti \201 batide or tiro \201 ban prior to a ngiography, 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. \200 Bivalirudin may be use d as an alternative to GPIIb/IIIa inhibitors plus unfractionated heparin/low molecular weig ht heparin (UFH/LMWH). \200 When coronary anatomy is known and PCI planned to be performe d within 24 hours with use of GPIIb/IIIa inhibitors, the most secure evidence is for abcixi mab. This page intentionally left blank 98 CHAPTER 2 Drugs for the heart Angiotensin-converting enzyme inhibitors (e.g. captopril, enalapril, lisinopril, ramipril, perindopril) Mode of action Angiotensin-converting enzyme inhibitors (ACE-Is) block the conversion of an giotensin 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 lea d to vasodilatation and prevent the build up of \202 uid that would result from aldostero ne release. Clinical trial data ACE-Is are supported by a wealth of clinical trials data across a range of indications including: \200 Hypertension : numerous clinical studies con \201 rm the blood pressure lowering ef \201 cacy 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 Lisin opril and Survival) 1999, lisinopril). Meta-analyzes 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 Ef \201 cacy) 1994, ramipril; GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza n ell 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 \201 rst four to six weeks post-MI. In the longer term, mortality is reduced by 1 3 % in unselected patients, with greater bene \201 ts in those with post-MI heart failure. Long-term follow-up of the SOLVD study showed a signi \201 cant reduction in all-cause mo rtality associated with ACE-I treatment, even at 12 years post index event. CV risk reduction (HOPE (Heart Outcomes Prevention Evaluation) 1999, ramipril; EUROPA (Euro pean Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Diseas e) 2004, perindopril). ACE-Is have been shown to reduce the risk of CV events in patients w ho 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 indi- c ations. It is recommended that a licensed agent, with trial evidence to support its use, is chosen for the indication being managed. Dose \200 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 prot ection. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS 99 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 m aximal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dysfunction, etc.). Compelling indications for ACE-I use \200 Hypertension : all non-black patients <55years old \200 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 CV risk reduction : all patients with symptomatic or asymptomatic CVD. Contraindications and cautions \200 Contrainidications : aortic/mitral stenosis \200 angioedema (any cause) \200 hypersensitivity to ACE-Is \200 bilateral renal artery stenosis \200 pregnancy. Cautions : hypotension (systolic blood pressure <90 mmHg) \200 Patients on high-dose diuretics (i.e. furosemide > 80 mg daily) \200 Breast-feeding \200 Moderate to severe renal impairment (i.e. creatinine > 150 mol/L or estimated glomerular \201 ltration rate (eGFR)<60 mL/m in/1.73 m 2 ) \200\224 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 Agent Starting dose Target dose Enalapril 2.5 \200\2235 mg daily 40 mg daily (dose may be divided) Lisinopril 2.5 \200\22310 mg daily depending on indication 35 \200\22380 mg daily Perindopril 2 \200\2234 mg once daily 4 \200\2238 mg daily depending on indication Ramipril 1.25 \200\2232.5 mg daily 10 mg daily (dose may be divided) 100 CHAPTER 2 Drugs for the heart Monitoring \200 Obtain baseline BP and urea and electrolytes (U&Es) before initiation \200 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: \200 systolic blood pressure > 90 mmHg \200 ser um 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 \202 uid intake Reduce dose if K + > 5.5 mmol/L; withdraw ACE-I if K + > 6 mmol/L. Dealing with adverse effects \200 First-dose hypotension : use a long-acting agent, avoid excessive diuresis prior to initiation. First dose may be given at night before bed to red uce the risk of hypotension and associated falls. Dry cough : may dissipate over time if patient persists with therapy. If troublesome, withd raw agent and re-introduce the same or an alternative ACE-I. Consider an angiotensin recept or 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. Rash : switch ACE-I and if rash persists consider ARB. Key drug interactions with ACE-Is \200 Ciclosporin : increases risk of hyperkalaemia \200 Diuretics : enhances hypotensive effect \200 Lithium : increases lithium levels \200 Potassium supplements : increased risk of severe hyperkalaemia. This page intentionally left blank 102 CHAPTER 2 Drugs for the heart Angiotensin receptor blockers (ARBs, also referred to as angiotensin II receptor antagonist s, AIIRAs) (candesartan, irbesartan, losartan, telmisartan, valsartan) Mode of action Angiotensin receptor blockers (ARBs) bind to the angiotensin II recep- tors and therefore block the action of angiotensin II. Angiotensin II is a potent vasoconstricto r and promotes the production of aldosterone, which increases sodium and water retention. A CE-Is therefore lead to vasodilatation and prevent the build up of \202 uid that would re sult from aldosterone release. Unlike ACE-Is the ARBs do not inhibit the break- down of bra dykinin that is responsible for ACE-I-induced cough. Clinical trial data ARBs are supported by fewer clinical trials than ACE-Is, but do have da ta across a range of indications including: \200 Hypertension : numerous clinical studies con \201 rm the blood-pressure- lowering ef \201 cacy of ARBs. Heart failure : con \202 icting data emerged from early studies, but CHARM (Candesartan in Heart Failure \200\224 Assessment of Mortality and Morbidity) con \201 rmed that candesartan reduced the risk of CV mortality or CV hospitalization in patien ts with HF, alone or in addition to ACE-I therapy, and with or without concurrent B -blocke r therapy. (ELITE-II (Evaluation of Losartan in the Elderly, 2000, losartan; ValHeFT (Valsa rtan Heart Failure Trial), 2001, valsartan; CHARM, 2006, candesartan) Post-MI heart failure : valsartan 160 mg bd was non-inferior to captopril in protecting aga inst death and CV event in patients with post MI heart failure (VALIANT (Valsartan in Acute Myocardial Infarction Trial), 2003) * CV risk reduction \200\224 telmisartan 80 mg daily was non-inferior to ramipril 10 mg dail y in protecting against CV events in patients with CV disease (ONTARGET (Ongoing Telmisarta n Alone and in combination with Ramipril, 2008) * . 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 fo r the indication being managed. Note: in these and other studies where ACE-Is and ARBs have been combined in one of the tre atment arms, there has been an increase in adverse events (renal dysfunction, symptomatic h ypotension, hyperkalaemia), with no demonstrable improvement in outcomes, with the exceptio n of the CHARM study. Therefore, the use of an ACE-I and ARB in combination should generall y be avoided. ANGIOTENSIN RECEPTOR BLOCKERS 103 Dose \200 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 maxi mal tolerated dose if the target dose cannot be achieved (i.e. due to hypotension, renal dy sfunction etc.). Compelling indications for ARB use \200 Hypertension : second line to ACE-I (i.e. ACE-I-i ntolerant 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