CHAPTER 14 Cardiac catheterization 578 Physiological assessment of coronary \202 ow The shortcomings of coronary angiography in the physiological assessment of coronary stenosis are clear. Intravascular ultrasound can p rovide infor- mation on the size of the lumen and the composition of plaque, but again give s no information on the effect that an atheromatous plaque may have on coronary \202 ow. The knowledge as to whether a narrowing seen on angiography is the culprit causing hemodyna mic effects, and thus anginal symptoms, is valuable when guiding percutaneous intervention. The fractional \202 ow reserve (FFR) correlates distal coronary pressure to myocardial bl ood \202 ow during maximum hyperemia (induced by infusion of adenosine, or papaverine). F FR is de \201 ned as maximum myocardial blood \202 ow in the presence of a stenosis divi ded by the theoretical maximum \202 ow in the absence of a stenosis (see Fig. 14.13). Thus the information derived from FFR allows an \200\234on-the-spot \200\235 diag- nosis o f the extent to which a given stenosis contributes to myocardial ischemia (and angina), and can guide decisions regarding revascularization. At present, the best established indicati on for coronary FFR estimation is as a diagnostic tool to assess \200\234severe \200\235 c oronary stenosis, and for this it is extremely sensitive when used with a cutoff point of 0 .75. The technique has also been used to optimize the results of stent implantation. Two technologies are currently available that provide hemodynamic information derived from FFR calculations; these are pressure wires (which consist of a pressure transducer mounted on a 0.014 \200\235 guide wire), and Doppler \202 ow wires (which examine coronary \202 ow velocities using spectral analysis). Pressure wire, e.g., the PressureWire \204 (Radi Medical Systems, Volcano Medical Systems) \200 The pressure transducer is located at the transition between the radiopaque wire tip and th e nonradiopaque stem. The analyzer shows simultanous aortic and intracoronary pressure, as well as instantaneous FFR. Doppler wire, e.g., FlowWire \204 (Endosonics) \200 This obtains information on coronary \202 ow velocity in the central area of the arterial lumen. Combining \202 ow and ECG information, it calculates systolic and diastolic compo nents of \202 ow velocity at baseline. Following induction of hyperemia, the machine can calculate the coronary \202 ow velocity reserve. PHYSIOLOGICAL ASSESSMENT OF CORONARY FLOW 579 Q Pa 100 Pd 100 Pv 0 P Pd 100 Pv 0 Pa 100 Pd FFRmyo = = 0.70 Pa Figure 14.13 During maximal arteriolar vasodilatation, the resistance of the myocardium is minimal, and so maximum myocardial blood \202 ow is proportional to hyperemic perfusion p ressure. This equals Pd \210\222Pv. As there is no decline in pressure along a normal coron ary artery, and neglecting Pv, this implies that in a normal epicardial artery, perfusion p ressure at hyperemia equals Pa. In the presence of a stenosis, hyperemic perfusion pressure decreases to Pd (after the stenosis). Thus the maximum \202 ow in the presence of a sten osis as a ratio (fraction) of normal maximum \202 ow is represented by the ratio of perfu sion pressures: Pd/Pa. This fraction of normal maximum \202 ow, which is maintained despi te the stenosis, is called the fractional \202 ow reserve (FFR). Reproduced with permissi on from Pijls NH (2004). Heart 90(9):1085 \200\2231093. CHAPTER 14 Cardiac catheterization 580 Primary angioplasty for STEMI Pathophysiology In the context of cardiac chest pain, ST segm ent elevation on the 12 lead ECG usually signi \201 es complete occlusion of a proximal ep icardial coronary artery. This occurs as a result of rupture or erosion of a vulnerable ath ero- matous plaque, which leads to platelet activation and adhesion, formation of platelet- rich (white) thrombus, \201 brin deposition, and red cell entrap- ment (forming red throm bus). If untreated, myocardial necrosis commences within 30 minutes, affect- ing full myocardial thickness within 6 hours; 30% of patients die before reaching the hospital. Treatment Urgent restoration of coronary blood \202 ow (reperfusion) prevents further LV damage and improves prognosis (Box 14.6). The amount of myocar- dium that can be salvaged f alls exponentially with time, with the greatest bene \201 t within 3 hours following sympt om onset, and little bene \201 t after 12 hours. Primary angioplasty is the preferred reperfusion strategy, where angiography can be perform ed within 90 minutes of presentation. Patients can be transferred safely (by a trained ambulance crew with an ACLS trained escort ) from a community hospital to a cardiac center for primary angioplasty. Box 14.6 Options for reperfusion Primary angioplasty Immediate coronary arteriography, culprit vessel angioplasty, and stent implantation without antecedent \201 brinolysis achieves full arterial patency (TIMI gra de 3 \202 ow) in 90% \200\22395%, treating the occlusive thrombus and the culprit plaque. Intravenous \201 brinolysis Immediate administration of a \201 brinolytic agent (also c alled thrombolysis) without planned coronary arteriography achieves full arterial patency ( TIMI grade 3 \202 ow) in 50% \200\22360%. It is contraindicated in up to 30% of patients and does not treat the culprit plaque. Rescue angioplasty Urgent coronary arteriography, culprit vessel angioplasty, and stent imp lantation are performed when \201 brinolysis has failed to achieve reperfusion (persisten t ST-segment elevation 9 pain at 60 \200\22390 minutes). PRIMARY ANGIOPLASTY: PROCEDURE 581 Primary angioplasty: procedure Indications \200 \200 Cardiac chest pain <12 hours (e.g., see Fig. 14.14) ST Elevation (cid:116)1 mm in 2 contiguous leads and/or new LBBB Contraindications \200 \200 Suspected aortic dissection Major contraindication to anticoagulation therapy Relative contraindications \200 Active bleeding (antiplatelet therapy may have to be avoided but may compromise outcome. Th ese cases should be discussed directly with the operator). Pre-procedure (work quickly \200\224minutes matter) \200 \200 Consent Basic blood work including CBC, chemistries, type and cross, cardiac biomarkers Oxy gen if saturations <94% Aspirin 325 mg (chewed) Systemic anticoagulation (i.e., heparin, bi valirudin) Platelet glycoprotein gpIIb/IIIa receptor antagonist (abciximab) is indicated wh en heparin alone is used and as a bailout option in cases where bivalirudin is used and the re is a signi \201 cant thrombus burden, non-re \202 ow, and high risk of vessel closure. Access \200\224femoral or radial. The femoral region should always be prepared in case of need for transvenous pacing or intra-aortic balloon pump (IABP) insertion. Diagnostic angio gram should be performed to identify the culprit vessel. Angioplasty should then performed. \200 \200 \200 Additional considerations \200 Culprit-vessel PCI is a Class I indication. PCI to a non-infarct-related artery is Class II I and should be deferred for a later time (typically >24 hours). Procedural success is de \201 ned by TIMI grade 2 or 3 \202 ow with residual stenosis <30%. CHAPTER 14 Cardiac catheterization 582 (a) (b) stent LAD occluded Figure 14.14 Angiographic images from a 54-year-old male presenting with chest pain and ant erior ST elevation. (a) The left anterior descending (LAD) artery is occluded mid-vessel (a rrow). (b) The same artery now widely patent following primary angioplasty; a 3.5 x 24 mm b are metal stent has been implanted (arrow). The patient sustained minimal left ventricular damage and was discharged 48 hours later. INVASIVE ASSESSMENT OF VULNERABLE PLAQUE 583 Invasive assessment of vulnerable plaque It has become apparent from intravascular ultrasou nd studies that non- obstructive and hemodynamically insigni \201 cant atherosclerotic pla ques can be responsible for sudden death due to myocardial infarction. These high- risk, or \200\234vulnerable, \200\235 plaques are left untreated, as it is unclear which will prog ress to rupture. Angiography does not help differentiate between sta- ble and vulnerable pl aques, thus new technologies have been developed to assist in the identi \201 cation of th ese plaques. Histopathological correlates of vulnerable plaque \200 \200 \200 \200 Lipid-rich core Thin \201 brous cap Necrotic core High degree of macrophage in \201 ltra tion Intravascular ultrasound \200 Able to discriminate plaques with low (lipid) and high ( \201 brous) echodensity Able to i dentify the capsule Able to identify areas of rupture within the plaque In combination with image analysis, information regarding the tissue types imaged can be derived to provide a histological map of the plaque. \200 \200 Optical coherence tomography (OCT) \200 This is similar in principle to intravascular ultrasound, but uses light instead of sound w aves. The system has high axial resolution, down to 20 m. At present, useful anatomical i nformation can be obtained by this technique, but this is yet to be correlated with functio nal data. \200 Intravascular elastography \200 \200 This technology uses sound waves in a similar way to IVUS. Images are based on radial strai n, and the system is therefore able to help differentiate soft from hard material. Plaque r upture is often seen to occur in areas of increased strain, such as at the edge of plaques. CHAPTER 14 Cardiac catheterization 584 Complex coronary angioplasty Chronic total occlusion Chronic total occlusion (CTO) is de \201 ned as a completely occluded coron- ary artery, with the occlusion being known to have been present for >3 months. The age and length of the occlusion are the main determinants of success of PCI (e.g., see Box 14.7). The objectives in treating CTOs per- cutaneously ar e as follows: \200 Crossing of the total occlusion with a guide wire and advancement of this wire into the dis tal vessel (inability to cross with the guide wire is the reason for failure in 50% of atte mpts at CTO PCI) Dilatation of the underlying occlusion Preservation of the newly recanaliz ed lumen by the implantation of a stent and by pharmacological means \200 Techniques that may improve success \200 Aggressive guide catheter support, including deep cannulation of the coronary artery Over-t he-wire balloon to support the guide wire as it is advanced against the CTO Stiffer guide w ires that require greater forces to de \202 ect the tip and may be more successful in pene trating the \200\234cap \200\235 of the CTO. Great care must be taken with guide wires of this nature, as there is risk of perforation of the target vessel. Unfortunately, if the lumen is recanalized, the rates of reocclusion are high, even when th e CTO is stented. Bifurcation lesions A simple de \201 nition of bifurcation lesions can be the involvement of a side branch with a reference diameter >2 mm in the stenosis. IVUS studies show that pl aque in the main vessel almost invariably extends some dis- tance into side branches that a rise within the plaque. Furthermore, angi- oplasty to a plaque will often cause plaque shif t (the so-called snow plow effect) into the daughter vessel. Unless \202 ow in the side branch was severely impaired, or the ostium severely narrowed, during the treatment of the main vessel, a single-stent technique is preferable to the use of two stents. This is the so-called pro- visional stenting technique (see Fig. 14.15). Dilating with a balloon through the stent struts carries the risk of deforming the distal p arts of the stent and failure of adequate apposition of stent to vessel wall. This carries a high risk of thrombosis and restenosis, thus a \201 nal \200\234kissing \200\235 ballo on should be employed. Recent data on the use of DES in the treatment of bifurcations suggest that implantation of DES reduces the restenosis and reintervention rates after bifurcation lesion treatment. COMPLEX CORONARY ANGIOPLASTY 585 Box 14.7 What makes angioplasty complex? \200 \200 \200 \200 Increased risk of procedural failure Suboptimal result likely Complication rate higher Wors e long-term outcome (death, MI, repeat procedure) Patient characteristics \200 \200 \200 \200 \200 Clinical presentation \200\224acute vs. stable Diabetes Body habitus Signi \201 cant comor bidity Access problems \200\224peripheral vascular disease Lesion characteristics \200 Lesion characteristics, e.g., long, calci \201 ed, bifurcation, left main stem, chronic to tal occlusions Dif \201 cult anatomy 1 2 5 7 8 1 1 1 1 or 2 2 2 2 1 or 2 Skirt technique 3 4 9 11 1 2 1 1 2 1 1 1 6 10 1 1 1 2 2 2 2 Figure 14.15 Methods of treating bifurcation lesions. The numbering refers to the order in which the stents are deployed. All of these methods have been tried, but recent data sugges t that the provisional stent technique (part 5) produces the best results. Adapted with per mission from Louvard Y, et al. (2004). Heart 90(6):713 \200\223722. CHAPTER 14 Cardiac catheterization 586 Left main stem angioplasty AHA/ACC/ESC guidelines suggest that patients with stenosis of th e left main coronary artery should be offered bypass graft surgery. However, the registry d ata for both bare metal stents and, more recently, drug- eluting stents have suggested that PCI to the left main stem (LMS) in patients with suitable LMS anatomy achieves acceptable results with low rates of procedural complication and long-term vessel patency. Nonetheless , it remains a Class III indication to perform LM PCI. The advent of drug-eluting stents and the reality of lower rates of in-stent restenosis wit h DES than with BMS have further changed the approach of many interventional cardiologists to this previously taboo subset. In patients treated electively for LMS stenosis, reference vessel size and left ventricular function appear to be the strongest predictors of favorab le outcome. Patient groups in whom LMS PCI may be appropriate Emergency LMS PCI \200 Bailout PCI after complications involving the LMS Elective LMS PCI \200 Patients considered to high risk to undergo CABG, but with continuing angina Patients who r efuse surgery Younger patients with favorable LMS anatomy (i.e., not ostial disease, not sh ort LMS) \200 Optimization of results of LMS PCI Nothing less than an excellent angiographic result shoul d be accepted. Intravascular ultrasound may be used both pre-procedure to ascertain the tru e vessel diameter and post-procedure to ensure that stents have been adequately deployed. LMS bifurcations may be approached using the techniques described before. There is emerging evidence that the use of DES in the LMS bifurca- tion results in improved clinical outcome s. Most operators routinely reexamine the LMS by angiography 6 \200\2239 months after PCI to look for restenosis. ADJUNCTIVE THERAPY FOR ANGIOPLASTY AND STENTING 587 Adjunctive therapy for angioplasty and stenting Aspirin The bene \201 cial effect of aspir in during PCI has been shown in multiple trials, in which treatment with aspirin and dipyri damole was superior to placebo in the prevention of periprocedural Q-wave MI. Subsequent studies have shown that dipyridamole added nothing to the bene \201 cial effect s provided by aspirin. Aspirin (usually 325 mg once daily), initiated at least 24 hours pri or to procedure, is recommended in patients undergoing elective PCI. Thienopyridines Clopidogrel and ticlopidine are thienopyridine derivatives that inhibit pla telet function independent of aspirin by interference with the platelet ADP receptor. Early studies showed that a dual antiplatelet therapy with aspirin and ticlopidine was superior to aspirin alone. The use of ticlopidine is limited by its side effects, including severe n eutropenia. Clopidogrel, a newer thienopyridine, with a safer side-effect pro \201 le, has thus become the agent of choice. The PCI-CURE study showed that pre-treatment with clopidogrel (300 mg loading dose, followed by 75 mg daily) in addition to aspirin for a median of 10 days befo re percutaneous coronary intervention, compared with aspirin alone, reduced the compos- ite of cardiovascular death, myocardial infarction, or urgent target vessel revascularization by 30% after 1 month. Most centers have adopted the policy of high loading dose clopidogrel (600 mg 2 \200\2234 hours pre-PCI) if the patient has not been preloaded. Heparin Although there is general agreement that patients undergoing PCI should receive hep arin before the intervention, there remains controversy regard- ing the issue of optimal he parin dosage. An inverse relation between the level of anticoagulation (measured by activat ed clotting time [ACT]) and the occurrence of acute ischemic complications has been observe d. However, longer ACTs are associated with higher bleeding risks. Currently, an ACT of 250 \200\223300 seconds is recommended for patients undergoing PCI. Lo w-molecular-weight heparin (enoxaparin) has been shown to be effective in PCI, although it has not yet replaced unfraction- ated heparin in routine use. Glycoprotein IIb/IIa inhibitors The \201 nal common pathway for platelet aggregation is m ediated by the platelet glycoprotein (gp) IIb/IIIa receptor. Trials in both diabetics and n ondiabetics undergoing percutaneous transluminal coronary angioplasty have found that the c ombination of stenting and a gpIIb/IIIa inhibitor reduces cardiovascular morbidity and mort ality compared with stent plus placebo. CHAPTER 14 Cardiac catheterization 588 Bivalirudin Bivalirudin is a direct thrombin inhibitor that exerts its activity by speci \201 - cally and reversibly interacting with circulating (inactive) and clot-bound (active) thrombin. Clinical trials in patients with stable or unstable angina or acute myocar- dial infarction (Replace, Acuity, Horizons) who received bivalirudin in PCI have demonstrated similar bene \201 ts to the combination of abciximab and heparin, with a reduced risk of clinically si gni \201 cant blood loss. EMBOLIC PROTECTION DEVICES 589 Embolic protection devices The distal embolization of particulate matter that lodges in the microcir- culation (e.g., plaque debris, thrombus, and \201 brin) during balloon in \202 ation and stent deployment is becoming increasingly recognized as a cause of suboptima l results after PCI. Distal embolization leads to poor \202 ow in the proximal vessel und ergoing intervention due to occlusion of distal micro- vasculature, the \200\234no-re \202 ow \200\235 phenomenon. Vein grafts, and thrombotic lesions are now recognized as being par- ticularly prone to com plications arising from distal embolization, which is seen in up to 30% of vein grafts (the se often contain thrombus at the time of PCI). Hence the use of distal protection devices s hould be considered in these angioplasty subsets. Devices for distal protection Devices can be broadly split into those that occlude the cond uit distally and then allow aspiration of debris, or distal \201 lters that capture debri s downstream. Balloon occlusion devices \200 PercuSurge GuardWire. This consists of three parts: 1. The GuardWire temporary occlusion ca theter, which is placed distally in the vessel to allow occlusion. 2. The MicroSeal adapter, which allows control over the in \202 ation and de \202 ation of the balloon. 3. The Export aspiration catheter, which allows collected debris to be aspirated into a 20 mL syringe. One of the main disadvantages of this system is that the target vessel is temporarily occlu ded, thus the distal myocardium may be rendered ischemic. Filter devices \200 AngioGuard. This device consists of an angioplasty guide wire with an expandable \201 lte r at the distal tip. The \201 lter can be expanded once the target lesion has been crosse d. Anterograde blood \202 ow in the vessel is maintained, and displaced debris should the oretically be collected in the \201 lter. The \201 lter is then collapsed and withdrawn into the retrieving catheter. FilterWire EZ \204 (Fig. 14.16). This device consists of a \200\234 \201 sh mouth \200\235 opening distal \201 lter, mounted on an angioplasty gui de wire. The \200\234mouth \200\235 of the \201 lter in theory expands to \201 ll the entire lumen of the vessel. The \201 lter is deployed by withdrawing a delivery sheath, a nd collected into a retrieval sheath. Limitations of distal protection devices \200 Crossing pro \201 le may cause distal embo lization \200 Incomplete \201 lter apposition or incomplete conduit occlusion \200 La ck of protection of side branches \200 Distal ischemia in balloon occlusion devices CHAPTER 14 Cardiac catheterization 590 Figure 14.16 FilterWire EZ \204 . Reproduced with permission from Boston Scienti \201 c. THROMBECTOMY 591 Thrombectomy In the context of the limitations of distal protection devices, devices that c an aspirate particulate debris and thrombus proximally have been developed. Transluminal extraction catheter (TEC) This is a rotational cutting device. However, the bl ades are not protected, thus limiting use in native coronary arteries. Export catheter This aspiration catheter allows collected debris to be aspirated into a 20 mL syringe. The Angiojet This device relies on the Venturi effect produced from backward-directed \202 uid jets. These jets create vortices and areas of low pressure that cause debris dista l to the catheter to be drawn in and aspirated. CHAPTER 14 Cardiac catheterization 592 Mitral valvuloplasty In carefully selected patients with mitral stenosis, percutaneous ball oon mitral valvuloplasty (PMV) (see Fig. 14.17) is now the treatment of choice, according t o the American Heart Association and American College of Cardiology: In centers with skilled, experienced operators, PMV should be consid- ered the initial proc edure of choice for symptomatic patients with mod- erate to severe mitral stenosis who have favorable valve morphology in the absence of signi \201 cant mitral regurgitation or left atrial thrombus. In asymptomatic patients with favorable valve morphology, PMV may be con- sidered if there is evidence of a hemodynamic effect on left atrial pressure (new-onset at rial \201 brillation) or pulmonary circulation (pulmonary artery pressure >50 mmHg at res t or 60 mmHg with exercise).1 Case selection Careful case selection is paramount. The factors that must be considered are described below. Age Older patients seem to have poorer outcomes in PMV. This outcome is likely related to v alve morphology in this group instead of age per se. In patients in whom surgery of the mit ral valve is contraindicated (e.g., extreme age, signi \201 cant comorbidity), adequate re sults can be obtained even in the presence of suboptimal valve morphology. Valve morphology A valve scoring system (an echocardiogram-based evaluation of valve cal- c i \201 cation and anatomy) is used to assess the valves suitability for PMV: lea \202 et mobility, lea \202 et thickening, valve calci \201 cation, and involvement of the subvalv ular apparatus. Each parameter evaluated receives from 0 (none) to 4 (severe). Studies have shown that patients with a valve score of (cid:100)8 consistently achieve supe rior and more sustained results from the procedure than patients with scores >8. Mitral regurgitation The presence of signi \201 cant mitral regurgitation is a contraindic ation to PMV. Left atrial thrombus This is a contraindication to PMV. Patients in AF should have been ful ly anticoagulated for a period of 4 \200\2236 weeks prior to the procedure. Pregnancy PMV can be performed in pregnancy. Radiation risk to the fetus is reduced after 1 4 weeks. 1 Bonow RO, et al. (2008). J Am Coll Cardiol 52(13):e1 \200\223142. MITRAL VALVULOPLASTY 593 Complications of mitral valvuloplasty \200 \200 \200 \200 Mitral regurgitation Pericardial tamponade Thromboembolic events Iatrogenic ASD Figure 14.17 Balloon mitral valvuloplasty. The upper panel shows the balloon partly in \202 ated across the mitral valve, demonstrating the typical dumb-bell shape. As the in \202 ation pressure and volume are increased, the stenosed valve dilates (lower panel). CHAPTER 14 Cardiac catheterization 594 Glossary of terms and abbreviations Bifurcation: A bifurcation lesion involving a main vess el and a side branch or a main vessel. Binary angiographic restenosis (BAR): Greater than 50% luminal narrow- ing on follow-up ang iogram. Canadian Cardiovascular Society (CCS) Angina Classi \201 cation 1. No chest pain. No limit ation of physical activity by pain. Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina with strenuous, rapid, or prolonged exertion at work or recreation. 2. Slight limitation of ordinary activity. Walking or climbing stairs rapidly, walking up h ill, walking or stair climbing after meals, in cold, in wind, or when under emotional stres s or during the \201 rst few hours after awakening may cause pain. Walking more than two blocks on the level and climbing more than one \202 ight of stairs at a normal pace and i n normal conditions. 3. Marked limitation of ordinary physical activity. Walking 1 \200\2232 blocks on a level a nd climbing one \202 ight of stairs at normal pace results in angina. 4. Inability to carry on any physical activity without discomfort. Anginal syndrome may be present at rest. Chronic occlusion: An occlusion presumed to have been present for at least 1 month prior to the procedure. Culprit (target) lesion revascularization (CLR/TLR): Repeat revasculari- zation of a culpri t lesion in the target vessel. In-segment: The portion of coronary artery located either within the mar- gins of the stent or 5 mm proximal or distal to the stent. In-stent: The portion of coronary artery located within the margins of the stent. IVUS: Intravascular ultrasound. Late lumen loss: Post-procedural minimum lumen diameter minus fol- low-up minimum lumen dia meter. Minimum luminal diameter (MLD): The average of two orthogonal views (when possible) of the narrowest point within the area of assessment \200\224in lesion, in-stent, or in-segment. National Heart Lung and Blood Classi \201 cation System A Minor radiolucencies within the lumen during contrast injection with Institute (NHLBI) Dissection no persistence after dye clearance. B Parallel tracts or double lumen separated by a radiolucent area during contrast injection with no persistence after dye clearance. C Extraluminal cap with persistence of contrast after dye clearance from the lumen. GLOSSARY OF TERMS AND ABBREVIATIONS 595 D Spiral luminal \201 lling defects. E New persistent \201 lling defects. F Non-A \200 \223E types that lead to impaired \202 ow or total occlusion. Percutaneous coronary intervention (PCI): Refers to all interventional cardiology methods f or treatment of coronary artery disease. QCA: Quantitative coronary analysis. QIVUS: Quantitative intravascular ultrasound. Reference vessel diameter (RVD): The mean of two angiographic meas- urements that are deriv ed by interpolation at the target lesion. Subtotal occlusion: TIMI grade I, and with collateral \201 lling of the distal segment. Target lesion revascularization (TLR): Repeat PCI or CABG to the tar- get lesion (culprit l esion). Target vessel revascularization (TVR): Repeat PCI or CABG to the tar- get vessel (culprit v essel), inclusive of target lesion. TIMI \202 ow grade 0 No contrast \202 ow through the stenosis. 1 A small amount of cont rast \202 ows through the stenosis but fails to fully opacify the vessel beyond. 2 Contrast material \202 ows through the stenosis to opacify the terminal vessel segment. However, contrast enters the terminal segment per- ceptibly more slowly than more proximal segments. 3 Antegrade \202 ow into the terminal coronary vessel segment through a stenosis is as pr ompt as antegrade \202 ow into a comparable segment proximal to the stenosis. Total occlusion: An occlusion with no antegrade \201 lling of contrast to the distal segm ent (TIMI grade 0). CHAPTER 14 Cardiac catheterization 596 Further reading Andersen HR, Nielsen TT, Rasmussen K, et al. (2003). A comparison of coronary angioplasty w ith \201 brinolytic therapy in acute myocardial infarction. N Engl J Med 349:733 \200\223742. Keeley EC, Boura JA, Grines CL (2003). Primary angioplasty vs. intravenous thrombolytic the rapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 361:13 \200\22320. Widimsky P, Budesinsky T, Vorac D, et al. (2003). Long distance transpo rtation for primary angio- plasty vs. immediate thrombolysis in acute myocardial infarction . Final results of the randomized national multicentre trial-PRAGUE-2. Eur Heart J 24:94 \200\223104. 597 Chapter 15 Major trials in cardiology EPISTENT 615 ENHANCE 615 EUROPA 616 FRISC 616 FRISC II 617 GISSI-I 617 GISSI-2 617 GISSI-3 618 GISSI- PURSUIT 633 RACE 634 RALES 634 RAVEL 635 REVERSAL 635 RITA-2 636 SAFE T 636 SAPPHIRE 637 SA VE 637 SIRIUS 638 SOLVD 638 SSSS (4S) 639 TAXUS 639 TIMI 1 640 TIMI 2A 640 TIMI 2B 640 TIMI 3A 641 TIMI 3B 641 TIMI 4 641 TIMI 5 641 TIMI 6 641 TIMI 7 641 TIMI 8 641 TIMI 9A 642 TIMI 9B 642 TIMI 10A 642 TIMI 10B 642 TIMI 11A 642 TIMI 11B 642 TIMI 12 642 TIMI 14 642 TIMI 15 A 642 TIMI 15B 642 TIMI 16 643 TIMI 17 643 TIMI 18 643 TIMI 22 643 TIMI 28 ACUITY 598 ADMIRAL 598 AFCAPS/ TexCAPS 598 AFFIRM 599 AHEFT 599 AIRE 600 AIREX 600 ALLHAT 601 ASCOT-LLA 601 ASSENT-1 602 ASSENT-2 602 ASSENT-3 and ASSENT-3 PLUS 603 Prevenzione 618 GUSTO-1 619 GUSTO IV-ACS 619 HOPE 620 HORIZONS- AMI 620 BARI 603 CADILLAC 604 CAMIAT 604 CAPRIE 605 CAPTURE 605 CARE 605 CARE HF 606 CARMEN 606 CHA RM 607 CIBIS 607 CIBIS II 607 COMET 608 COMPANION 608 COPERNICUS 609 COURAGE 609 CREDO 610 CTOPP 610 CURE 611 DANAMI 611 DANAMI II 612 DAVID 612 DIAMOND 613 DIG 613 DIGAMI 613 DINAMI T 614 EMIAT 614 EPILOG 614 HPS 621 ICTUS 622 ISAR REACT 622 ISIS-1 623 ISIS-2 623 ISIS-3 624 ISIS-4 624 JUPITER 624 LI FE 625 LIPID 626 MADIT 626 MADIT II 626 MERIT-HF 627 MICRO-HOPE 627 MIRACL 627 MIRACLE 628 MIRACLE ICD 628 MOST 629 MUSTIC 629 MUSTT 630 OPTIMAAL 630 PASE 630 PCI-CURE 631 PRAGUE Tri als 631 PRISM 632 PRISM PLUS 632 PROGRESS 633 CLARITY 644 VANQWISH 644 V-HEFT II 645 WOSCOPS 645 CHAPTER 15 Major trials in cardiology 598 Bivalirudin for Patients with Acute Coronary Syndromes ACUITY Purpose: To evaluate treatment with heparin plus glycoprotein inhibition compared with biva lirudin with or without gpIIb/IIIa inhibition among patients with acute coronary syndromes. (gp) IIb/IIIa Follow-up: 1 year Results: Treatment with bivalirudin alone was associated with a reduction in the net clinic al bene \201 t end point compared with UFH/Enox plus gpIIb/IIIa inhibitors, driven primari ly by a reduction in bleeding. Major bleeding was signi \201 cantly lower in the bivalirud in alone group than in the heparin plus gpIIb/IIIa group (3.0% vs. 5.7%, p < 0.001 for supe riority), and was noninferior but not superior for the comparison of bivalirudin plus gpIIb /IIIa inhibitor with the UFH/Enox plus gpIIb/IIIa group (5.3% vs. 5.7%, p = 0.001 for nonin feriority). Reference: Stone GW, et al. (2006). N Engl J Med 355: 2203 \200\2232216. ADMIRAL Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute a nd Long-term follow-up Purpose: To demonstrate the superiority of abciximab over placebo in primary PTCA with sten ting in 300 patients with acute myocardial infarction of <12 hours symptom onset. Patients were given unfractionated heparin, aspirin, and ticlopidine prior to randomization. Coronar y angiography was performed at the time of randomization, 24 hours later, and at 6 months. Follow-up: 30 days and 6 months Results: Abciximab in conjunction with primary stenting improved early TIMI 3 \202 ow rat e, left ventricular function and 30-day mortality, recurrent MI, and rates of any revascula rization. There was excess minor bleeding in the abciximab group. Reference: ADMIRAL Investigators (2001). N Engl J Med 344: 1895 \200\2231903. AFCAPS/ TexCAPS Airforce/Texas Coronary Atherosclerosis Prevention Study Purpose: To determine if lovastatin 20 \200\22340 mg/day has a role in the primary preventi on of acute coronary events (MI, unstable angina, sudden cardiac death) in 5608 men and 997 women with normal or mildly elevated total or LDL cholesterol, low HDL cholesterol, and no clinically evident atherosclerotic disease, in a randomized, placebo- controlled trial. Follow-up: 5.2 years MAJOR TRIALS IN CARDIOLOGY 599 Results: Lovastatin reduced LDL cholesterol by 25% and increased HDL cholesterol by 6%. The incidences of \201 rst major acute coronary events, MI, unstable angina, coronary revasc ularization, and cardiovascular events were all signi \201 cantly reduced. There were too few fatal cardiovascular and fatal coronary heart disease events to perform a survival anal ysis. AFCAPS/ TexCAPS Reference: Downs JR, et al. (1998). JAMA 279:1615 \200\2231622. AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators Purpose: To evaluate two management strategies in treating AF: 1) cardioversion followed by drugs to maintain sinus rhythm (a choice of amiodarone, disopyramide, \202 ecainide, mor ocizine, procainamide, propafenone, quinidine, sotalol); 2) rate-control drugs, allowing AF to persist (a choice of B-blockers, verapamil, diltiazem, digoxin). Anticoagulation was re commended for both groups. 4060 patients with recent-onset AF and a high risk of stroke or death were randomized. The primary end point was overall mortality. 71% had hypertension, a nd 38% had coronary artery disease. 3311 had echocardiograms, and of these, 65% had enlarge d left atria, and 26% had impaired LV function. Follow-up: 5 years Results: Mortality at 5 years was 23.8% in the rhythm- control group and 21.3% in the rate- control group (hazard ratio 1.15, p = 0.08). More patients in the rhythm-control group were hospitalized and had more adverse drug effects. In both groups, most strokes occurred afte r warfarin had been stopped or if INR was subtherapeutic; this occurred more often in the r hythm-control group. During the course of the study, 594 patients assigned to the rhythm-co ntrol group crossed over to the rate-control group, mainly because of inability to maintain sinus rhythm and drug intolerance. Reference: The AFFIRM Investigators (2002). N Engl J Med 347:1825 \200\2231833. AHEFT African American Heart Failure Trial Purpose: To evaluate treatment with \201 xed-dose isosorbide dinitrate plus hydralazine c ompared with placebo among black patients with heart failure. 1050 patients were randomized to either \201 xed-dose hydralazine and isosorbide dinitrate vs. placebo. Randomization was strati \201 ed by B-blocker use. Initial dosing was 20 mg isosorbide dinitrate and 37. 5 mg hydralazine and titrated up to 120 mg isosorbide dinitrate and 225 mg hydralazine. Mos t patients were NYHA Class III, with a mean age of 57 years and a mean ejection fraction of 24%. Follow-up: Mean 18 months CHAPTER 15 Major trials in cardiology 600 Results: Mortality was lower in the combination-therapy group, 6.2% vs. placebo 10.2%. The survival difference began at 6 months after randomization and continued to diverge through follow-up. The primary composite score was signi \201 cantly improved in the combination-t herapy group compared with placebo ( \200\2230.1 1.9 vs. \200\2230.5 2.0, p = 0.01). Target dose was given in 68.0% of patients in the combination-therapy group and 88.9% of p atients in the placebo group (p < 0.001). Blood pressure (BP) was lower in the combination- therapy group than in the placebo group (systolic BP \200\2231.9 mmHg vs. +1.2 mmHg for pl acebo, p = 0.02; diastolic BP \200\2232.4 mmHg vs. +0.8 mmHg for placebo, p < 0.001). Adve rse events of headache (47.5% vs. 19.2%, p < 0.001) and dizziness (29.3% vs. 12.3%, p < 0.0 01) were higher in the combination-therapy group, but exacerbations of CHF were lower, incl uding all exacerbations (8.7% vs. 12.8%, p = 0.04) and severe exacerbations (3.1% vs. 7.0%, p = 0.005). AHEFT Reference: Taylor AL, et al. (2004). N Engl J Med 351:2049 \200\2232057. Acute Infarction Ramipril Ef \201 cacy Study AIRE Purpose: To evaluate the effect of ramipril on total mortality of AMI survivors with early clinical evidence of heart failure, and to assess progression to severe or resistant heart failure, nonfatal reinfarction, and stroke, compared to placebo. 2006 patients aged (cid:11 6)18 years with con \201 rmed AMI 3 \200\22310 days prior to randomization with clinical e vidence of heart failure were given ramipril at a starting dose of 2.5 mg or placebo. Follow-up: Mean 15 months Results: All-cause mortality was signi \201 cantly lower at 30 days and maintained at the end of follow-up in the ramipril group (27% risk reduction), with 30% reduced risk of sudde n death. 38% of the reduction in overall mortality was in the sudden-death subgroup that ha d developed severe resistant heart failure. There was no alteration in risk of stroke or re infarction in the ramipril group. The study was continued in the AIREX study. Reference: Cleland J, et al. (1997). Eur Heart J 18:41 \200\22351. AIRE Extension Study AIREX Purpose: To assess the long-term (3 years after the end of AIRE) bene \201 t of ramipril i n the 603 UK patients from the AIRE study retrospectively, 302 initially on ramipril, 301 o n placebo. Follow-up: 3 years Results: All-cause mortality occurred in 27% of ramipril- treated patients compared to 39% of placebo controls, representing a relative risk reduction of 36%. Reference: Hall AS, et al. (1997). Lancet 349:1493 \200\2231497. MAJOR TRIALS IN CARDIOLOGY 601 ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Purpose: To compare outcomes in high-risk hypertensive patients >55 years old in a prospect ive, randomized trial using standard antihypertensive drugs and newer agents as initial mon otherapy. Initially, more than 42,000 patients were randomized, but this number dropped to 33,357 after the doxazosin arm was halted because of increased morbidity (mainly stroke and heart failure) in this group compared to the chlorthalidone arm. The remainder was randomi zed to receive chlorthalidone, amlodipine, or lisinopril. 50% were women, and 35% were blac k. The primary end point was combined incidence of fatal CHD or nonfatal MI by intention to treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (fatal CHD, nonfa tal MI, coronary revascularization, or angina with hospitalization), or combined cardiovasc ular disease (combined CHD plus stroke, treated angina without hospitalization, heart failu re, and peripheral arterial disease). Follow-up: Mean 4.9 years Results: All-cause mortality was not different between groups. Systolic pressures were high er with both amlodipine and lisinopril than with chlorthalidone, but diastolic pressures we re slightly better with amlodipine. Secondary outcome measures were also better with chlort halidone than with lisinopril. Reference: The ALLHAT Of \201 cers and Coordinators for the ALLHAT Collaborative Research Group (2000). JAMA 283:1967 \200\2231975. ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial \200\224Lipid Lowering Arm