Evidence-based Cardiology – part 6 doc

the 1996 guidelines. The time for the first APTT measure- ment is not specified. Although the recent reduction in the unfractionated heparin regimen is aimed at lowering the rates of major bleeding and intracranial hemorrhage while maintaining efficacy as assessed by TIMI-3 flow rates, this is only supported by Grade C evidence. The ACC/AHA and ACCP guidelines recommend the use of intravenous heparin in patients treated with streptokinase if they have high-risk features (Table 33.5). Our personal approach is to use intravenous heparin (com- mencing with a weight adjusted bolus) to achieve a high level of thrombin inhibition in patients receiving streptokinase, and to measure the APTT at 3 hours. This is based on the results of the overview (which indicated a possible saving with unfractionated heparin of 2и2 lives and 1и8 infarctions prevented per 1000 patients treated, at a cost of 3и2 transfu- sions and 0и3 non-fatal disabling strokes compared with a placebo or control treatment), 29 angiographic data from GUSTO-I (showing significantly better patency at 5–7 days Grade A1c with intravenous versus subcutaneous heparin), 6 and follow up data from GUSTO-I (showing that the 5 year survival rate of patients given streptokinase and intravenous heparin was equal to that of patients given alteplase, and higher than those given streptokinase plus subcutaneous heparin). 31 If a fibrin-specific fibrinolytic agent is being used, the patient should receive a weight adjusted bolus of intravenous heparin followed by an infusion to maintain the APTT at 50–70 seconds for 48 hours if the patient is not undergoing PCI (see Table 33.5). The APTT should be measured at 3 hours. Further trials of adjunctive intravenous low molecular weight heparins with fibrinolytic therapy will need to be performed before recommendations can be made regarding combinations of these agents. Future directions Despite greater understanding of the mechanism of benefit of adjunctive antithrombin therapies, and recent large Evidence-based Cardiology 472 Table 33.5 Recommendations for the use of adjunctive unfractionated heparin with fibrinolytic therapy from two consensus conferences Fibrinolytic agent ACC/AHA 1999 34 ACCP 2000 91 Fibrin-specific agents Intravenous unfractionated heparin should be Patients receiving alteplase, reteplase or used in patients undergoing reperfusion therapy tenecteplase should be given intravenous with alteplase. The recommended regimen is unfractionated heparin for 48 hours. Either 60 IU/kg as a bolus at initiation of the alteplase standard dosing (a 5000 IU bolus and infusion, then an initial maintenance dose of 1000 IU/hour infusion) or weight adjusted dosing approximately 12IU/kg/hour (maximum 4000 IU (a 60 IU/kg bolus (maximum 4000 IU) and bolus and maximum 1000 IU/hour infusion for 12 IU/kg/hour infusion (maximum 1000 IU/hour) patients weighing Ͼ70 kg), adjusted to maintain may be used, both adjusted to maintain an APTT the APTT at 1·5–2·0 times control of 50–70 seconds (50–70 seconds) for 48 hours. Continuation of the heparin infusion beyond 48 hours should be considered in patients at high risk of systemic or venous thromboembolism Streptokinase Intravenous unfractionated heparin should be Patients at high risk of systemic or venous used in patients at high risk of systemic emboli thromboembolism (that is, those with Q wave (large or anterior MI, atrial fibrillation, previous anterior MI, severe left ventricular dysfunction, embolus or known left ventricular thrombus). It is congestive heart failure, a history of systemic or recommended that heparin be withheld for 6 hours pulmonary embolism, evidence of left ventricular and that APTT testing begin at that time. Heparin thrombus, or atrial fibrillation) should receive should be started when the APTT returns to intravenous unfractionated heparin, starting not Ͻ2 times control (approximately 70 seconds), less than 4 hours after the commencement of then infused to keep the APTT at 1.5–2.0 times streptokinase and when the APTT is control (initial infusion rate approximately Ͻ70 seconds. The target APTT should be 1000 IU/hour). After 48 hours, a change to 50–70 seconds, and the infusion should continue subcutaneous heparin, warfarin or aspirin alone for Ն48 hours should be considered Patients who are not at high risk of systemic or venous thromboembolism should receive subcutaneous unfractionated heparin (12 500IU) every 12 hours for 48 hours clinical trials in patients with ST-segment elevation MI, many questions remain unanswered. It has not yet been resolved whether combinations of newer fibrinolytic agents with newer antithrombin agents and/or glycoprotein IIb/ IIIa inhibitors improve clinical outcomes with acceptable bleeding risks. These regimens, along with agents such as P-selectin inhibitors 92 and tissue factor pathway inhibitors, 93 will need to be tested in combination with clopidogrel and with facilitated PCI. Key points ● There is ongoing thrombin generation in patients with ST-segment elevation acute coronary syndromes. ● Fibrinolytic therapy results in a procoagulant state. ● Unfractionated heparin has proven efficacy in the absence of aspirin and a modest effect in the presence of aspirin. ● Unfractionated heparin has several limitations as an antithrombin agent, including variable pharmacokinetics and pharmacodynamics and relative inefficacy against clot-bound thrombin. ● Reduction of the unfractionated heparin dose may reduce the risk of major bleeding, but does not alter the risk of intracranial hemorrhage. ● Low molecular weight heparins are easier to administer than unfractionated heparin, and have been shown to reduce the risk of re-infarction when used as adjuncts to fibrinolytic therapy. However, they may increase the need for transfusion compared with unfractionated heparin. ● Bivalirudin has no effect on mortality when used as adjunctive therapy with streptokinase, but does reduce the incidence of re-infarction compared with unfractionated heparin increases the risks of minor and moderate bleeding. ● When combined with reteplase or tenecteplase, abciximab reduces the risk of re-infarction compared with unfractionated heparin, but increases the risk of major bleeding, particularly in elderly patients. References 1.French JK, Williams BF, Hart HH et al. Prospective evaluation of eligibility for thrombolytic therapy in acute myocardial infarction. BMJ 1996;312:1637–41. 2.Chesebro JH, Knatterud G, Roberts R et al. Thrombolysis in Myocardial Infarction (TIMI) trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987;76:142–54. 3.TIMI Study Group. 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Circulation 2002;105:279–81. 94.The Continuous Infusion Versus Double-Bolus Administra-tion of Alteplase (COBALT) Investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. N Engl J Med 1997;337:1124–30. 95.The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997;337:1118–23. 96.Lincoff AM. One-year follow-up of the GUSTO-V trial. Proceedings of the Late Breaking Clinical Trials Session, XIVth World Congress of Cardiology. Sydney, Australia; May 2002. Evidence-based Cardiology 476 The prognosis of patients admitted to hospital with acute myocardial infarction (AMI) has improved greatly since the introduction of reperfusion therapies into clinical practice. Several trials testing different fibrinolytic agents, aspirin, and more recently, primary PTCA, have shown that mortality can be reduced by 20–30% when these therapies are begun in the first few hours after the onset of symptoms of AMI. The favorable effects were proportional to the patency rates obtained. Although there is no objective evidence for mortality reduction, pain relief, oxygen, bed rest, and adjunctive therapies should be considered to reduce clinical symptoms and possibly improve prognosis. Pain relief The relief of pain is a priority in patients with AMI, not only for humane reasons, but also because pain activates the sympathetic nervous system increasing cardiac work and myocardial oxygen consumption . Two approaches are used: ● reduction of ischemia ● direct analgesia. Nitroglycerin by the sublingual route or by IV infusion is the most commonly used drug to reduce pain due to ischemia (see the section on Nitrates below). A double-blind randomized trial on 69 patients 1 showed that inhaled nitrous oxide can decrease pain in the absence of hemodynamic changes or other major adverse events. Few controlled data are available, so the recommendations are based mainly on empiricism and personal expertise . Among direct analgesics, morphine is the drug of choice, while meperidine and pentazocine can be substituted in patients with documented hypersensitivity to morphine. Morphine, besides its analgesic effect, has useful hemodynamic actions, including peripheral vasodilation without a decrease of left ventricular (LV) filling pressure. This action, together with central reduction of tachypnea, can be particularly useful in patients with pulmonary edema. 2–5 Effective analgesia should not be delayed because of the fear of masking the effects of anti-ischemic therapy with Grade C Grade A1b recommended agents – fibrinolytic agents, ␤ blockers, aspirin, nitrates. Morphine is given at doses of 4–8 mg IV and repeated every 5–15 minutes in doses of 2–8mg until pain is relieved. Morphine also reduces anxiety, thereby decreasing metabolic demands of the heart during the early critical phase. The decrease in heart rate resulting from the reduction of sympathetic tone and the vagomimetic action of morphine contributes to the reduction of anxiety. Usually opioids are sufficient and tranquillizers are not needed. Adverse reactions to morphine such as severe vomiting, hypotension, and respiratory depression may limit its administration. Hypotension (systolic blood pressure Ͻ100mmHg) can be minimized by keeping the patient supine with ele- vated lower extremities. In the case of excessive bradycardia, atropine may be administered IV (0·5–1·5mg). Depression of respiration seldom occurs and can be treated with intravenous naloxone (0·1–0·2mg, repeated after 15 minutes if necessary). Nausea and vomiting, if severe or recurrent, may be treated with a phenothiazine. The widespread use of reperfusion therapy early after AMI has decreased the intensity and duration of pain, which is largely due to ongoing cardiac ischemia. The addi- tional use of IV ␤ blockers 6,7 further decreases the severity of pain by reducing cardiac work. New approaches to analgesia after AMI include synthetic and semisynthetic narcotics like fentanyl and sufentanyl and thoracic epidural anesthesia, but clinical experience is too limited to recommend regimens and modalities. General management Oxygen Experimental studies have shown that breathing oxygen can decrease myocardial injury; 8 moreover, in patients with AMI the administration of oxygen reduced ST segment elevation. 9 It is assumed that oxygen breathing might improve the ventilation/perfusion mismatch which may be seen in AMI patients. Arterial PO 2 is reduced for about 48 hours in many uncomplicated cases of AMI. 10 Grade B 477 34 Pain relief, general management, and other adjunctive treatments Aldo P Maggioni, Roberto Latini, Gianni Tognoni, Peter Sleight There are no objective randomized trials on the benefit of oxygen breathing after AMI. However, in the presence of severe hypoxemia oxygen is recommended, while in uncomplicated cases its use should probably be limited to the first day or less. Oxygen therapy is indicated if monitored oxygen satura- tion is lower than 90%. In complicated AMI, with severe heart failure, pulmonary edema or mechanical complications, supplemental oxygen is not sufficient and continuous positive pressure breathing or tracheal intubation with mechanical ventilation are sometimes required. 11 Excessive oxygen can cause systemic vasoconstriction with a consequent increase in cardiac workload, an important consideration in uncomplicated patients. Bed rest Bed rest has been traditionally advised for patients with AMI on the assumption that it would decrease cardiac workload. However, it is now recognized that the intensive use of Grade C Grade C recommended treatments – fibrinolysis, IV ␤ blockade, aspirin – allows a much shorter stay in bed for AMI patients. This may decrease the risk of thromboembolism and help to prevent the adverse effects of deconditioning. 12 Prophylactic use of lidocaine (lignocaine) The observation that life-threatening arrhythmias occur within the first 24–48 hours of onset of AMI in a sub- stantial proportion of patients led to the hypothesis that the prophylactic administration of lidocaine could prevent or reduce the incidence of ventricular fibrillation and resulting early mortality. 13 However, an overview of 14 controlled trials testing the effects of prophylactic lidocaine (administered by the IM or IV route) on a total of 9155 patients confirmed a significant reduction of 35% in the rate of ventricular fibrillation, but a strong trend to an increase of 38% in early mortality (OR 1·38, 95% CI 0·98–1·95). 14 The increase in mortality appeared to be caused by bradyarrhythmias, advanced atrioventricular Grade A Grade B Evidence-based Cardiology 478 Table 34.1 Other adjunctive therapies: summary of evidence Therapies Study n Follow up duration Mortality (%) P value NNT Treated Control ␤ blockers ISIS-1 19 LSRCT 16 027 7 days 3·9 4·6 0·04 143 Sleight et al. 18 OV 27 536 7 days 3·7 4·3 0·03 167 CAPRICORN 23 LSRCT 1 959 1.3 years 12 15 0·03 34 ACE inhibitors Early unselected strategy GISSI-3 34 LSRCT 19 394 42 days 6·4 7·2 0·03 125 ISIS-4 35 LSRCT 58 050 35 days 7·2 7·7 0·02 200 ACE-i MICG 37 OV 98 469 30 days 7·1 7·6 0·004 200 Late selected strategy SAVE 38 LSRCT 2 231 42 months (mean) 20·4 24·6 0·019 24 AIRE 39 LSRCT 2006 15 months (mean) 17·0 23·0 0·002 17 TRACE 40 LSRCT 1749 34·7 62·3 0·001 13 Nitrates Yusuf et al. 55 OV 3 041 Inhospital 13·3 18·9 0·002 18 GISSI-3 34 LSRCT 19 394 42 days 6·5 6·9 NS – ISIS-4 35 LSRCT 58 050 35 days 7·3 7·5 NS – Overview 35 OV 81908 35 days 7·4 7·7 0·03 333 Calcium antagonists Teo et al. 62 OV 20 342 — 9·6 9·3 NS – Magnesium Teo et al. 67 OV 1 301 Inhospital 3·8 8·2 0·001 23 LIMIT-2 68 LSRCT 2 316 28 days 7·8 10·4 0·04 42 ISIS-4 35 LSRCT 58 050 35 days 7·6 7·2 NS – Overview 35 OV 61860 35 days 7·6 7·5 NS – Abbreviations: LSRCT, large-scale randomized clinical trials; NNT, number of patients needed to treat to save one life; NS, non-significant; OV, overview block, and asystole. In view of these findings, prophylactic lidocaine is no longer considered as a standard treatment in patients with AMI, but is reserved for those patients who have already experienced ventricular fibrillation. Other adjunctive treatments (Table 34.1) We will now discuss adjunctive drug therapy with ␤ blockers, ACE inhibitors, nitrates, magnesium, and calcium- antagonists. The results of published randomized trials which were of adequate size to show reliable data in terms of mortality, together with overviews of the data, will be summarized. We will also indicate areas of doubt. Specific therapy ␤ Blockers Rationale Early after AMI, activation of the sympathetic nervous system occurs. ␤ Blockers reduce oxygen demand by lowering heart rate and blood pressure, and decreasing myocardial wall stress, thereby limiting infarct size, the incidence of cardiac rupture, and improving ventricular function and mortality. 15 By their ␤ adrenergic antagonist properties, they can also prevent the life-threatening ventricular arrhythmias related to the increased adrenergic activity occurring in the first hours after the onset of AMI. 16 Evidence from trials and overviews of early IV ␤ blockade Studies testing the effects of early IV ␤ blockade on the mortality of patients with AMI show consistent results. 17 Available data on more than 27000 patients from 27 trials show that the mortality rate of the patients allocated to the active treatment was significantly reduced by about 14% in comparison with placebo-allocated patients (from 4·3% to 3·7%; in absolute terms, six lives saved per 1000 patients treated with ␤ blockers). 18 The largest study testing this treatment, the ISIS-1 trial, showed that the mortality reduction by atenolol treatment in patients with AMI was con- centrated in the first day or two from the onset of AMI symptoms. 19 Further, this study suggested that reduction in cardiac rupture and cardiac arrest were the most notable changes in early death associated with ␤ blocker therapy. 20 These observations may be considered as the rationale for the combined use of ␤ blockers and fibrinolytics, which are both known to reduce mortality. In particular, in the first few days from the onset of AMI, ␤ blockers may reduce cardiac rupture, the incidence of which may be increased by fibrinolytic induced hemorrhage of infarcted myocardium. 21,22 However, ␤ blocker trials in AMI were Grade A conducted mostly during the 1970s and 1980s, when no fibrinolysis or primary angioplasty was performed, and adjunctive therapy was characterized by much less use of aspirin and no ACE inhibitors. Further, study populations were mostly at lower risk and patients with heart failure were usually excluded. For these reasons, the CAPRICORN trial was planned with the aim to evaluate whether long- term treatment with carvedilol (titrated up to 25mg ϫ2/day) could reduce all-cause mortality in postinfarction patients (from 3 to 21 days from symptom onset) with an LV ejection fraction ഛ 40% and who were receiving an ACE inhibitor for Ն48 hours. 23 All-cause mortality was reduced from 15% in the placebo group and to 12% in the carvedilol group (23% relative reduction), while the combined end point of all-cause deaths plus CV hospitalizations was not modified by the active treatment. Recommendations All patients with AMI, in the absence of specific contraindications, should be treated with a ␤ blocker within 24 hours from the onset of symptoms and treatment should be continued for at least 2 years. Clear contraindications are pulmonary edema, asthma, hypotension, bradycardia, or advanced atrioventricular block. Even in the absence of trials of adequate size testing specifically the effects of the combination of a ␤ blocker and a fibrinolytic, pathophysiologic premises, observational data, and the few controlled studies suggest that this treatment should be considered in association with reperfusion treatment with fibrinolysis. In the GISSI-2 trial, IV atenolol was used in conjunction with fibrinolytics in 48% of the patients. Lack of randomized trials of early ␤ blockade in the era of reperfusion With the exception of the recently published CAPRICORN trial that included patients with LV dysfunction some days after AMI, the trials testing the early effects on mortality of ␤ blockers in all-comers with AMI were conducted in the early 1980s, before the widespread use of reperfusion therapy. Trials formally testing the effects of the combination of a ␤ blocker and a fibrinolytic are few and underpowered to provide reliable data in terms of mortality reduction. The only data available are from the TIMI-2B trial, in which 1434 patients, all treated with tPA and aspirin, were randomized to receive immediate or delayed (6–8 days) oral metoprolol. 24 Total mortality rate at 6 and 42 days was not significantly decreased by the immediate treatment, but the number of deaths was fewer, and the rate of non-fatal re-infarction was reduced in the group receiving immediate metoprolol. More recently, data from the National Registry of Myocardial Infarction 2 showed that immediate ␤ blocker administration in patients with AMI treated with tPA Grade A Pain relief, general management, and other adjunctive treatments 479 reduces the occurrence of intracranial hemorrhage. Among patients receiving tPA, the incidence of intracranial hemorrhage was 0·7% (158/23749) in patients receiving ␤ blockers and 1·0% (384/3658) in patients not receiving ␤ blockers (P Ͻ 0·001). 25 Multivariate analysis showed that immediate ␤ blocker use was associated with a 31% reduction in the rate of intracranial hemorrhage. No other drugs given within the first 24 hours were associated with a reduction in the rate of intracranial hemorrhage. Long-term use The effects of ␤ blocker therapy started after the acute phase of MI (5–28 days from the onset of symptoms) have been tested among more than 35000 patients not receiving a reperfusion therapy in several placebo-controlled trials. 26 Overall, the long-term composite outcome of mortality and non-fatal infarction was reduced by 20–25%. Timolol, metoprolol, and propranolol were the most exten- sively studied drugs. 27–29 In the Norwegian Multicenter Study, 27 patients allocated to timolol showed a 39% mortality reduction and a 28% reduction of re-infarction. The initial benefit persisted for at least 72 months in the patients who continued timolol treatment after trial termination. Similar results have been obtained by the Beta-Blocker Heart Attack Trial (BHAT), 28 in which 3837 patients were allocated to propranolol or placebo. After 25 months of treatment overall mortality was reduced by 28%. Subgroup analysis showed that the beneficial effects of ␤ blockers were apparent among the various subgroups, but the magnitude of the benefit was greater in high-risk patients (those with large or anterior AMI or with signs or symptoms of moderate left ventricular dysfunction). This subgroup analysis of the BHAT trial has been recently confirmed by the results of the CAPRICORN trial, which showed a significant mortality reduction in post-AMI patients with LV dysfunction treated with carvedilol. 23 Definite contraindications to ␤ blocker therapy are pulmonary edema, asthma, severe hypotension, bradycardia, or advanced atrioventricular block. Evidence from trials and overviews suggests that all patients with AMI who do not have clear contraindications should be treated with intravenous ␤ blockers within 24 hours from the onset of symptoms. If tolerated, the treatment should be continued for at least 2–3 years, and perhaps longer. A debate is still open about whether ␤ blockers should be prescribed to all patients without contraindications or whether they should be given only to the patients at moderate to high risk who have the most to gain from a long-term treatment. Despite the clear evidence of benefit, observational studies showed that in clinical practice ␤ blockers are generally underused, only 36–42% of patients receiving a ␤ blocker at discharge. 30 Grade A Grade A ACE inhibitors Rationale The rationale behind this strategy is based mainly on the fact that activation of the renin–angiotensin system occurs during the very early phase of MI, with deleterious conse- quences, including an increase of peripheral resistance and heart rate, decrease of coronary perfusion, and alteration in endogenous fibrinolytic activity. 31,32 Evidence from trials and overviews After the disappointing results of the CONSENSUS-2 trial, 33 which did not show a benefit from enalapril treatment, the results of GISSI-3 and ISIS-4 studies were published. 34,35 In the GISSI-3 trial, 6 week total mortality was significantly lower in the patients treated with lisinopril: 6 week lisinopril treatment significantly reduced mortality from 7·2% to 6·4% (in absolute terms eight lives saved per 1000 treated patients). 34 The favorable results on mortality shown by the GISSI-3 study have been confirmed by the larger ISIS-4 trial. During the first 5 weeks there were 2088 (7·19%) deaths recorded among 29028 captopril-allocated patients compared with 2231 (7·69%) among 29022 patients allocated placebo. 35 This 7% relative reduction in total mortality was statistically significant (P ϭ 0·02) and corresponded in absolute terms to five fewer deaths per 1000 patients treated with captopril for 1 month. The reduction in total mortality shown by CCS-1 36 was similar to that demonstrated by the larger GISSI-3 and ISIS-4 trials, but statistical significance was not achieved, presumably because of inadequate sample size. An overview of the trials testing an early unselected approach with ACE inhibitors in 98496 patients with AMI showed that immediate treatment is safe, well tolerated and that it produces a small, but significant reduction of 30 day mortality. 37 This benefit is quantifiable as about five extra lives saved for every 1000 patients treated with ACE inhibitors early after the onset of AMI. With respect to the safety profile, persistent hypotension and renal dysfunction were (as expected) reported significantly more often in the patients treated with ACE inhibitors than in corresponding controls. The overview also confirmed the important benefit achievable with early ACE inhibitor treatment. Of the total 239 lives saved by early ACE inhibitor treatment, 200 were saved in the first week after AMI. The “selective” strategy of starting ACE inhibitors some days after AMI only in patients with clinical heart failure and/or objective evidence of LV dysfunction was tested in three trials (SAVE, AIRE, TRACE), involving about 6000 patients overall. 38–40 These trials consistently showed that long-term ACE inhibitor treatment in this selected popula- tion of patients was associated with a significant reduction of mortality. 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N Engl J Med 2002;3 46: 95 7 6 6. 84.Schömig. Inhospital 3·8 8·2 0·001 23 LIMIT-2 68 LSRCT 2 3 16 28 days 7·8 10·4 0·04 42 ISIS-4 35 LSRCT 58 050 35 days 7 6 7·2 NS – Overview 35 OV 61 860 35 days 7 6 7·5 NS – Abbreviations: LSRCT, large-scale randomized. 7·5 NS – Overview 35 OV 81908 35 days 7·4 7·7 0·03 333 Calcium antagonists Teo et al. 62 OV 20 342 — 9 6 9·3 NS – Magnesium Teo et al. 67 OV 1 301 Inhospital 3·8 8·2 0·001 23 LIMIT-2 68 LSRCT

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