On-Line Data Suppl Part II
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Online Data Supplement, Part II/1 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Antiplatelets/Antithrombins/Anticoagulants Acute UA (mean Heparin RR by 88% vs Théroux P, 1993 8.3±7.8 h after 484 Aspirin vs heparin MI 5.7 ± 3.3 d aspirin (0.8% vs 3.7%; [1] last episode of P=0.035) pain) Combination therapy total UA/Non-Q-wave Aspirin alone vs Recurrent angina ischemic events vs aspirin alone ATACS, 1994 MI (mean aspirin plus 214 with ECG changes, 12 wk at 12 wk (13% vs 25%; P=0.06) [2] 9.5±8.8 h of anticoagulation MI, and/or death as well as at 14 d (10.5% vs qualifying pain) (heparin, warfarin) 27%; P=0.004) Warfarin (target INR Warfarin RR by 58% (95% 2.0-2.5) vs standard OASIS pilot UA or suspected Composite CV death, CI, –15 to 85%; P=0.08); therapy (heparin or study, 1998 non-Q-wave 197 new MI, and 3 mo warfarin was associated with a hirudin; 85% in both [3] MI<48 h refractory angina significant excess of minor groups received bleeds (P=0.004) aspirin) Antiplatelets: Thienopyridines Major peripheral or Clopidogrel 300-mg bleeding Combined clopidogrel groups loading dose then 75 complications, had 50% in RR of composite CLASSICS, Successful mg/d vs clopidogrel neutropenia, primary end point (95% CI, 19- 2000 coronary stent 1020 28 d 75 mg/d vs thrombocytopenia, or 69%; P=0.005); incidence of [4] implantation 6 h ticlopidine 250 mg early discontinuation major adverse clinical events bid (all + aspirin) due to noncardiac comparable among all groups adverse event
Clopidogrel (300 mg (1) CV death, (1) Clopidogrel RR by 20% Non-ST-segment immediately, then 75 nonfatal MI, or stroke CURE, 2001 (95% CI, 10-28%; P<0.001) elevation ACS 12,562 mg once daily) vs (2) First primary 3-12 mo [5] (2) Clopidogrel RR by 14% 24 h placebo (both plus outcome plus aspirin) refractory ischemia (95% CI, 6-21%; P<0.001)
Antiplatelets: GP IIb/IIIa Inhibitors Online Data Supplement, Part II/2 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Lamifiban 1 μg/min No difference in composite end (low dose) ± heparin point at 30 d; at 6 mo, vs lamifiban 5 composite end point occurred in PARAGON-A, UA/Non-Q-wave μg/min (high dose) ± Composite all-cause 13.7% of low-dose lamifiban 1998 2282 30 d MI 12 h heparin vs placebo + death or nonfatal MI patients (P=0.027), 16.4% of [6] heparin (standard high-dose lamifiban patients therapy) (all + (P=0.45), and 17.9% of aspirin) standard-therapy patients Tirofiban RR of composite Ischemic Composite death, MI, end point by 33% (95% CI, 8- PRISM, 1998 Aspirin + tirofiban vs symptoms of UA 3232 or refractory ischemia 48 h 52%; P=0.01); no difference in [7] aspirin + heparin 24 h at 48 h composite end point + UA at 30 d Tirofiban-alone arm stopped early because of excess PRISM-PLUS, Composite death, MI, mortality at 7 d (4.6% vs 1.1% UA/Non-Q-wave Tirofiban vs heparin 1998 1915 or refractory ischemia 6 mo for heparin alone); combination MI 12 h vs tirofiban + heparin [8] within 7 d therapy RR of composite end point by 32% (95% CI, 12- 47%; P=0.004) vs heparin alone Eptifibatide vs Non-ST-segment Eptifibatide absolute risk of PURSUIT, 1998 placebo for 72-96 h Composite death and elevation ACS 10,948 30 d composite end point by 1.5% [9] (both + nonfatal MI at 30 d 24 h (P=0.04) aspirin/heparin) Study terminated early because Composite death, MI, of increased 30-d mortality in Orbofiban 50 mg bid, recurrent ischemia OPUS-TIMI 16, the orbofiban 50/30 group; Unstable ACS vs 50 mg bid for 30 d requiring 2000 10,288 10 mo mortality rates at 10 mo: 3.7% 72 h then 30 mg bid, vs rehospitalization, [10] placebo, 5.1% orbofiban 50/30 placebo urgent revasculariza- (P=0.008), and 4.5% orbofiban tion, or stroke 50/50 (P=0.11) Online Data Supplement, Part II/3 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Low-dose (25% No significant difference in Composite death, SYMPHONY, Post ACS, platelet inhibition) or primary end point; major nonfatal MI or 2000 clinically stable 9233 high-dose (50% 90 d bleeding more common with reinfarction, or severe [11] for 12 h inhibition) sibrafiban high-dose sibrafiban than with recurrent ischemia vs aspirin aspirin or low-dose sibrafiban Abciximab bolus + Abciximab did not GUSTO IV- ACS 24 h, not 24-h or 48-h infusion All-cause mortality or occurrence of primary end point ACS, 2001 undergoing early 7800 30 d vs placebo (plus MI vs placebo (odds ratios, 1.0 for [12] revascularization aspirin & heparin) 24-h and 1.1 for 48-h infusion) No significant difference in composite end point among groups; major bleeding Low-dose sibrafiban Time to all-cause SYMPHONY II, Post ACS 7 d, significantly in low-dose + aspirin vs high- mortality, MI, or 2001 clinically stable 6671 90 d sibrafiban + aspirin group vs dose sibrafiban alone severe recurrent [13] for ≥12 h aspirin alone; mortality and MI vs aspirin alone ischemia significantly in high-dose sibrafiban group vs aspirin alone No significant difference in Lamifiban bolus and PARAGON-B, Non-ST-segment Composite death, MI, primary efficacy end point; 72-h infusion vs 2002 elevation ACS 5225 or severe recurrent 30 d bleeding but not intracranial placebo (both + [14] <12 h ischemia hemorrhage more common in aspirin and UFH) lamifiban-treated patients
Major bleeding not Enoxaparin given with a GP related to CABG IIb/IIIa inhibitor did not Non-ST-segment Enoxaparin + GP surgery NICE-3, 2003 increase the risk of major elevation ACS 671 IIb/IIIa antagonists (+ (Secondary: 30 d [15] bleeding or clinical outcomes, 24 h aspirin) composite death, MI, including among patients who and urgent underwent PCI revascularization)
Antithrombins: LMWH Online Data Supplement, Part II/4 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Clinical Dalteparin RR of primary end FRISC, 1996 UA/NSTEMI Death and new MI 1506 Dalteparin vs placebo follow-up point by 63% (95% CI, 32- [16] 72 h during the first 6 d to 150 d 80%; P=0.001) UA 24 h + Enoxaparin RR of composite evidence of Enoxaparin 1 mg/kg Composite death, MI, Clinical end point by 20% (95% CI, 4- ESSENCE, 1997 underlying 3171 bid vs UFH given for or recurrent angina at follow-up 33%; P=0.019) at 14 d and by [17] ischemic heart 48 h-8 d 14 d to 30 d 19% (95% CI, 4-32%; P=0.016) disease at 30 d Death, MI, and recurrent angina at 6- No difference in clinical Dalteparin vs UFH 45 d (double-blind outcomes between dalteparin Clinical FRIC, 1997 UA/Non-Q-wave (days 1-6) or placebo phase) and UFH during acute phase or 1482 follow-up [18] MI 72 h (days 6-45) (all + (Secondary: death, between dalteparin and aspirin to 3 mo aspirin) MI, and recurrent (placebo) during double-blind angina during acute phase phase) No differences among groups in Composite cardiac primary outcome; nadroparin FRAX.I.S., 1999 UA/Non-Q-wave Nadroparin for 6 ± 2 death, MI, refractory 3468 14 d for 14 d risk of major [19] MI 48 h d or 14 d vs UFH angina, or recurrence hemorrhages vs UFH (3.5% vs of UA 1.6%; P=0.0035) Dalteparin RR of composite Dalteparin vs placebo FRISC II, 1999 Unstable CAD Composite death and end point nonsignificantly at 3 2267 (both after ≥5 d open- 6 mo [20] 48 h MI at 3 mo mo but significantly (47% [95% label dalteparin) CI, 20-65%]; P=0.002) at 30 d Enoxaparin RR of primary TIMI 11B, 1999 UA/Non-Q-wave Death, MI, or urgent end point by 17% at 8 d 3910 Enoxaparin vs UFH 43 d [21] MI 24 h revascularization (P=0.048) and by 15% at 43 d (P=0.048) Online Data Supplement, Part II/5 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Safety: incidence of non–CABG-related Enoxaparin primary safety major bleeding at 96 end point (1.8% vs 4.6%; Enoxaparin vs UFH h P=0.03) and primary efficacy INTERACT, Clinical UA/NSTEMI for 48 h (both + Efficacy: recurrent end point at 48 h (14.3% vs 2003 746 follow-up 24 h aspirin and ischemia on 25.4%; P=0.0002) and 96 h [22] to 30 d eptifibatide) continuous ECG (12.7% vs 25.9%; P<0.0001) as monitoring during well as death or MI at 30 d (5% first 48 h and >48-96 vs 9%; P=0.031) h Enoxaparin RR of primary Enoxaparin 1 mg/kg A to Z (Phase Non-ST-segment Composite all-cause end point by 12% (95% CI, –8 vs weight-adjusted A), 2004 elevation ACS 3987 death, new MI, or 7 d to 29%), which met the UFH (both + [23] 24 h refractory ischemia prespecified criterion for tirofiban and aspirin) noninferiority Non-ST-segment elevation ACS No difference in primary end 24 h, at high Efficacy: Composite Enoxaparin 1 mg/kg point or in ischemic events SYNERGY, risk for ischemic all-cause death or vs weight-adjusted during PCI; enoxaparin 2004 cardiac 9978 nonfatal MI 30 d UFH (both + aspirin significantly TIMI major [24] complications Safety: Major or clopidogrel) bleeding (9.1% vs 7.6%; and undergoing bleeding or stroke P=0.008) early invasive treatment Online Data Supplement, Part II/6 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Antithrombins: Direct Thrombin Inhibitors There was a trend for increased cerebral hemorrhage in patients Ischemic chest NA GUSTO IIa, Intravenous heparin receiving hirudin vs heparin, discomfort 12 h [trial 1994 2564 versus recombinant NA but incidence was significantly with abnormal stopped [25] hirudin higher in patients also receiving ECG early] thrombolytic therapy (eg, t-PA, streptokinase) 12,142 (4131 Hirudin RR of combined end with, GUSTO IIb, Intravenous heparin point by 11% (95% CI, 0-21%; Chest discomfort 8011 1996 versus recombinant Death or nonfatal MI 30 d P=0.06) at 30 d and by 39% 12 h w/o ST- [26] hirudin for 72 h (95% CI, 19-54%; P=0.001) at segment 24 h eleva- tion) Hirudin RR of combined end point by 16% (95% CI, –2 to Recombinant hirudin OASIS-2, 1999 UA or suspected CV death or new MI 31%; P=0.077); decreases in 10,141 (lepirudin) vs heparin 7 d [27] NSTEMI 12 h at 7 d CV events observed primarily for 72 h during the 72-h treatment period Fibrinolytics Primary end point achieved in Measurable 25% of t-PA patients vs 19% of improvement in placebo patients (P=0.25); t-PA vs placebo (both TIMI IIIA, 1993 UA/Non-Q-wave culprit lesions (≥10% substantial improvement (≥20% 306 + conventional 18-48 h [28] MI reduction in stenosis reduction or 2 TIMI flow antianginal therapy) or 2 TIMI flow grades) occurred in 15% with grades) t-PA vs 5% with placebo (P<0.003) Online Data Supplement, Part II/7 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings t-PA vs placebo: death, MI, or failure No significant differences in t-PA vs placebo as of initial therapy at 6 occurrence of primary end initial therapy; early wk; points in either comparison; TIMI IIIB, 1994 UA/Non-Q-wave 1473 invasive vs Invasive vs 6 wk early invasive therapy resulted [29] MI 24 h conservative conservative: death, in shorter length of initial treatment MI, or unsatisfactory hospital stay and fewer exercise stress test at rehospitalizations 6 wk Lipid-Lowering Therapy Death, nonfatal MI, cardiac arrest with Atorvastatin RR of composite Atorvastatin 80 mg/d resuscitation, or end point by 16% (95% CI, 0- MIRACL, 2001 UA/Non-Q-wave vs placebo given 24- recurrent 30%; P=0.048 [not 3086 16 wk [30] MI 24 h 96 h after hospital symptomatic significant]), primarily due to admission myocardial ischemia 26% risk of myocardial requiring emergency ischemia (P=0.02) rehospitalization Composite all-cause Although study was designed to death, MI, UA Hospitalization show noninferiority of PROVE-IT requiring rehospital- for ACS (UA, Atorvastatin 80 mg 24 mo pravastatin, atorvastatin RR (TIMI-22), 2004 4162 ization, revasculari- NSTEMI, vs pravastatin 40 mg (mean) of the primary end point by [31] zation ≥30 d after STEMI) 10 d 16% (95% CI, 5-26%; P=0.005) randomization, and vs pravastatin stroke At 4 mo, no difference in Simvastatin 40 mg/d occurrence of primary outcome; ACS (STEMI, Composite CV death, A to Z (Phase for 1 mo then 80 from 4 mo to end of study, NSTEMI ), total nonfatal MI, 721 d Z), 2004 4497 mg/d vs placebo for 4 simvastatin 80 mg/d RR of cholesterol 250 readmission for ACS, (median) [32] mo then simvastatin primary outcome by 25% (95% mg/dL and stroke 20 mg/d CI, 5-40%; P=0.02) vs simvastatin 20 mg/d
Trial Acronyms: ATACS, Antithrombotic Therapy in Acute Coronary Syndromes; A to Z, Aggrastat to Zocor; CLASSICS, Clopidogrel Aspirin Stent International Cooperative Study; CURE, Clopidogrel in Unstable angina to prevent Recurrent Events; ESSENCE, Efficacy and Safety of Online Data Supplement, Part II/8 Table 1. Clinical Trials of Medical Therapy for UA/NSTEMI
Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events; FRAX.I.S., FRAXiparine in Ischaemic Syndrome; FRIC, Fragmin in Unstable Coronary Artery Disease; FRISC, Fragmin during Instability in Coronary Artery Disease; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; INTERACT, Integrelin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment; MIRACL, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering; NICE, National Investigators Collaborating on Enoxaparin; OASIS, Organization to Assess Strategies for Ischemic Syndromes; OPUS-TIMI 16, Orbofiban in Patients with Unstable coronary Syndromes; PARAGON A/B, Platelet IIb/IIIa Antagonism/Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network; PRISM, Platelet Receptor Inhibition in Ischemic Syndrome Management; PRISM-PLUS, Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PROVE-IT (TIMI-22), Pravastatin or Atorvastatin Evaluation and Infection Therapy; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; SYMPHONY, Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes; SYNERGY, Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors; TIMI, Thrombolysis in Myocardial Infarction.
Other Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; ECG, electrocardiogram/electrocardiographic; GP, glycoprotein; INR, international normalized ratio; LMWH, low- molecular-weight heparin; MI, myocardial infarction; NA, data not available; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RR, relative risk; STEMI, ST-elevation myocardial infarction; t-PA, tissue plasminogen activator; UA, unstable angina; UFH, unfractionated heparin. Online Data Supplement, Part II/9 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings PTCA In-hospital rates of combined end point were 5.1% in PTCA PAMI, 1993 Acute STEMI PTCA vs fibrinolytic Combined death and 395 6 mo patients and 12.0% in t-PA [33] <12 h therapy (t-PA) nonfatal reinfarction patients (P=0.02); at 6 mo, rates were 8.5% and 16.8% (P=0.02) Upon arrival at the cath lab, rt-PA 50-mg bolus vs TIMI grade 2 or 3 flow was placebo before observed in 61% of rt-PA Acute STEMI Follow-up PACT, 1999 angiography; if TIMI Early infarct-related patients vs 34% of placebo symptoms ≥30 606 angiograph [34] flow 0-2, angioplasty; artery patency patients (P<0.001); timing of min y at 5-7 d if TIMI flow 3, restoration of TIMI grade 3 second bolus of rt-PA flow significantly impacted LV function at follow-up Angioplasty rate of combined end point (14.9% vs 23%; P=0.034), recurrent ischemia Long-term PAMI-I, 1999 PTCA vs fibrinolytic Combined death and (36.4% vs 48%; P=0.026), follow-up of 395 2 y [35] therapy (t-PA) nonfatal reinfarction reinterventions (27.2% vs PAMI patients 46.5%; P<0.0001), and hospital readmission rates (58.5% vs 69%; P=0.035) PTCA RR of mortality by Zijlstra et al, Acute STEMI All-cause mortality; 46% (95% CI, 13-64%; P=0.01) PTCA vs 5 ± 2 y 1999 symptoms ≥30 395 combined death and and of combined death and streptokinase (mean) [36] min and 24 h nonfatal reinfarction nonfatal reinfarction by 38% (95% CI, 9-57%) Online Data Supplement, Part II/10 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings PCI RR of composite end Accelerated t-PA (+ Composite death, point by 48% (95% CI, 11- Acute MI C-PORT, 2002 aspirin and heparin) recurrent MI, and 70%; P=0.03) at 6 wk and by symptoms ≥30 451 6 mo [37] vs primary PCI (+ stroke; median 43% (95% CI, 5-66%; P=0.03) min and <12 h aspirin) hospital stay at 6 mo; median hospital stay from 6 d to 4.5 d (P=0.02) PCI with balloon occlusion and (1) ST-segment aspiration distal resolution measured No significant difference in Acute MI Clinical EMERALD, microcirculatory 30 min after PCI; either primary end point; no symptoms >30 501 follow-up 2005 [38] protection system (2) Infarct size significant difference in major min and <6 h to 6 mo (Guidewire) vs measured 5-14 d after adverse cardiac events at 6 mo angioplasty without procedure distal protection Coronary Stenting Composite death, Elective stenting reinfarction, or repeat Stenting primary end point Acute STEMI FRESCO, 1998 following successful TVR (9% vs 28%; P=0.003) and symptoms >30 150 6 mo [39] PTCA vs no further (Secondary: secondary end point (17% vs min and <24 h intervention restenosis or 43%; P=0.001) reocclusion) Major cardiac complications (death, Stenting in-hospital major Balloon angioplasty recurrent ischemia, cardiac events (3.8% vs 19.2%; GRAMI, 1998 Acute MI >30 104 with elective stenting reinfarction, 30 d [40] min and <24 h P=0.03) and % of patients vs angioplasty alone emergency coronary with TIMI grade 3 flow (98% bypass); TIMI grade vs 83%; P<0.03) 3 flow at discharge Online Data Supplement, Part II/11 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings Stenting rates of major Repeat MI, target cardiac events during Acute MI lesion revascular- PASTA, 1999 Stenting vs balloon Up to 12 hospitalization (6% vs 19%; symptoms ≥30 136 ization, and cardiac [41] angioplasty mo P=0.023), at 6 mo (21% vs min and <12 h death (+ angiographic 46%; P<0.0001), and at 12 mo parameters) (22% vs 49%; P=0.0011) Composite death, Primary end point occurred in nonfatal MI, 12.6% of stent patients and Stent-PAMI, PTCA alone vs disabling stroke, or 20.1% of PTCA alone patients 1999 Acute MI <12 h 900 PTCA with stent 6 mo target-vessel (P<0.01); the difference was [42] placement revascularization for due entirely to difference in ischemia need for revascularization Rates of primary end point: PTCA, 20%; PTCA + Composite death, CADILLAC, Acute MI abciximab, 16.5%; stenting, PTCA vs stenting, reinfarction, disabling 2002 symptoms ≥30 2082 6 mo 11.5%; stenting + abciximab, each ± abciximab stroke, and ischemia- [43] min and <12 h 10.2% (P<0.001); the driven TVR differences were entirely due to reductions in rates of TVR
Follow-up Median myocardial salvage Salvage index (ratio imaging at 13.6% of left ventricle with Stenting plus STOPAMI-2, Acute MI of degree of 11 d stenting vs 8% with alteplase abciximab vs 2002 symptoms ≥20 162 myocardial salvage to (median); (P=0.007); stenting RR of alteplase plus [44] min and <12 h the initial perfusion clinical mortality at 6 mo by 44% (95% abciximab defect) follow-up CI, –88 to 83%; P=0.35 [4 vs 7 to 6 mo deaths, respectively])
Fibrinolytic/Antithrombotic Therapy Online Data Supplement, Part II/12 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings Primary end point occurred in Refractory UA Abciximab vs CAPTURE, All-cause death, MI, 11.3% abciximab patients vs 48 h, placebo for 18-24 h 1997 1265 or urgent intervention 30 d 15.9% placebo patients (RR = undergoing before PTCA and 1 h [45] for recurrent ischemia 0.71; P=0.012), primarily due PTCA after to lower rate of MI Composite of all- cause mortality, MI, CABG due to Balloon Tirofiban vs placebo angioplasty failure or Tirofiban RR of composite RESTORE, angioplasty or during and for 36 h recurrent ischemia, end point by 16% (P=0.16) at 1997 DCA <72 h after 2141 30 d after procedure (+ repeat target-vessel 30 d and by 38% (P=0.005) at 2 [46] acute coronary aspirin and heparin) angioplasty for d syndrome recurrent ischemia, and emergency stent placement Stenting + abciximab Stent + abciximab RR of vs balloon composite end point by 52% Urgent or angioplasty + Composite all-cause (95% CI, 31-67%; P<0.001) vs EPISTENT, elective abciximab vs stenting mortality, MI, or stent + placebo; 1998 percutaneous 2399 + placebo (all with 30 d urgent [47] coronary heparin, aspirin, and balloon + abciximab RR of revascularization revascularization standard composite end point by 37% pharmacologic (95% CI, 12-55%; P=0.007) vs therapy) stent + placebo Online Data Supplement, Part II/13 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings Acute MI Abciximab RR by 59% (95% ADMIRAL, Composite death, symptoms 12 h, Abciximab + stenting CI, 7-82%; P=0.01) at 30 d and 2001 300 reinfarction, or urgent 6 mo undergoing vs placebo + stenting by 54% (95% CI, 7-78%; [48] TVR primary PCI P=0.02) at 6 mo Acute coronary Clopidogrel RR of primary Clopidogrel vs syndromes 24 h end point by 30% (95% CI, 3- PCI-CURE, placebo (both + Composite CV death, 8 mo without ST- 50%; P=0.03) and of CV death 2001 2658 aspirin) for 6 d MI, or urgent TVR (mean) segment and MI by 25% (95% CI, 0- [49] (median) before PCI within 30 d after PCI elevation, 44%; P=0.047) at end of and up to 8 mo after undergoing PCI follow-up Primary end point occurred Facilitated PCI (ie, significantly more often in with fibrinolytic facilitated PCI group (19%) therapy using full- than in PCI alone group (13%) dose tenecteplase) or Combined death, (RR, 1.39; 95% CI, 1.11–1.74; STEMI <6 h, PCI alone (with ASSENT-4 PCI, cardiogenic shock, or P=0.0045); other individual end eligible for 1667 UFH) (both GP 90 d 2006 [50] congestive heart points also favored the PCI primary PCI IIb/IIIa inhibitors failure alone arm; in-hospital stroke and, in patients (P<0.0001), but not noncerebral receiving stent bleeding complications, also placement, significantly more common in clopidogrel) facilitated PCI group Bivalirudin + GP IIb/IIIa Moderate- to UFH or enoxaparin + (1) Composite net inhibition met criteria for non- high-risk UA or a GP IIb/IIIa clinical benefit, (2) inferiority vs UFH/enoxaparin NSTEMI patients inhibitor, bivalirudin ischemic composite + GP IIb/IIIa inhibition; ACUITY, 2006 undergoing PCI + a GP IIb/IIIa (all-cause death, MI, bivalirudin alone met non- 13,819 30 d [51] (56%), CABG inhibitor, or unplanned inferiority criteria for all 3 (~11%), or bivalirudin alone (all revascularization for endpoints and superiority medical therapy + aspirin and ischemia), (3) major criteria for net clinical outcome (~33%) clopidogrel) bleeding (10.1% vs 11.7%) and major bleeding (3.0% vs 5.7%) Invasive Procedures vs Medical Management Online Data Supplement, Part II/14 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings Conservative treatment nonsignificantly cumulative RR of primary end point by VANQWISH, Invasive vs Acute non-Q- Composite death or 23 mo 13% (95% CI, –10 to 32%; 1998 920 conservative wave MI nonfatal MI (mean) P=0.35) but significantly before [52] treatment hospital discharge (P=0.004), at 1 mo (P=0.012), and at 1 y (P=0.05) Symptoms of Invasive treatment RR of ischemia Early invasive vs composite end point by 22% increasing or conservative FRISC II, 1999 Composite death or (95% CI, 2-38%; P=0.031); occurring at rest, 2457 treatment (both ± 6 mo [53] MI invasive treatment halved or suggesting dalteparin or placebo symptoms of angina and possible acute MI for 3 mo) hospital re-admissions 48 h Early invasive vs Composite death, TACTICS-TIMI UA 24 h with conservative nonfatal MI, and Invasive treatment RR of 18, 2001 evidence of MI or 2220 treatment (both + rehospitalization for 6 mo primary end point by 22% (95% [54] prior CAD aspirin, heparin, and an acute coronary CI, 3-38%; P=0.025) tirofiban) syndrome At 4 mo, invasive treatment RR of combined end point by Invasive 34% (95% CI, 15-49%; UA and (revascularization) vs Combined death, P=0.001), primarily due to documented conservative nonfatal MI, or halving of refractory angina; at RITA-3, 2002 5 y CAD; evolving 1810 (antianginal and refractory angina at 4 1 y, no significant difference; at [55, 56] (median) acute MI antithrombotic mo; combined death 5 y, invasive treatment RR of excluded medications) or nonfatal MI at 1 y death or nonfatal MI by 22% treatment (95% CI, 1-39%; P=0.044) and of CV death or MI by 26% (95% CI, 3-44%; P=0.03) Online Data Supplement, Part II/15 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
Trial, year [ref no.] Patients N Intervention Primary End Point Follow-up Findings Early invasive treatment RR of composite primary end point ACS with chest Early inveasive (PCI by 7% (95% CI, –13% to 33%; pain, no ST- or CABG) or Composite all-cause P=0.33); mortality at 1 y was ICTUS, 2005 segment selectively invasive death, nonfatal MI, or low (2.5%) in both groups of 1200 1 y [57] elevation, and strategy (both + rehospitalization for high-risk patients; early elevated cardiac optimal medical anginal symptoms invasive treatment significantly troponin T levels therapy) RR of MI (P=0.005) but significantly RR of rehospitalization (P=0.04) UA 24 h Antithrombotic pretreatment (UFH, (myocardial Prolonged antithrombotic ischemia with aspirin, clopidogrel, ISAR-COOL, Composite all-cause pretreatment RR of composite ST-segment tirofiban) for 3-5 d 2003 410 mortality or large, 30 d end point (1.96 [95% CI, 1.01- depression and/or before PCI vs [58] nonfatal MI 3.82]; P=0.04) due to events cardiac troponin immediate (<6 h) occurring before catheterization T concentration coronary angiography ≥0.03 mg/L) and revascularization
Trial Acronyms: ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; ADMIRAL, Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up; ASSENT-4 PCI, Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention; CADILLAC, Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications; CAPTURE, C7E3 Fab Antiplatelet Therapy in Unstable Refractory angina; C-PORT, Atlantic Cardiovascular Patient Outcomes Research Team; EMERALD, Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris; EPISTENT, Evaluation of Platelet IIb/IIIa Inhibition in Stenting; FRESCO, Florence Randomized Elective Stenting in Acute Coronary Occlusions; FRISC II, FRagmin and Fast Revascularisation during InStability in Coronary artery disease; GRAMI, Gianturco-Roubin in Acute Myocardial Infarction; ICTUS, Invasive versus Conservative Treatment in Unstable Coronary Syndromes; ISAR-COOL, Intracoronary Stenting with Antithrombotic Regimen Cooling-Off; PACT, Plasminogen-activator Angioplasty Compatibility Trial; PAMI, Primary Angioplasty in Myocardial Infarction; PASTA, Primary Angioplasty versus Stent implantation in Acute myocardial infarction; PCI-CURE, Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events; RESTORE, Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis; RITA-3, Randomized Intervention Trial of unstable Angina; Stent-PAMI, Stent Primary Angioplasty in Myocardial Infarction; STOPAMI, Stent versus Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction; TACTICS (TIMI Online Data Supplement, Part II/16 Table 2. Clinical Trials of PCI for Acute Coronary Syndromes
18), Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy; VANQWISH, Veterans Affairs Non- Q-Wave Infarction Strategies in Hospital.
Other Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; DCA, directional coronary atherectomy; LV, left ventricular; MI, myocardial infarction; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RR, relative risk; rt-PA, recombinant tissue plasminogen activator; STEMI, ST-elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction study; t-PA, tissue plasminogen activator; TVR, target vessel revascularization; UA, unstable angina; UFH, unfractionated heparin. Online Data Supplement, Part II/17 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Fibrinolytics No difference in primary end point between aspirin + heparin vs aspirin alone or between streptokinase and t-PA/anistreplase; aspirin + heparin was associated with excess major noncerebral bleeds Streptokinase vs t-PA but no excess risk of stroke; ISIS-3, 1992 Suspected acute MI (duteplase) vs All-cause mortality at anistreplase was associated with 41,299 6 mo [59] 24 h anistreplase; aspirin + 35 d significantly more noncerebral heparin vs aspirin alone bleeds and a slight excess of strokes compared with streptokinase; t-PA was associated with significantly more reports of noncerebral bleeds and a significant excess of strokes compared with streptokinase Streptokinase (+ either subcutaneous or IV t-PA RR of mortality by 14% heparin) vs accelerated (95% CI, 5.9-21.3%; P=0.001) vs GUSTO I, 1993 STEMI <6 h 41,021 t-PA (+ IV heparin) vs All-cause mortality 30 d the 2 streptokinase-only strategies [60] combination and by 10% (95% CI, 0.8-19.2%; streptokinase/t-PA (+ P=0.04) vs combination therapy IV heparin) Alteplase nonsignificantly Alteplase 100 mg IV overall mortality; in patients LATE, 1993 over 3 h vs placebo treated <12 h after symptom Acute MI 6-24 h 5711 All-cause mortality 6 mo-1 y [61] (between 6-24 h after onset, alteplase significantly RR symptom onset) of 35-d mortality by 25.6% (95% CI, 6.3-45%; P=0.023) Online Data Supplement, Part II/18 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Double-bolus reteplase No significant difference in INJECT, 1995 (10 MU each, 30 min Equivalence in all- mortality, meeting the study STEMI 12 h 6010 35 d [62] apart) vs streptokinase cause mortality criterion for equivalence but not 1.5 MU IV over 60 min superiority Compared with alteplase, double- bolus reteplase (10+10 MU) Reteplase bolus Clinical significantly patency at 90 min RAPID, 1995 (various regimens) vs TIMI grade 2 or 3 STEMI <6 h 606 follow-up to (63% vs 49%; P=0.019) and at 5- [63] alteplase bolus + patency at 90 min 6 mo 14 d (88% vs 71%; P<0.001) infusion without an increased risk of complications Reteplase significantly infarct- Double-bolus reteplase related patency (TIMI grade 2 or Coronary patency as Clinical RAPID II, 1996 (10+10 MU) vs front- 3; 83.4% vs 73.3%; P=0.03) and STEMI 12 h 324 assessed by TIMI flow follow-up to [64] loaded, “accelerated” complete patency (TIMI grade 3; grade at 90 min 35 d alteplase 59.9% vs 45.2%; P=0.01) at 90 min and also at 60 min Double-bolus reteplase No significant difference in GUSTO III, STEMI or bundle- (10 MU each, 30 min primary end point or in combined 1997 15,059 All-cause mortality 30 d branch block 6 h apart) vs alteplase 100 end point of death or nonfatal, [65] mg infused over 90 min disabling stroke Study stopped early because of safety concerns with double Alteplase 100 mg via bolus; 30-d mortality rates were COBALT, 1997 accelerated infusion 7.98% for double bolus vs 7.53% STEMI 6 h 7169 All-cause death 30 d [66] over 90 min vs double for infusion; the one-sided 95% bolus 30 min apart upper boundary of 1.49% did not meet the prespecified definition of equivalence Online Data Supplement, Part II/19 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Tenecteplase 40 mg produced a similar rate of flow as alteplase at Single-bolus 90 min, but tenecteplase 30 mg Clinical TIMI 10B, 1998 tenecteplase 30 or 40 TIMI grade 3 flow at resulted in significantly lower rate STEMI 12 h 886 follow-up to [67] mg vs front-loaded 90 min of flow (54.3% vs 62.7%; 30 d alteplase P=0.035); no significant differences between groups in clinical events Covariate-adjusted 30-d mortality Single-bolus rates were almost identical; ASSENT-2, STEMI or left tenecteplase injection Equivalence in all- tenecteplase the rate of 1999 bundle-branch 16,949 vs front-loaded 30 d cause mortality noncerebral bleeding (P=0.0003) [68] block <6 h alteplase infusion (both and need for blood transfusions + aspirin and heparin) (P=0.0002) Single-bolus InTIME-II, 2000 lanoteplase 120 KU/kg All-cause mortality at Follow-up to No difference in mortality rates at STEMI 6 h 15,078 [69] vs accelerated alteplase 30 d 1 y 30 d, 6 mo, or 1 y 100 mg over 90 min Full-dose tenecteplase + enoxaparin; half-dose Mortality, in-hospital Enoxaparin RR by 26% ASSENT-3, STEMI or left tenecteplase with low- reinfarction, or in- (P=0.0002) vs UFH; 2001 bundle-branch 6095 dose UFH and a 12-h 30 d hospital refractory abciximab RR by 28% [70] block <6 h infusion of abciximab; ischemia full-dose tenecteplase (P<0.0001) vs UFH with UFH for 48 h Online Data Supplement, Part II/20 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Prehospital vs In-hospital Fibrinolytic Therapy At-home fibrinolysis RR of all- Anistreplase 30 U IV vs cause mortality by 49% (P=0.04); Suspected acute Time saving, adverse placebo, given either at full thickness Q-wave infarction GREAT, 1992 MI, seen at home events, Q-wave 311 home by a general 3 mo less common in patients with [71] 4 h of symptom infarction, left practitioner or in confirmed infarction receiving onset ventricular function hospital treatment at home(53.3% vs 67.9%; P=0.02) Prehospital group had Prehospital anistreplase nonsignificant 13% lower rate of followed by in-hospital EMIP, 1993 overall mortality; after adjustment Acute MI 6 h 5469 placebo vs prehospital All-cause death 30 d [72] for baseline variables, treatment placebo followed by in- had no significant effect on hospital anistreplase outcomes No difference in composite score; Prehospital vs hospital- Ranked composite secondary analysis showed that initiated thrombolytic score combining death, MITI, 1993 treatment within 70 min of STEMI 6 h 360 therapy with aspirin + stroke, serious NA [73] symptom onset (in hospital or not) alteplase (+ heparin in bleeding, and infarct significantly improved outcomes hospital) size (P=0.009 for composite score) Rate of primary end point 8.2% in fibrinolysis group vs 6.2% in angioplasty group (risk difference Prehospital fibrinolysis Composite death, 1.96; 95% CI, –1.53 to 5.46; CAPTIM, 2002 with accelerated nonfatal reinfarction, P=0.29) STEMI 6 h 840 30 d [74] alteplase vs primary and nonfatal disabling Unplanned revascularization angioplasty stroke (angioplasty or PTCA) performed in 34.5% of fibrinolysis group vs 4.7% of angioplasty group (P<0.0001) Online Data Supplement, Part II/21 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Enoxaparin primary efficacy Efficacy: Composite end point (14.2% vs 17.4%; all-cause mortality, in- P=0.08), with a significant hospital reinfarction, or difference in subgroup of patients Prehospital tenecteplase ASSENT-3 in-hospital refractory <75 y; no difference in primary plus either enoxaparin PLUS, 2003 STEMI 6 h 1639 ischemia; 30 d efficacy + safety end point up to 7 d or UFH for 48 [75] Efficacy/safety: above (18.3% vs 20.3%; P=0.3); h + in-hospital enoxaparin significantly risk of intracranial hemorrhage stroke and intracranial or major bleeding hemorrhage, especially in patients >75 y Antiplatelets: Glycoprotein IIb/IIIa Inhibitors No difference in primary end Composite all-cause point; abciximab significantly death, nonfatal decreased composite death, RAPPORT, reinfarction, or any Acute MI < 12 h, reinfarction, or urgent 1998 483 Abciximab vs placebo (urgent or elective) 6 mo undergoing PTCA revascularization at all time points [76] target-vessel evaluated (7 d, 30 d, 6 mo), but revascularization at 6 was associated with excess mo bleeding Angiographic efficacy: TIMI 3 flow rates were Alteplase 100 mg TIMI grade 3 flow at significantly higher in the 50-mg (control) vs abciximab 90 min; alteplase + abciximab group vs alone or in combination Clinical efficacy: all- the alteplase-only group at both with reduced-dose TIMI 14A, 1999 cause mortality, 60 min (72% vs 43%; P=0.0009) STEMI <12 h 888 alteplase or 30 d [77] recurrent MI, recurrent and 90 min (77% vs 62%; streptokinase (control + ischemia ≥5 min, P=0.02); no overall differences in standard-dose heparin; severe pump failure, rates of composite clinical end abciximab + low-dose revascularization point; abciximab did not increase heparin) procedures bleeding Online Data Supplement, Part II/22 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Full-dose reteplase TIMI 3 flow rates at 90 min were (10+10 U; control) vs 70% for reteplase alone, 73% for abciximab plus 5+5 U reteplase + abciximab, and reduced-dose reteplase TIMI 14B, 2000 77% for 10+5 U reteplase + STEMI <12 h 299 (control + standard- As in TIMI 14A 30 d [78] abciximab; the 10+5 U reteplase + dose heparin; abciximab group had numerically abciximab + low-dose higher mortality rate and higher or very-low-dose rates of hemorrhagic events heparin) Phase A: 62% abciximab- reteplase 5 + 5 U patients vs 27% Phase A: Abciximab abciximab-only patients had TIMI alone vs abciximab + grade 3 flow (P=0.001); Phase A: reteplase at various Clinical Phase B: 54% of abciximab- SPEED, 2000 304; TIMI grade 3 flow at Acute MI 12 h doses; Phase B: follow-up to reteplase patients vs 47% [79] Phase B: 60-90 min Abciximab + reteplase 30 d reteplase-only had TIMI grade 3 224 5 + 5 U vs reteplase 10 flow (P=0.32); rates of ischemic + 10 U alone complications and of composite CV events did not differ between groups Group I: double bolus eptifibatide (180/90 μg/kg, 30 min apart, with infusion of 1.33 Incidence of TIMI flow grade 3 at μg/kg/min) plus low- 60 min = 42%, 56%, and 40% for dose t-PA; Incidence of TIMI flow Groups I-III, respectively INTRO AMI, Acute MI, Clinical Group II: double bolus grade 3 at 60 ± 15 min (P=0.04, Group II vs Group III); 2002 candidates for 305 follow-up for eptifibatide (180/90 after administration of similar incidence of death, [80] fibrinolytic therapy 30 d μg/kg, 10 min apart, t-PA bolus reinfarction, or revascularization with infusion of 2.0 at 30 d among the 3 treatment μg/kg/min) plus low- groups dose t-PA; Group III: full-dose t-PA (control) Online Data Supplement, Part II/23 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Double-bolus eptifibatide (180 μg/kg, Double-bolus eptifibatide + half- 10 min apart, with dose tenecteplase tended to infusion of 2 INTEGRETI, Clinical improve angiographic flow and μg/kg/min) + half-dose TIMI grade 3 epicardial 2003 STEMI 6 h 249 follow-up to ST-segment resolution but was tenecteplase vs flow at 60 min [81] 30 d associated with more transfusions standard-dose and noncerebral bleeding vs tenecteplase tenecteplase monotherapy monotherapy (both + aspirin and UFH) Combination therapy was not inferior to standard reteplase in Standard-dose reteplase GUSTO V, 2001 risk of death (3% absolute risk STEMI 6 h 16,588 vs half-dose reteplase + All-cause mortality 30 d [82] reduction) but was associated full-dose abciximab with more non-intracranial bleeding complications Antiplatelets/Anticoagulants No significant difference in First occurrence of primary end point; spontaneous Aspirin 160 mg vs 33 mo (max); CARS, 1997 reinfarction, nonfatal major bleeding occurred Acute MI 3-21 d 8803 aspirin 80 mg + 14 mo [83] ischemic stroke, or CV significantly more often in 3-mg warfarin 1 or 3 mg (median) death warfarin group vs aspirin alone (P=0.014) No significant difference in total Combined warfarin mortality, recurrent MI, or stroke; CHAMP, 2002 (target INR 1.5-2.5 IU) 2.7 y Acute MI 14 d 5059 All-cause mortality major bleeding occurred more [84] and aspirin 81 mg/d vs (median) frequently in combination therapy aspirin 162 mg/d alone group (P<0.001) Chest pain ≥30 min Reocclusion occurred in 15% of and 6 h, refractory Aspirin plus coumadin APRICOT-2, Reocclusion of the patients taking aspirin + to nitrates; TIMI vs aspirin alone (both 2002 274 infarct-related artery at 3 mo coumadin vs 28% in those grade 3 flow in plus standard [85] angiographic follow-up receiving aspirin alone (RR infarct-related heparinization) reduction, 45%; P<0.02) artery Online Data Supplement, Part II/24 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Warfarin alone RR of primary end point by 19% (95% CI, 5- Warfarin (INR goal Composite death, 31%; P=0.03) vs aspirin alone; 2.8-4.2) vs aspirin 160 WARIS-II, 2002 nonfatal reinfarction, or Acute MI 3630 mg/d vs warfarin (INR 4 y (mean) warfarin + aspirin RR of [86] thromboembolic goal 2.0-2.5) + aspirin primary end point by 29% (95% cerebral stroke 75 mg/d CI, 17-40%; P=0.001) vs aspirin alone; warfarin was associated with a higher risk of bleeding Antiplatelets: Thienopyridines Clopidogrel RR of primary end Composite of occluded Clopidogrel (300-mg point by 36% (95% CI, 24-47%; infarct-related artery loading dose, then 75 P<0.001) and of 30-d composite CLARITY-TIMI (TIMI flow 0/1) on mg/d) vs placebo (both 30 d (clinical CV death, recurrent MI, or 28, 2005 STEMI 12 h 3491 angiography, death, or + standard fibrinolytic follow-up) recurrent ischemia requiring [87] MI by the time of therapy, aspirin, and urgent revascularization by 20% angiography (2-8 d heparin as appropriate) (95% CI, 3-35%; P=0.03) vs after randomization) placebo Clopidogrel RR of the primary (1) Composite of death, composite end point by 9% (95% COMMIT/CCS- Suspected acute MI Clopidogrel 75 mg/d vs reinfarction, or stroke CI, 3-14%; P=0.002) and RR of 2 (clopidogrel 24 h (93% STEMI 45,852 placebo (both added to and (2) All-cause death, 15 d (mean) in-hospital deaths by 7% (95% arm), 2005 or bundle branch aspirin) up to 4 wk in hospital CI, 1-13%; P=0.03) vs placebo; [88] block) or prior to discharge no difference between groups in rate of major bleeding events Antithrombins: LMWH Enoxaparin vs UFH for TIMI 2 and 3 5% absolute difference in patency HART II, 2001 ≥3 d (+aspirin and reperfusion rates at 90 5-7 d (repeat rates at 90 min confirmed STEMI 12 h 400 [89] accelerated minutes (noninferiority angiography) noninferiority of enoxaparin and rt-PA) hypothesis) approached superiority Online Data Supplement, Part II/25 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Rate of TIMI grade 3 flow was Angiographic efficacy: similar among all enoxaparin TIMI grade 3 flow at patients and all UFH patients; Enoxaparin vs UFH as 60 min in the infarct- clinical events at 30 d occurred in adjunctive therapy to ENTIRE-TIMI related artery; 4.4% of enoxaparin patients vs either full-dose 23, 2002 STEMI 6 h 483 Clinical efficacy: 30 d 15.9% of UFH patients (P=0.005) tenecteplase or half- [90] composite all-cause on full-dose tenecteplase, but no dose tenecteplase + death and nonfatal MI; significant difference in abciximab Safety: TIMI major combination-therapy group; hemorrhage no significant differences in major hemorrhage Composite death, Enoxaparin and UFH had similar Enoxaparin, enoxaparin STEMI, ineligible reinfarction, or effects on primary end point TETAMI, 2003 + tirofiban, UFH, or for reperfusion 1224 recurrent angina in 30 d (15.7% and 17.3%, respectively); [91] UFH + tirofiban (all + therapy pooled enoxaparin and tirofiban did not appear to provide aspirin) UFH groups additional clinical benefit Antithrombins: Direct Thrombin Inhibitors Composite death, Hirudin vs heparin recurrent nonfatal MI, TIMI 9B, 1996 No significant difference in Acute MI 12 h 3002 (+aspirin and t-PA or or development of 30 d [92] primary end point streptokinase) severe CHF or cardiogenic shock No difference in primary end point; bivalirudin significantly Bivalirudin vs UFH All-cause mortality RR of reinfarction within 96 h by HERO-2, 2001 (both, bolus + 48-h (Secondary: 30% (95% CI, 13-44%; P=0.001) Acute STEMI 6 h 17,073 30 d [93] infusion) (+ reinfarction within 96 but risk of severe bleeding (58 streptokinase) h; bleeding) vs 40 patients; P=0.07) and intracerebral bleeding (47 vs 32 patients; P=0.09) Online Data Supplement, Part II/26 Table 3. Clinical Trials of Medical Therapy in STEMI
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Beta-Blocker No significant difference in either (1) Composite of death, primary outcome; metoprolol Metoprolol (up to 15 COMMIT/CCS- Suspected acute MI reinfarction, or cardiac RR of reinfarction by 18% and of mg IV over 15 min, 2 (metoprolol 24 h (93% STEMI arrest and (2) All-cause ventricular fibrillation by 17% vs 45,852 then 200 mg/d orally) 15 d (mean) arm), 2005 or bundle branch death, up to 4 wk in vs placebo (both added placebo (both, P=0.001) but RR [94] block) hospital or prior to to aspirin) of cardiogenic shock by 30% discharge (P<0.00001), chiefly on the first day of hospitalization
Trial Acronyms: APRICOT-2, Antithrombotics in the Prevention of Reocclusion In COronary Thrombolysis-2; ASSENT-2, Assessment of the Safety and Efficacy of a New Thrombolytic; ASSENT-3, Assessment of the Safety and Efficacy of a New Thrombolytic Regimen; CAPTIM, Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction; CARS, Coumadin Aspirin Reinfarction Study; CHAMP, Combination Hemotherapy and Mortality Prevention; CLARITY-TIMI 28, Clopidogrel as Adjunctive Reperfusion Therapy– Thrombolysis in Myocardial Infarction 28; COBALT, Continuous Infusion versus Double-Bolus Administration of Alteplase; COMMIT/CCS-2, Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study; EMIP, European Myocardial Infarction Project; ENTIRE-TIMI 23, ENoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy in ST Elevation MI–Thrombolysis in Myocardial Infarction 23; GREAT, Grampian Region Early Anistreplase Trial; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; GUSTO I, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HART, Heparin and Aspirin Reperfusion Therapy; HERO, Hirulog and Early Reperfusion or Occlusion; INJECT, International Joint Efficacy Comparison of Thrombolytics; INTEGRETI, Integrilin and Tenecteplase in Acute Myocardial Infarction; InTIME, Intravenous NPA for the Treatment of Infarcting Myocardium Early; INTRO AMI, Integrilin and Low-Dose Thrombolysis in Acute Myocardial Infarction; ISIS-3, Third International Study of Infarct Survival; LATE, Late Assessment of Thrombolytic Efficacy; MITI, Myocardial Infarction Triage and Intervention; RAPID, Recombinant plasminogen activator Angiographic Phase II International Dose-finding study; RAPID II, Reteplase (r-PA) vs Alteplase Patency Investigation During myocardial infarction; RAPPORT, ReoPro And Primary PTCA Organization and Randomized Trial; SPEED, Strategies for Patency Enhancement in the Emergency Department; TETAMI, Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction; TIMI, Thrombolysis in Myocardial Infarction; TIMI 9B, Thrombolysis and Thrombin Inhibition in Myocardial Infarction; WARIS II, Warfarin Aspirin Reinfarction Study.
Other Abbreviations: CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; MI, myocardial infarction; NA, data not available; PTCA, percutaneous transluminal coronary angioplasty; RR, relative risk; rt-PA, recombinant tissue plasminogen activator; STEMI, ST-elevation myocardial infarction; t-PA, tissue plasminogen activator; UFH, unfractionated heparin. Online Data Supplement, Part II/27 Table 4. Clinical Trials in Post-MI Patients
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Beta-Blocker Carvedilol RR of all-cause Acute MI 3-21 d, All-cause mortality CAPRICORN, mortality by 23% (95% CI, 2- LVEF 40%, Carvedilol up to 25 and all-cause 1.3 y 2001 1959 40%; P=0.03); no difference in ACE-inhibitor mg bid vs placebo mortality or CV (mean) [95] combined all-cause mortality treatment hospital admissions and CV hospital admissions ACE Inhibitors Study terminated early because Acute MI <24 h, Enalapril (beginning of higher mortality in enalapril- CONSENSUS BP >100/60 mm with infusion, then treated patients (10.2% vs 9.4% II, 1992 6090 All-cause mortality 6 mo Hg (later changed orally up to 20 mg/d) with placebo; P=0.26), possibly [96] to >105/65) vs placebo because of hypotensive reactions in elderly patients Post-MI (3-16 d) patients with Captopril RR of all-cause LVEF 40% but All-cause mortality; mortality (19%; P=0.019), CV SAVE, 1992 Captopril 6.25-50 mg 42 mo no HF or 2231 CV mortality; CV death (21%; P=0.014), and [97] tid vs placebo (average) evidence of morbidity; others recurrent MI (25%; P=0.015) vs myocardial placebo ischemia Enalapril RR of all-cause mortality by 8% (95% CI, –8 to Total mortality 21%; P=0.30 [NS]), SOLVD Asymptomatic (Secondary: Enalapril 2.5-20 mg/d 37.4 mo development of HF by 37% Prevention, 1992 CHD patients 4228 incidence of HF and vs placebo (mean) (95% CI, 28-44%; P<0.001), [98] with LVEF 35% hospitalizations for and of first HF hospitalization HF) by 36% (95% CI, 22-46%; P<0.001) vs placebo Online Data Supplement, Part II/28 Table 4. Clinical Trials in Post-MI Patients
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Lisinopril RR of all-cause mortality by 12% (95% CI, 1- 21%; 2P=0.03) and of Lisinopril 10 mg/d combined end point by 10% and/or transdermal All-cause mortality; (95% CI, 2-18%; 2P=0.009) vs GISSI-3, 1994 glyceryl trinitrate combined mortality Acute MI 24 h 19,394 6 wk control; [99] (GTN) vs open plus CHF or no independent effect in control (no trial extensive LV damage reducing risk for GTN vs therapy) control; lisinopril + GTN RR of all-cause mortality by 17% (95% CI, 3-30%) vs control Oral captopril up to 50 mg bid for 1 mo Captopril significantly RR of vs placebo; oral primary end point by 7% (95% mononitrate up to 60 CI, 1-13%; 2P=0.02), with ISIS-4, 1995 Suspected acute Total mortality at 5 58,050 mg/d for 1 mo vs >1 y greater benefit among high-risk [100] MI 24 h wk placebo; IV groups (prior MI, HF); no magnesium sulfate mortality benefit observed with for 24 h vs open the other treatments studied control Zofenopril RR of primary end point by 34% (95% CI, 8-54%; SMILE, 1995 Acute anterior Zofenopril (up to 30 All-cause mortality or 1556 6 wk P=0.018); at 1-y follow-up, [101] MI 24 h mg bid) vs placebo severe CHF zofenopril RR of death by 29% (95% CI, 6-51%; P=0.011) Trandolapril significantly RR Post-MI (3-7 d) of all-cause mortality by 22% TRACE, 1995 Trandolapril 1-4 patients with 1749 All-cause mortality 24-50 mo (95% CI, 9-33%; P=0.001) and [102] mg/d vs placebo LVEF 35% of CV death by 25% (95% CI, 11-37%; P=0.001) Captopril nonsignificantly All-cause mortality, mortality (P=0.2) and CCS, 1997 Suspected acute Captopril 12.5 mg tid 14,962 other in-hospital CV 4 wk significantly incidence of HF [103] MI 36 h vs placebo events (absolute reduction, 1.7%; P=0.01) Online Data Supplement, Part II/29 Table 4. Clinical Trials in Post-MI Patients
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings ARBs No significant difference in primary end point: 499 (18%) deaths in losartan group vs 447 Patients surviving (16%) deaths in captopril group OPTIMAAL, acute MI with Losartan 50 mg/d vs 2.7 y (P=0.07); no significant 2002 5477 All-cause mortality clinical HF captopril 50 mg tid (mean) differences in sudden cardiac [104] symptoms death or resuscitated cardiac arrests, fatal or nonfatal reinfarctions, or all-cause hospital admissions No difference in primary end point among treatment groups; Valsartan (up to 160 valsartan met the prespecified mg bid), captopril (up margin for noninferiority to VALIANT, Acute MI 0.5-10 to 50 mg tid), or 24.7 mo captopril for mortality and for 2003 14,703 All-cause mortality d valsartan + captopril (median) the composite end point of fatal [105] (up to 80 mg bid/50 and nonfatal CV events; mg tid) combination therapy increased the rate of adverse events without improving survival Aldosterone Antagonist All-cause mortality; Eplerenone RR of all-cause CV death or mortality by 15% (95% CI, 4- EPHESUS, 2003 Post-MI, LVEF Eplerenone 25-50 hospitalization for 16 mo 25%; P=0.008) and combined 6632 [106] 40% and/or HF mg/d vs placebo HF, acute MI, stroke, (mean) death/hospitalization for CV or ventricular causes by 13% (95% CI, 5- arrhythmia 21%; P=0.002) Online Data Supplement, Part II/30 Table 4. Clinical Trials in Post-MI Patients
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Anticoagulants/Antiplatelets No significant difference in Coumarin total deaths, but anticoagulant (nicoumalone or treatment significantly RR of ASPECT, 1994 All-cause mortality, 37 mo Post MI 3404 phenprocoumon) vs recurrent MI by 53% (95% CI, [107] MI, stroke (mean) placebo within 6 wk 41-62%) and of cerebrovascular of hospital discharge events by 40% (95% CI, 10- 60%) Recent ischemic stroke (6 mo), Composite ischemic Clopidogrel RR of composite CAPRIE, 1996 Clopidogrel 75 mg/d 1.91 y 19,185 stroke, MI, or end point by 8.7% (95% CI, [108] recent MI (35 d), vs aspirin 325 mg/d (mean) or symptomatic vascular death 0.3-16.5%; P=0.043) PAD Coumadin RR of primary end Aspirin (equivalent to point by 45% (95% CI, 0-70%; 80 mg/d), coumadin 12 mo ASPECT-2, Acute MI or P=0.0479) vs aspirin alone; with target INR of First occurrence of (median); 2002 unstable angina 999 3.0-4.0, or aspirin + MI, stroke, or death 26 mo combination therapy RR of [109] pectoris <8 wk coumadin with target (max) primary end point by 50% (95% INR of 2.0-2.5 CI, 8-73%; P=0.03) vs aspirin alone
Trial Acronyms: ASPECT, Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis; CAPRICORN, Carvedilol Post- Infarct Survival Control in Left Ventricular Dysfunction; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; CCS, Chinese Cardiac Study; CONSENSUS II, Cooperative New Scandinavian Enalapril Survival Study II; EPHESUS, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico; ISIS-4, Fourth International Study of Infarct Survival; OPTIMAAL, Optimal Therapy In Myocardial Infarction with the Angiotensin II Antagonist Losartan; SAVE, Survival And Ventricular Enlargement; SMILE, Survival of Myocardial Infarction Long-term Evaluation; SOLVD, Studies of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation; VALIANT, Valsartan in Acute Myocardial Infarction.
Other Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CHD, coronary heart disease; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HF, heart failure; INR, international normalized ratio; LV, left ventricular; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NS, not significant; PAD, peripheral arterial disease; RR, relative risk. Online Data Supplement, Part II/31 Table 5. Clinical Trials of Medical Therapy in Heart Failure
Trial, year [ref no.] Patients N Agent* Primary End Point Follow-up Findings ACE Inhibitors Enalapril RR of all-cause mortality by 16% (95% CI, 5- SOLVD HF, ejection Enalapril 2.5-20 mg/d 41.4 mo 26%; P=0.0036) and deaths or Treatment, 1991 2569 All-cause mortality fractions 35% vs placebo (mean) hospitalizations for HF by 26% [110] (95% CI, 18-34%; P<0.0001) vs placebo Patients surviving Ramipril RR by 27% vs AIRE, 1993 acute MI who Ramipril 1.25-5 mg 15 mo 2006 All-cause mortality placebo (95% CI, 11-40%; [111] had clinical HF bid vs placebo (mean) P=0.002) symptoms Long-term Ramipril RR by 36% vs AIREX, 1997 Ramipril 1.25-5 mg 59 mo follow-up of 603 All-cause mortality placebo (95% CI, 15-52%; [112] bid vs placebo (mean) AIRE patients P=0.002) High-dose RR of all-cause mortality by 8% (95% CI, –3 to Low-dose (2.5-5 NYHA class II- 18%; P=0.128 [NS]), death or ATLAS, 1999 mg/d ) vs high-dose 45.7 mo IV HF; LVEF 3164 All-cause mortality any hospitalization by 12% [113] (32.5-35 mg/d) (median) 30% (95% CI, 4-18%; P=0.002), and lisinopril HF hospitalizations by 24% (P=0.002) ARBs No significant differences in Elderly patients all-cause mortality (11.7% (60 y; mean, losartan vs 10.4% captopril; ELITE II, 2000 Losartan 50 mg/d vs 555 d 71.5 y) with 3152 All-cause mortality P=0.16) or in sudden death or [114] captopril 50 mg tid (median) NYHA class II- resuscitated cardiac arrests (9% IV HF losartan vs 7.3% captopril; P=0.08) Online Data Supplement, Part II/32 Table 5. Clinical Trials of Medical Therapy in Heart Failure
Trial, year [ref no.] Patients N Agent* Primary End Point Follow-up Findings No difference in all-cause All-cause mortality; mortality; valsartan Val-HeFT, 2001 NYHA class II- Valsartan 160 mg bid combined CV 23 mo significantly RR of combined 5010 [115] IV HF vs placebo mortality and (mean) end point by 13% (97.5% CI, 3- morbidity 23%; P=0.009), mainly due to fewer hospitalizations for HF Candesartan covariate CHARM- Candesartan (target adjusted RR of primary end OVERALL, NYHA class II- 37.7 mo 7599 dose 32 mg/d) vs All-cause mortality point by 10% (95% CI, 1-18%; 2003 IV HF (median) placebo P=0.032), with fewer CV [116] deaths and HF hospitalizations CHARM- NYHA class II- Candesartan (target Composite CV death Candesartan covariate ADDED, IV HF, LVEF 41 mo 2548 dose 32 mg/d) vs or hospital admission adjusted RR by 15% (95% CI, 2003 40%, taking (median) placebo for CHF 4-25%; P=0.01) [117] ACE inhibitors CHARM- NYHA class II- Candesartan (target Composite CV death Candesartan covariate ALTERNATIV IV HF, LVEF 33.7 mo 2028 dose 32 mg/d) vs or hospital admission adjusted RR by 30% (95% CI, E, 2003 40%, intolerant (median) placebo for CHF 19-40%; P<0.0001) [118] of ACE inhibitors CHARM- NYHA class II- Candesartan (target Composite CV death Candesartan covariate PRESERVED, 36.6 mo IV HF, LVEF 3023 dose 32 mg/d) vs or hospital admission adjusted RR by 14% (95% CI, 2003 (median) >40% placebo for CHF 0-26%; P=0.051 [NS]) [119] Beta-Blockers Carvedilol RR of all-cause US Carvedilol, Death or mortality by 65% (95% CI, 39- Carvedilol up to 50 6.5 mo 1996 HF, LVEF 35% 1094 hospitalization for 80%; P<0.001) and CV mg bid vs placebo (median) [120] CV causes hospitalizations by 27% (95% CI, 3-45%; P=0.036) Online Data Supplement, Part II/33 Table 5. Clinical Trials of Medical Therapy in Heart Failure
Trial, year [ref no.] Patients N Agent* Primary End Point Follow-up Findings At 12 mo, carvedilol LVEF Changes in LVEF by 5.3% (2P<0.0001) vs and treadmill exercise 12 mo placebo, with no change in duration (primary); treadmill exercise time; ANZ, 1997 Chronic stable Carvedilol 6.25 mg 415 (Secondary: 19 mo [121] HF, LVEF <45% bid vs placebo at 19 mo, carvedilol RR of frequency of death, (mean; death or hospital admission by hospital admission, or clinical) 26% (95% CI, 5-43%; worsening HF) 2P=0.02), but no difference in frequency of worsening HF Bisoprolol RR of all-cause NYHA class III- mortality by 34% (95% CI, 19- CIBIS-II, 1999 Bisoprolol 1.25-10 1.3 y IV HF, LVEF 2647 All-cause mortality 46%; P<0.0001) and of sudden [122] mg/d vs placebo (mean) 35% deaths by 44% (95% CI, 20- 61%; P=0.0011) NYHA class III- BEST, 2001 Bucindolol up to 100 Nonsignificant trend for lower IV HF, LVEF 2708 All-cause mortality 2 y (mean) [123] mg bid vs placebo mortality in bucindolol group 35% Carvedilol RR of all-cause mortality by 35% (95% CI, 19- 48%; P=0.0014), combined COPERNICUS, death or hospitalization for CV Symptoms of HF, Carvedilol up to 25 10.4 mo 2001, 2002 2289 All-cause mortality events by 27% (95% CI, 16- LVEF <25% mg bid vs placebo (mean) [124, 125] 37%; P<0.0001), and combined death or hospitalization for HF by 31% (95% CI, 19-41%; P<0.0001) Online Data Supplement, Part II/34 Table 5. Clinical Trials of Medical Therapy in Heart Failure
Trial, year [ref no.] Agent Patients N Primary End Point Follow-up Findings NYHA class II- All-cause mortality; Carvedilol RR of all-cause IV HF, previous Carvedilol 25 mg bid composite all-cause mortality by 17% (95% CI, 7- COMET, 2003 58 mo admission for CV 3029 vs metoprolol 50 mg mortality and all- 26%; P=0.0017) and composite [126] (mean) event, LVEF bid cause hospital end point by 6% (95% CI, –2 to <35% admission 14%; P=0.122) NYHA class II- Metoprolol CR/XL 1 y (mean) IV HF, LVEF Metoprolol RR of all-cause MERIT-HF 12.5 mg/d (class III- (study 40% on 3991 All-cause mortality mortality by 34% (95% CI, 19- [127] IV) or 25 mg/d (class terminated standard HF 47%; P<0.0001) II) vs placebo early) therapy Aldosterone Antagonist NYHA class III- 24 mo IV HF, LVEF Spironolactone RR of all- RALES, 1999 Spironolactone 25 (mean; 35%, receiving 1663 All-cause mortality cause mortality by 30% (95% [128] mg/d vs placebo terminated ACE inhibitors CI, 18-40%; P<0.001) early) and diuretics Digoxin No difference in primary end Digoxin (median point; digoxin significantly DIG, 1997 37 mo HF, LVEF 45% 6800 dose 0.25 mg/d) vs All-cause mortality RR of hospitalization for [129] (mean) placebo worsening HF by 28% (95% CI, 21-34%; P<0.001) Direct Vasodilators Study terminated early because Composite score of significantly higher mortality comprising weighted African in placebo group (10.2% vs Isosorbide values for all-cause A-HeFT, 2004 Americans with 10 mo 6.2%; P=0.02); primary 1050 dinitrate/hydralazine death, first [130] NYHA class III- (mean) composite endpoint score vs placebo hospitalization for IV HF significantly better in active- HF, and change in treatment group vs placebo QOL (P=0.01) Online Data Supplement, Part II/35 Table 5. Clinical Trials of Medical Therapy in Heart Failure
*Subjects in all trials continued to receive standard HF therapy in addition to the study medications.
Trial Acronyms: A-HeFT, African-American Heart Failure Trial; AIRE, Acute Infarction Ramipril Efficacy; AIREX, AIRE extension; ANZ, Australia/New Zealand Heart Failure Research Collaborative Group; ATLAS, Assessment of Treatment with Lisinopril And Survival; BEST, Beta-blocker Evaluation of Survival Trial; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; CIBIS, Cardiac Insufficiency Bisoprolol Study; COMET, Carvedilol Or Metoprolol European Trial; COPERNICUS, Carvedilol Prospective Randomized Cumulative Survival; DIG, Digoxin Digitalis Investigation Group; ELITE II, Losartan Heart Failure Survival Study; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure; RALES, Randomized Aldactone Evaluation Study; SOLVD, Studies of Left Ventricular Dysfunction; Val-HeFT, Valsartan Heart Failure Trial.
Other Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NS, difference not significant; NYHA, New York Heart Association; QOL, quality of life; RR, relative risk. Online Data Supplement, Part II/36 Table 6. Clinical Trials of Cardiac Resynchronization Therapy in Heart Failure
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings In 48 patients who completed Atriobiventricular both phases of the study, active NYHA class III pacemaker during pacing significantly 6-min MUSTIC, 2001 6-min walk distance 6 mo (3-mo HF, QRS interval 67 active pacing vs walk distance (23%, P<0.001), [131] (Secondary: QOL) crossover) >150 msec inactive pacing QOL score (32%, P<0.001), (ventricular inhibited) and hospitalizations by two thirds (P<0.05) Compared with baseline, BiV 131 (67 Biventricular pacing pacing improved 6-min walk normal (BiV) vs inactive distance (SR group, 20% , sinus pacing (SR group) or rhythm BiV pacing vs right P=0.0001; AF group, 17% , MUSTIC NYHA class III 6-min walk distance, [SR], univentricular rate- P=0.004), peak oxygen uptake follow-up, 2002 HF, QRS interval peak oxygen uptake, 12 mo 64 adaptive, ventricular- (SR group, 11%; AF group, [132] >150 msec QOL, NYHA class atrial inhibited pacing (AF 9%), QOL (SR group 36%, fibril- group) for 6-mo P=0.0001; AF group, 32%, lation crossover phase; then P=0.002), and NYHA class (SR [AF]) BiV pacing to 12 mo group, 25%, P=0.0001; AF group, 27%, P=0.0001) Resynchronization significantly NYHA class III- improved functional class MIRACLE Cardiac NYHA functional IV HF, LVEF (P<0.001), 6-min walk distance (InSync), 2002 453 resynchronization class, QOL, and 6- 6 mo 35%, QRS (+39 vs +10 m, P=0.005), and [133] (InSync) vs control min walk distance interval ≥130 sec QOL (–18 vs –9 points, P=0.001) NYHA class III- IV HF, LVEF CRT patients had greater 35%, QRS Changes from Combined ICD and improvements in median QOL MIRACLE-ICD, interval 130 baseline to 6 mo in CRT vs controls score (P=0.02) and functional 2003 msec, and high 369 QOL, NYHA 6 mo (ICD activated, CRT class (P=0.007) vs controls, but [134] risk of life- functional class, and off) no difference in 6-min walk threatening 6-min walk distance distance ventricular arrhythmias Online Data Supplement, Part II/37 Table 6. Clinical Trials of Cardiac Resynchronization Therapy in Heart Failure
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings For Optimal primary pharmacologic end point, therapy alone vs in Compared with pharmacologic NYHA class III- median of combination with therapy alone, pacemaker RR COMPANION, IV HF (ischemic Composite of time to 11.9 mo, cardiac by 19% (95% CI, 4-31%; 2004 or nonischemic), 1520 all-cause death or any 16.2 mo, resynchronization P=0.014) and pacemaker- [135] QRS interval of hospitalization and 15.7 therapy with either a defibrillator RR by 20% (95% ≥120 msec mo in the 3 pacemaker or a groups, CI, 5-32%; P=0.010) pacemaker- respectivel defibrillator y NYHA class III- CRT added to medical therapy IV HF due to LV Time to all-cause Standard medical the RR of primary end point systolic death or an CARE-HF, 2005 therapy alone vs 29.4 mo by 37% (95% CI, 23-49%; dysfunction, 813 unplanned [136] medical therapy with (mean) P<0.001) and RR of all-cause cardiac hospitalization for a CRT (no ICD) death by 36% (95% CI, 15- dyssynchrony, major CV event 52%; P<0.002) LVEF 35%
Trial Acronyms: CARE-HF, Cardiac ResynchronizationHeart Failure; COMPANION, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; MIRACLE (InSync), Multicenter InSync Randomized Clinical Evaluation; MIRACLE-ICD, Multicenter InSync ICD Randomized Clinical Evaluation; MUSTIC, Multisite Stimulation in Cardiomyopathies.
Other Abbreviations: CI, confidence interval; CRT, cardiac resynchronization therapy; CV, cardiovascular; HF, heart failure; ICD, implantable cardioverter defibrillator; LV, left ventricular; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; QOL, quality of life; RR, relative risk. Online Data Supplement, Part II/38 Table 7. Selected Clinical Trials in Arrhythmia Management
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings Implantable Cardioverter Defibrillators (ICDs) ICD vs Survivors of antiarrhythmic drug ICD was associated with a cardiac arrest therapy (amiodarone, nonsignificant 23% reduction in CASH, 2000 secondary to propafenone 57 ± 34 mo 288 All-cause mortality all-cause mortality; the benefit [137] documented [discontinued (mean) was more evident during the ventricular because of excess first 5 y after the index event arrhythmias mortality], or metoprolol) Resuscitated ventricular ICD nonsignificantly RR of Mean: 2.9 fibrillation, All-cause mortality mortality by 20% (95% CI, –7.7 CIDS, 2000 y (amio- ventricular 659 ICD vs amiodarone (Secondary: death to 40%; P=0.142) and of [138] darone), tachycardia, or from arrhythmia) arrhythmic death by 33% (95% 3.0 y (ICD) unmonitored CI, –7.2 to 57.8%; P=0.094) syncope Survivors of near-fatal Crude death rates during ventricular ICD vs follow-up were 15.8 ± 3.2% for AVID, 1997 fibrillation, or antiarrhythmic drugs 18.2 ± 12.2 ICD vs 24.0 ± 3.7% for 1013 All-cause mortality [139] cardioversion (primarily mo (mean) antiarrhythmic drugs (P<0.02, from sustained amiodarone) adjusted for sequential ventricular monitoring) tachycardia NYHA class I-III HF, prior MI, MADIT, 1996 LVEF 35%, ICD vs conventional 27 mo ICD RR of mortality by 54% 196 All-cause mortality [140] documented medical therapy (mean) (95% CI, 18-74%; P=0.009) ventricular tachycardia Online Data Supplement, Part II/39 Table 7. Selected Clinical Trials in Arrhythmia Management
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings Antiarrhythmic therapy 5-y Electrophysiologi- CAD, LVEF Kaplan-Meier estimates of RR cally guided 40%, and of primary end point by 27% antiarrhythmic Cardiac arrest or MUSTT, 1999 asymptomatic, 39 mo (95% CI, 1-47%; P=0.04) vs no 704 therapy (including death from [141] unsustained (median) drugs and/or ICD) vs arrhythmia antiarrhythmic therapy; ICD ventricular no antiarrhythmic RR of primary end point by tachycardia therapy 76% (95% CI, 55-87%; P<0.001) vs no ICD ICD RR of mortality by 31% (95% CI, 7-49%; P=0.016); the MADIT II, 2002 Prior MI, LVEF ICD vs conventional 20 mo effect was similar in subgroup 1232 All-cause mortality [142] 30% medical therapy (mean) analyses stratified according to age, sex, EF, NYHA class, and QRS interval No difference in all-cause Acute MI 6-40 d, mortality; compared with no All-cause mortality LVEF 35%, at ICD, ICD RR of death from DINAMIT, 2004 (Secondary: death 30 ± 13 mo high risk for 674 ICD vs no ICD cardiac arrhythmia by 58% [143] due to cardiac (mean) ventricular (95% CI, 17-78%; P=0.009) but arrhythmia) arrhythmias RR of nonarrhythmic death by 75% (P=0.02) Shock-only, single- ICD RR of mortality by 23% NYHA class II- lead ICD vs placebo; (97.5% CI, 4-38%; P=0.007) vs SCD-HeFT, III HF (ischemic amiodarone vs 2005 2521 All-cause mortality 5 y placebo; amiodarone slightly or nonischemic), placebo (all plus [144] risk of mortality vs placebo LVEF 35% conventional HF (hazard ratio, 1.06; 97.5% CI, therapy) 0.86–1.30; P=0.53) Online Data Supplement, Part II/40 Table 7. Selected Clinical Trials in Arrhythmia Management
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings Atrial Arrhythmia: Rhythm Control vs Rate Control Cardioversion and/or antiarrhythmic drugs (eg, amiodarone, Rhythm control sotalol) to maintain nonsignificantly risk of all- 3.5 y Atrial fibrillation sinus rhythm vs use cause mortality (hazard ratio, AFFIRM, 2002 (mean); and high risk of 4060 of heart rate- All-cause mortality 1.15; 95% CI, 0.99-1.34; [145] maximum stroke or death controlling drugs (eg, P=0.08); rhythm control was 6 y beta-blockers, associated with more adverse nondihydropyridine drug effects calcium channel blockers) Serial cardioversions + antiarrhythmic Primary end point occurred in Composite of CV drugs (eg, sotalol, 17.2% of rate-control group vs death, HF, flecainide, 22.6% of rhythm-control group; thromboembolic propafenone) to the absolute difference reflects Persistent atrial complications, maintain sinus a trend in favor of rate control, RACE, 2002 fibrillation after a bleeding, need for 2.3 y 522 rhythm vs use of and the 90% CI met the [146] prior electrical pacemaker (mean) heart rate-controlling criterion for noninferiority; the cardioversion implantation, or drugs (eg, digitalis, distribution of the various severe adverse effects beta-blockers, components of the primary end of antiarrhythmic nondihydropyridine point was similar in the 2 drugs calcium channel groups blockers) Online Data Supplement, Part II/41 Table 7. Selected Clinical Trials in Arrhythmia Management
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings Physiologic vs Ventricular Pacing All-cause mortality, Atrial pacing RR of mortality CV death, atrial by 34% (95% CI, 1-56%; Single-chamber atrial fibrillation, P=0.045), CV death by 53% Anderson et al, Sick-sinus pacing vs single- thromboembolic (95% CI, 18-73%; P=0.0065), 1997 225 8 y syndrome chamber ventricular events, HF, and and atrial fibrillation by 46% [147] pacing atrioventricular block (95% CI, 11-67%; P=0.012); (in the atrial pacing HF was less severe in the atrial group) pacing group (P<0.05) Scheduled for a first implantation Physiologic (dual- of a pacemaker to chamber or atrial) CTOPP, 2000 Combined stroke or No significant difference in treat symptomatic 2568 pacing vs single- 3 y (mean) [148] CV death primary outcome bradycardia; no chamber (ventricular) chronic atrial pacing fibrillation Standard indications for Dual-chamber pacing was ICD implantation associated with an increased 8.4 mo but without Composite of time to risk of the primary end point Dual-chamber pacing (median) DAVID, 2002 indications for death or first (relative hazard, 1.61; 95% CI, 506 vs backup ventricular [trial [149] antibradycardia hospitalization for 1.06-2.44; P0.03); 1-y event- pacing terminated pacing, LVEF congestive HF free survival rates were 73.3% early] 40%, no for dual-chamber pacing vs persistent atrial 83.9% for backup pacing arrhythmias Online Data Supplement, Part II/42 Table 7. Selected Clinical Trials in Arrhythmia Management
Trial, year [ref no.] Patients N Agent/Device Primary End Point Follow-up Findings No significant difference in Sinus-node primary end point; dual- dysfunction Single-chamber chamber pacing RR of atrial MOST, 2002 All-cause death or requiring 2010 ventricular pacing vs 5 y fibrillation by 21% (95% CI, 6- [150] nonfatal stroke permanent pacing dual-chamber pacing 34%; P=0.008) and decreased for bradycardia signs and symptoms of HF (P<0.001)
Trial Acronyms: AFFIRM, Atrial Fibrillation Follow-up Investigation of Rhythm Management; AVID, Antiarrhythmics versus Implantable Defibrillators; CASH, Cardiac Arrest Study Hamburg; CIDS, Canadian Implantable Defibrillator Study; CTOPP, Canadian Trial of Physiologic Pacing; DAVID, Dual Chamber and VVI Implantable Defibrillator; DINAMIT, Defibrillator in Acute Myocardial Infarction Trial; MADIT, Multicenter Automatic Defibrillator Implantation Trial; MOST, Mode Selection Trial in Sinus-Node Dysfunction; MUSTT, Multicenter Unsustained Tachycardia Trial; RACE, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation; SCD-HeFT, Sudden Cardiac Death in Heart Failure trial.
Other Abbreviations: CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; EF, ejection fraction; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; RR, relative risk. Online Data Supplement, Part II/43 Table 8. Selected Clinical Trials in Stroke Prevention
Trial, year [ref no.] Patients N Agent/Intervention Primary End Point Follow-up Findings Carotid Endarterectomy Carotid Cerebral infarction in Surgery estimated 5-y RR of Asymptomatic endarterectomy vs the distribution of the ACAS, 1995 2.7 y ipsilateral stroke and any carotid artery 1662 medical risk-factor study artery; any [151] (median) perioperative stroke or death by stenosis ≥60% management (both + stroke or death in the 53% (95% CI, 22-72%) aspirin) perioperative period Cumulative risk of any Prior stroke or Carotid ipsilateral stroke was 26% for TIA <120 d and Fatal and nonfatal NASCET, 1995 endarterectomy vs medical care and 9% for ipsilateral carotid 659 stroke, all-cause 2 y [152] medical management surgery (P<0.001); for major or artery stenosis of death (both + aspirin) fatal stroke, 13.1% and 2.5%, 70-99% respectively (P<0.001) High-dose (650 mg or 1300 mg/d) vs Combined incidence of stroke, low-dose (81 or 325 MI, and death lower in low- ACE, 1999 Carotid artery 2849 mg/d) aspirin in Stroke, MI, and death 3 mo dose vs high-dose groups at 30 [153] stenosis patients undergoing d (5.4% vs 7%; P=0.07) and 3 carotid mo (6.2% vs 8.4%; P=0.03) endarterectomy Aspirin and Other Antiplatelet/Antithrombin/Anticoagulant Agents Prior minor Aspirin RR of primary end SALT, 1991 Aspirin 75 mg/d vs Stroke, all-cause 32 mo ischemic stroke 1360 point by 18% (95% CI, 1-33%; [154] placebo death (median) or TIA P=0.02) RR of primary end point 15% (95% CI, –3 to 29%; 2P=0.01) High-dose (600 mg in combined aspirin groups vs UK-TIA, 1991 TIA or minor bid) or low-dose (300 MI, major stroke, 2435 4 y (mean) placebo; no definite difference [155] ischemic stroke mg/d) aspirin vs vascular death in events between high- and placebo low-dose aspirin, but the lower dose was less gastrotoxic Online Data Supplement, Part II/44 Table 8. Selected Clinical Trials in Stroke Prevention
Trial, year [ref no.] Patients N Agent/Intervention Primary End Point Follow-up Findings 571 (46 with 1.7 y Warfarin RR of stroke by Men with chronic prior SPINAF, 1992 (placebo), 21% (95% CI, 10-48%; nonrheumatic cere- Warfarin vs placebo Cerebral infarction [156] 1.8 y P=0.001) in patients with no atrial fibrillation bral (warfarin) history of stroke infarct- tion) All treatments significantly RR of stroke vs placebo: aspirin Aspirin (50 mg/d), by 18% (P=0.013), dipyridamole (400 ESPS 2, 1996 Prior stroke or Recurrent stroke, dipyridamole by 16% 6602 mg/d), aspirin + 2 y [157] TIA <90 d death, or both (P=0.039), and combination dipyridamole, or treatment by 37% (P<0.001); placebo no significant differences in all- cause mortality All-cause death Aspirin RR of all-cause death Aspirin (160 mg/d) during 4-wk CAST, 1997 Acute ischemic by 14% (2P=0.04) and of in- 21,106 vs placebo <48 h of treatment period and 4 wk [158] stroke hospital death or nonfatal stroke stroke onset death or dependence by 12% (2P=0.03) at discharge Heparin nonsignificantly Heparin 5000 or death at 14 d (9.0% vs 9.3%) 12,500 IU bid vs no but no difference at 6 mo; All-cause death at 14 IST, 1997 Acute ischemic heparin; aspirin 300 19,435 d; death or 6 mo aspirin nonsignificantly death [159] stroke mg/d vs no aspirin dependency at 6 mo at 14 d (9.0% vs 9.4%), with a (both <48 h of stroke nonsignificant trend toward onset) fewer deaths or dependencies at 6 mo Online Data Supplement, Part II/45 Table 8. Selected Clinical Trials in Stroke Prevention
Trial, year [ref no.] Patients N Agent/Intervention Primary End Point Follow-up Findings Aspirin nonsignificantly RR of major CV events by 9% (95% CI, -3 to 20%; P=0.13) First major CV event Women’s Health Low-dose aspirin but significantly RR of first Initially healthy (nonfatal MI, 10.1 y Study, 2005 39,876 (100 mg every other stroke by 17% (95% CI, 1-31%; women ≥45 y nonfatal stroke, or (mean) [160] day) vs placebo CV death) P=0.04); aspirin significantly risk of major CV events, ischemic stroke, and MI in women ≥65 years of age Fibrinolytic Therapy Clinical outcome as Patients given rt-PA were 70% assessed by scores on NINDS rt-PA more likely to have a favorable Barthel index, Stroke Study Acute ischemic rt-PA vs placebo <3 h clinical outcome (odds ratio, 333 modified Rankin 3 mo Group, 1995 stroke of symptom onset 1.7; 95% CI, 1.2-2.6) and 30% scale, Glasgow [161] more likely to have minimal or outcome scale, and no disability at 3 mo NIH stroke scale Antihypertensive Therapy Chlorthalidone 12.5- ISH (mean SBP 25 mg/d (+ atenolol 170.3 mm Hg, 25-50 mg/d or Active treatment RR of total SHEP, 1991 Fatal and nonfatal 4.5 y DBP 76.6 mm 4736 reserpine 0.05-0.1 stroke by 36% (95% CI, 18- [162] stroke (mean) Hg), mean age mg/d as needed to 50%; P=0.0003) 71.6 y reach goal) vs placebo Active treatment RR of total Nitrendipine (and/or stroke by 42% (95% CI, 17- Syst-Eur, 1997 ISH, mean age 70 Fatal and nonfatal 2 y 4695 enalapril, HCTZ, or 60%; P=0.003) and nonfatal [163] y stroke (median) both) vs placebo stroke by 44% (95% CI, 14- 63%; P=0.007) Online Data Supplement, Part II/46 Table 8. Selected Clinical Trials in Stroke Prevention
Trial, year [ref no.] Patients N Agent/Intervention Primary End Point Follow-up Findings Vascular disease or DM + 1 other Composite of MI, HOPE, 2000 Ramipril RR of stroke by CV risk factor, Ramipril 10 mg vs stroke, or CV death 4.5 y [164] 9297 32% (95% CI, 16-44%; ≥55 y, no LV placebo (stroke analyzed (mean) P<0.001) dysfunction or separately) HF Perindopril RR of stroke by 28% (95% CI, 17-38%; Prior stroke or PROGRESS, Perindopril 4 mg/d (± P<0.0001) vs placebo, TIA, mean age Fatal and nonfatal 3.9 y 2001 6105 indapamide) vs regardless of concurrent 64 y, 48% stroke (mean) [165] placebo hypertension; combination hypertension therapy reduced BP and stroke risk more than perindopril alone Losartan 50-100 SBP 160-200 mm mg/d vs atenolol 50- Losartan RR of stroke by LIFE, 2002 Hg, DBP 95-115 Composite of CV 4.8 y 9193 100 mg/d (both ± 25% (95% CI, 11-37%; [166] mm Hg, LVH, mortality, stroke, MI (mean) HCTZ 12.5-25 mg/d P=0.001) vs atenolol mean age 66.9 y and/or other agents) Composite CV death, Candesartan RR of nonfatal SBP 160-179 mm Candesartan 8-16 nonfatal stroke, and stroke by 28% (95% CI, 1-47%; SCOPE, 2003 Hg, DBP 90-99 mg/d vs placebo (± 3.7 y 4964 nonfatal MI P=0.04) and of total stroke by [167] mm Hg, 70-89 y other agents to reach (mean) (Secondary: 24% (95% CI, -42 to +1%; (mean, 76 y) BP goals) individual CV events) P=0.056) Statins Simvastatin RR of fatal plus 4S (post hoc Prior CHD, mean Simvastatin 20-40 5.4 y nonfatal cerebrovascular events analysis), 1994 baseline LDL-C 4444 All-cause mortality mg/d vs placebo (median) by 30% (95% CI, 4-48%; [168] 188 mg/dL P=0.024) Prospectively Pravastatin RR of all strokes Pravastatin defined pooled by 20% (95% CI, 7%-32%; Pooling Project, analysis of data Pravastatin 40 mg/d 19,768 Stroke 5 y P=0.01) and nonfatal strokes by 2001 from WOSCOPS, vs placebo 24% (95% CI, 10%-36%; P not [169] CARE, and reported) LIPID Online Data Supplement, Part II/47 Table 8. Selected Clinical Trials in Stroke Prevention
Trial, year [ref no.] Patients N Agent/Intervention Primary End Point Follow-up Findings High-risk (CHD, diabetes All-cause mortality; Simvastatin RR of any stroke HPS, 2002 mellitus); mean Simvastatin 40 mg/d 20,536 fatal or nonfatal 5 y (mean) by 25% (95% CI, 15-34%; [170] baseline LDL-C vs placebo vascular events P<0.0001) 131 mg/dL; 41% hypertensive
Trial Acronyms: ACAS, Asymptomatic Carotid Atherosclerosis Study; ACE, ASA and Carotid Endarterectomy; CARE, Cholesterol And Recurrent Events; CAST, Chinese Acute Stroke Trial; ESPS, European Stroke Prevention Study; HOPE, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; IST, International Stroke Trial; LIFE, Losartan Intervention For Endpoint reduction in hypertension; LIPID, Long- term Intervention with Pravastatin in Ischaemic Disease; NASCET, North American Symptomatic Carotid Endarterectomy Trial; PROGRESS, Perindopril Protection against Recurrent Stroke Study; 4S, Scandinavian Simvastatin Survival Study; SALT, Swedish Aspirin Low-dose Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation; Syst-Eur, Systolic Hypertension–Europe; UK-TIA, United Kingdom Transient Ischaemic Attack study; VA- HIT, Veterans Affairs High-density lipoprotein cholesterol Intervention Trial; WOSCOPS, West of Scotland Coronary Prevention Study.
Other Abbreviations: BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; DBP, diastolic blood pressure; DM, diabetes mellitus; HCTZ, hydrochlorothiazide; HF, heart failure; ISH, isolated systolic hypertension; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; LVH, left ventricular hypertrophy; MI, myocardial infarction; NIH, National Institutes of Health; NINDS, National Institute of Neurological Disorders and Stroke; RR, relative risk; rt-PA, recombinant tissue plasminogen activator; SBP, systolic blood pressure; TIA, transient ischemic attack. Online Data Supplement, Part II/48 Table 9. Clinical Trials in Renal Disease
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Diabetic Patients Type 1 DM (≥7 y and onset before Captopril RR of primary end Collaborative age 30); urinary point by 48% (95% CI, 16- Study Group protein excretion Doubling of serum 69%; P=0.007) and of Captopril 25 mg tid 3 y (Lewis et al), 500 mg/d and 409 creatinine to ≥2 combined death, dialysis, and vs placebo (median) 1993 serum creatinine mg/dL transplantation by 50% (95% [171] 2.5 mg/dL; 75% CI, 18-70%; P=0.006) hypertensive at independent of effects on BP baseline Irbesartan RR of doubling Type 2 DM, Doubling of baseline serum creatinine by 33% vs hypertension, Irbesartan 300 mg/d, IDNT, 2001 serum creatinine, 2.6 y placebo (P=0.003) and 37% vs proteinuria, 1715 amlodipine 10 mg/d, [172] onset of ESRD, all- (mean) amlodipine (P<0.001), and RR elevated serum or placebo cause mortality of ESRD by 23% vs both creatinine (P=0.07) Type 2 DM, hypertension, Irbesartan adjusted RR of microalbumin- diabetic nephropathy by 44% IRMA-2, 2001 uria, serum Irbesartan 150/300 Time to onset of (150 mg/d) (95% CI, 1-69%; 590 2 y [173] creatinine ≤1.5 mg/d or placebo overt nephropathy P=0.05) and by 68% (300 mg/dL (men) and mg/d) (95% CI, 35-85%; ≤1.1 mg/dL P<0.001) (women) Type 2 DM and Baseline urinary albumin micro- Percent change in excretion 44% with valsartan MARVAL, 2002 Valsartan 80 mg/d vs albuminuria 332 urinary albumin 24 wks vs 8% with amlodipine [174] amlodipine 5 mg/d with/without excretion (P<0.001; 95% CI for ratio, hypertension 0.539–0.729) Online Data Supplement, Part II/49 Table 9. Clinical Trials in Renal Disease
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings Losartan 50-100 Losartan RR of doubling of mg/d vs placebo Time to first event of serum creatinine by 25% (95% RENAAL, 2001 Type 2 DM, (both added to open- composite doubling 3.4 y CI, 8-39%; P=0.006) and of 1513 [175] nephropathy label conventional of serum creatinine, (mean) ESRD by 28% (95% CI, 11- antihypertensive ESRD, or death 42%; P=0.002), but no effect on treatment) all-cause mortality Nondiabetic Patients No significant difference in Usual-protein diet vs GFR decline between groups; Moderate renal low-protein diet; MDRD Study 1, no significant differences in insufficiency usual BP (goal MAP Rate of change in 2.2 y 1994 585 development of ESRD or death; (GFR 25-55 107 mm Hg) vs low GFR (mean) [176] greater BP control slowed mL/min) BP (goal MAP 92 decline in GFR in patients with mm Hg) proteinuria Very-low-protein group had marginally slower decline in Severe renal Low-protein diet vs MDRD Study 2, GFR (P=0.07); no significant insufficiency very-low-protein diet; Rate of change in 2.2 y 1994 255 differences in development of (GFR 13-24 BP groups as in GFR (mean) [176] ESRD or death; greater BP mL/min) Study 1 control slowed decline in GFR in patients with proteinuria Effects of low BP goal greater Analysis of BP 53 MDRD (post in blacks than in whites, but not results for black blacks hoc analysis), Rate of change in 2.2 y statistically significant; blacks vs white and As in MDRD Study 1 1997 GFR (mean) had 7-fold greater GFR decline participants in 495 [177] at same achieved follow-up MDRD Study 1 whites MAP Online Data Supplement, Part II/50 Table 9. Clinical Trials in Renal Disease
Trial, year [ref no.] Patients N Agent Primary End Point Follow-up Findings No significant difference between low BP goal and usual Amlodipine 5-10 BP goal in GFR change or African mg/d vs ramipril 2.5- Rate of change in composite clinical events; Americans (18- 10 mg/d vs GFR (Secondary: no significant differences 70 y) with metoprolol 50-200 composite clinical among drug groups in GFR AASK, 2002 hypertensive 1094 mg/d (± other agents index of >50% or 25 4 y (mean) change; [178, 179] renal disease to reach 1 of 2 mean mL/min per 1.73 m2 ramipril RR of composite (GFR 20-65 arterial BP goals: decrease in GFR, clinical end point by 22% (95% mL/min per 1.73 102-107 mm Hg or ESRD, or death) CI, 1-38%; P=0.04) vs m2) 92 mm Hg) metoprolol and by 38% (95% CI, 14-56%; P=0.004) vs amlodipine Nondiabetic renal Combination therapy RR of disease (serum combined primary end point by COOPERATE, creatinine 133- Losartan 100 mg/d, Combined time to 2.9 y 62% (95% CI, 37-82%; 2003 398 μmol/L or 263 trandolapril 3 mg/d, doubling of serum (median) P=0.018) vs trandolapril alone [180] GFR 20-70 or combination creatinine or ESRD and by 60% (95% CI, 31-83%; mL/min per 1.73 P=0.016) vs losartan alone m2)
Trial Acronyms: AASK, African American Study of Kidney disease and hypertension; COOPERATE, Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease; IDNT, Irbesartan Diabetic Nephropathy Trial; IRMA- 2, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria; MARVAL, MicroAlbuminuria Reduction With VALsartan; MDRD, Modification of Diet in Renal Disease; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan.
Other Abbreviations: BP, blood pressure; CI, confidence interval; DM, diabetes mellitus; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MAP, mean arterial pressure; RR, relative risk. Online Data Supplement, Part II/51
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