REMATCH (2001)

Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure

PURPOSE
Investigation of LVAD as destination therapy

METHODS
Total 129 patients with NYHA 3-4 CHF were randomized to LVAD vs. optimal medical therapy Patients were ineligible for transplant There were 91 patients on inotropes at study entry

CLINICAL ENDPOINTS
Primary death, hospitalization and stroke

EXCLUSIONS
EF<30% LM stenosis CVA histoy Transmural MI in last week Severe hepatic or renal disease and need for concomitant major surgery

CONCLUSIONS
There was a 52% vs. 25% survival in favor of LVAD at 1 year and 23 vs. 8% at 2 years
The NNT=2 in year one, unusually good for any therapy in medicine

SHORTCOMINGS

High rate of complications: 44% in LVAD vs. 7% in medical therapy including TIA, stroke, infection and bleeding Later data showed survival benefit only in the patients on inotropes at entry

BOTT OM LINE !!
Reasonable option in the appropriate patient, with an extremely high rate of complication

Rose EA; Gelijns AC; Moskowitz AJ; Heitjan DF; Stevenson LW; Dembitsky W; Long JW; Ascheim DD; Tierney AR; Levitan RG; Watson JT; Meier P; Ronan NS; Shapiro PA; Lazar RM; Miller LW; Gupta L; Frazier OH; Desvigne-Nickens P; Oz MC; Poirier VL. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001 Nov 15;345(20):1435-43.

60

CARP (2004)
The Coronary Artery Revascularization Prophylaxis Trial

PURPOSE
To assess the benefit of coronary artery revascularization prior to elective major vascular surgery.

METHODS
510 pts with stable CAD who are considered high risk and are undergoing vascular operations (ie AAA repair or arterial occlusive disease of the legs) at 18 VA hospitals Randomly assigned to either coronary artery revascularization prior to surgery or no revascularization.

CLINICAL ENDPOINTS
Primary mortality Secondary MI, CVA, limb loss, and dialysis

EXCLUSIONS

Need for emergent surgery Severe coexisting illness Prior revascularization without evidence of recurrent ischemia LM stenosis >50% LVEF <20%

Severe AS

CONCLUSIONS

Post op outcomes: Before vascular surgery there were increased deaths in the revascularization group vs the no revascularization group (10 vs 1). No difference at 30 days after surgery Long term outcomes: At median of 2.7 yrs, mortality was 22% in the revascularization group and 23% in the norevascularization group (P=0.92) Post op MI was not decreased in pts who underwent preop revascularization

SHORTCOMINGS
No major shortcomings

BOTT OM LINE !!

Among patients with stable CAD, coronary artery revascularization before elective major vascular surgery DOES NOT improve long term survival. Thus, CABG and PCI should be reserved for patients with UNSTABLE cardiac symptoms or advanced CAD, for whom a survival benefit with CABG has been proved

Mcfalls EO, Ward HB, Moritz TE, et al. Coronary-Artery Revascularization Before Elective Major Vascular Surgery. N Engl J Med 2004; 351: 2795-804.

59

ARTS (2005)
Arterial Revascularization Therapy Study

PURPOSE
Comparison of CABG vs BMS

METHODS
Randomization of 1205 patients to CABG vs. BMS Total 208 patients had diabetes

CLINICAL ENDPOINTS
Primary freedom from major cardiac or cardiovascular adverse event at one year Secondary above criteria at 5 yrs

EXCLUSIONS
EF<30% LM stenosis CVA history Transmural MI in last week Severe hepatic or renal disease and need for concomitant major surgery

CONCLUSIONS
There was 8% stent vs. 7.6% CABG mortality There was more revascularization in (30.3% to 8.8%) and more angina (21.2% vs 15.5%) in stent group
For DM there was significant difference in mortality (13.4% BMS vs.8.3% CABG)

SHORTCOMINGS
Not in stent era, but studies have since shown no difference in mortality between stents and PTCA

BOTT OM LINE !!
Overall there was no difference in mortality, but less revascularization and less angina in CAGB group Diabetic patients benefit more from surgical revascularization

Serruys PW; Ong AT; van Herwerden LA; etc. Five-year outcomes after coronary stenting versus bypass surgery for the treatment of multivessel disease: the final analysis of the Arterial Revascularization Therapies Study (ARTS) randomized trial. J Am Coll Cardiol 2005 Aug 16; 46(4): 575-81.

58

BARI (1998)
Bypass Angioplasty Revascularization Investigation

PURPOSE
Comparison of CABG vs PTCA (not stents!) for revascularization

METHODS
1829 patients with symptomatic CAD were randomlized to CABG vs. PTCA There was a mean follow up of 10.4 years

CLINICAL ENDPOINTS
Primary all cause mortality Secondary death of cardiac cause, MI, anginal status

EXCLUSIONS
Left Main disease Insufficient angina

CONCLUSIONS
There was no difference in survival for cardiac or any death if patients that were NOT diabetic There was a 12-13% difference in mortality favoring CABG if patient had DM Significantly less revascularization with CABG (2.5 times less likely)
No change in anginal symptoms between groups

SHORTCOMINGS
Not in stent era, but studies have since shown no difference in mortality between stents and PTCA

BOTT OM LINE !!
CABG with LIMA's are preferable in patients with diabetes
The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol. 2007 Apr 17;49(15):1600-6. Epub 2007 Apr 2. Circulation. 98(13):1279-1285, September 29, 1998

57

TAXUS-IV (2004)
PURPOSE
Long-term (9-12 month) benefits/outcomes of drug eluting stents (paclitaxel-eluting) vs bare metal stents

METHODS
1314 patients with new coronary lesions coverable by a single study stent prospective, randomized (DES vs BMS), doubled-blinded ASA, heparin, plavix for 6 months was given, G2B3A-i was given during procedure at operators discretion

CLINICAL ENDPOINTS
Primary ischemia-driven target vessel revascularization at 9 months (secondary 12 months) Secondary Major adverse cardiac event (cardiac death, MI, ischemiadriven TVR) Secondary Target vessel failure (death, MI, ischemia-driven TVR related to target vessel)

EXCLUSIONS

Previous or planned use of brachytherapy MI within 72 hours LVEF <25% High risk lesions: Left main, ostial lesion, calcification, bifurcation lesion, thrombus, surgical intervention Bleeding or allergic contraindication

CONCLUSIONS
Reduction in revascularization in 9 and 12 months with DES vs BMS
Decreased major adverse cadiac events and target vessel failure composites at 9 and 12 months

SHORTCOMINGS
Use of G2B3A was up to operator which has independently been shown to improve certain outcomes. Plavix was only continued for 6 months. (standard of care at the time). This study population had to take the plavix, so presumably high compliance rate! Secondary end-point benefits were primarily driven by reduction in revascularizations, not mortality

BOTT OM LINE !!
If you choose your patient wisely (compliant) , DES may offer signficiant improvements in mordibity (revascularization)

Stone GW, Ellis SG, Cox DA, Hermiller J, etc; TAXUS-IV Investigators. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation. 2004 Apr 27;109(16):1942-7. Epub 2004 Apr 12. 56

RAVEL (2004)
Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions

PURPOSE
Investigate sirolimus (drug-eluting) stent vs. bare metal stent

METHODS
Randomized, double-blind, length of 12 months, 238 patients with stable or unstable angina or silent ischemia, stenosis of 51-99% and TIMI I flow or higher

CLINICAL ENDPOINTS
Primary composite of major cardiac events including death, MI, CABG, and revascularization of lesion

EXCLUSIONS

Evolving MI Unprotected left main Ostial lesions Vessels with significant calcification EF<30% Allergy to aspirin, clopidogrel, ticlid, heparin, contrast or steel

CONCLUSIONS
There was decreased lumen loss in DES stents at 6 months, but no difference before the 6 months
Significant decrease in major cardiac events after 1 year (6% for DES vs. 29% in BMS)

SHORTCOMINGS
Limitations: lesions were limited to those <18mm in length

BOTT OM LINE !!
DES significantly decreased repeat revascularization from stenosis
Morice MC; Serruys PW; Sousa JE; Fajadet J; Ban Hayashi E; Perin M; Colombo A; Schuler G; Barragan P; Guagliumi G; Molnar F; Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002 Jun 6; 346(23): 1773-80.

55

SIRIUS (2003)
SIRolImUS Stent Trial

PURPOSE
To compare sirolimus (drug-eluting) stent vs. bare metal stent

METHODS
Randomized, double blind study of 1058 patients with stable or unstable angina and signs of myocardial ischemia Had to have native coronary artery stenosis of 51-99% and lesion had to be 15-30mm in length All patients managed with standard med management +/- G IIbIIIa inhibitor at MD's discretion

CLINICAL ENDPOINTS
Primary "target vessel failure", composite of death from cardiac causes, MI, repeated percutaneous or surgical revascularization. Secondary Death from any cause, stent thrombosis, revasc of target lesion

EXCLUSIONS
MI within 48 hours EF<25% Lesion in ostium or bifurcation Active thrombus or severe calcification of lesion Unprotected left main

CONCLUSIONS
Target vessel failure reduced from 21% in BMS to 8.6% in DES. Reduction in restenosis across sub-groups.
NO REDUCTION in all-cause mortality or in-stent thrombosis

SHORTCOMINGS
Limitations: lesions that were high risk were excluded (bifurcations, heavy calcifications, unprotected LAD, etc)

BOTT OM LINE !!
DES showed decreased restenosis of vessels, but no benefit in mortality
Moses JW; Leon MB; Popma JJ; Fitzgerald PJ; Holmes DR; O'Shaughnessy C; Caputo RP; Kereiakes DJ; Williams DO; Teirstein PS; Jaeger JL; Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003 Oct 2; 349(14): 1315-23.

54

OAT (2005)
Open Artery Trial

PURPOSE

Designed to test the hypothesis that opening a totally occluded infarct-related artery (IRA) 3 to 28 days after MI in high-risk asymptomatic patients will improve clinical outcome and be cost-effective

METHODS

CLINICAL ENDPOINTS

EXCLUSIONS

Randomized multi-center study of 2,166 Primary death, recurrent nonfatal MI, and patients assigned to routine angioplasty hospitalization or treatment with stenting combined with drug NYHA IV CHF over an therapy vs. drug therapy alone average 3 years of follow-up Most patients had blockages in one Secondary comparison of coronary artery only the 2 treatments for medical costs, cost-effectiveness of PCI, and quality of life

Severe inducible ischemia Severe renal disease Severe valvular disease Infarct artery too small Chronic occlusion of IRA NYHA classes III-IV CHF Contraindication to anticoagulation Cardiogenic shock

CONCLUSIONS
No statistically significant difference in major cardiovascular events between the two groups over an average of three years and up to five years. At four years, the rate of death, heart attack, or serious heart failure was 17.2 percent in the angioplasty group compared to 15.6 percent of the medical therapy group There was trend toward more heart attacks in the angioplasty group

SHORTCOMINGS
Nothing significant

BOTT OM LINE !!
No clinical benefit to opening occluded arteries in asymptomatic patients

Hochman JS; Lamas GA; Buller CE; etc. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med. 2006 Dec 7; 355(23): 2395-407. Epub 2006 Nov 14

53

COURAGE (2005)
Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation Trial

PURPOSE
To investigate if PCI plus intensive medical therapy vs. intensive medical therapy alone has a benefit

METHODS
Randomized trial enrolling 2287 patients into two groups: PCI + medical therapy vs. medical therapy alone Medical therapy used in both groups includes: aspirin, clopidogrel, simvastatin (low-density lipoprotein cholesterol target 60-85 mg/dL), long-acting metoprolol and/or amlodipine, lisinopril or losartan, and long-acting nitrates, as well as lifestyle interventions Primary acute MI

CLINICAL ENDPOINTS
All cause mortality and

EXCLUSIONS

Unstable angina No prior CABG and left main coronary disease 50% Nonsignificant CAD EF <30% or cardiogenic shock, Pulmonary edema or CHF unresponsive to standard medical therapy CABG or PCI within the last 6 mo HTN (BP >200/100 mm Hg) unresponsive to medical therapy Valvular heart disease likely to require surgery

CONCLUSIONS
No difference in primary events between the two groups (19% PCI vs. 18.5% medical therapy) groups, although more rapidly in PCI group. recurrent UA and revascularization

No difference in incidence of MI or hospitalization rates for ACS. The severity of angina declined in both treatment

SHORTCOMINGS
Too many exclusion criteria that would not be practical in typical clinical setting

BOTT OM LINE !!
PCI DID NOT have any benefits over intensive medical therapy

Boden WE; O'Rourke RA; Teo KK; Hartigan PM; etc. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12; 356(15): 1503-16. Epub 2007 Mar 26.

52

FRISC II (1999)
Fragmin and Fast Revascularisation during Instability in Coronary artery disease

PURPOSE
Invasive vs. non-invasive treatment in unstable coronary-artery disease.. FRISC II had 2 goals 1) evaluate LMWH use and 2) evaluate early vs. conservative therapy

METHODS

CLINICAL ENDPOINTS
death or MI at 6

EXCLUSIONS

Total of 2457 patients with unstable CAD were Primary randomized early invasive vs. non-invasive months therapy They were also put into a placebo-controlled long-term LMWH therapy protocol for 3 months at that time PCI with revascularization was done within the first 10 days in 71% of the invasive group vs. 9% of the non-invasive group

Angioplasty in past 6 months Previous open heart surgery Age > 75 years

CONCLUSIONS
The composite endpoint of death or MI in the invasive group was 9.4% vs. 12.1% in the non-invasive group (p=0.031) The endpoint of MI alone was 7.8% in the invasive group vs. 10.1% in the non-invasive group (p=0.045)

SHORTCOMINGS
Highest mortality was in patients >75 years of age which were excluded from study

BOTT OM LINE !!
Use of an early invasive strategy significantly reduced the incidence of major cardiac events
Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Fragmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999 Aug 28; 354 (9180): 708-15.

51

TACTICS-TIMI18 (2001)
Thrombolysis in Myocardial Infarction 18

PURPOSE

Debate over whether routine, early invasive strategy is superior to a conservative strategy for the management of UA and NSTEMI Comparison of Early Invasive and Conservative Strategies in Patients with Unstable Coronary Syndromes Treated with the Glycoprotein IIb/IIIa Inhibitor Tirofiban

METHODS
Total of 2220 patients were randomly assigned to early invasive strategy (PCI within 4-48hrs) or conservative strategy (PCI only if there was objective evidence of recurrent ischemia or an abnormal stress test Included patients with UA and NSTEMI who had changes in the ST or T wave, elevated cardiac markers, CAD, or all three. All patients were treated with ASA, heparin, and GP IIb/IIIa inhibitor (tirofiban)

CLINICAL ENDPOINTS
Primary composite endpoint of death, nonfatal MI, and rehospitalization for ACS at 6 months

EXCLUSIONS

Persistent ST elevation PCI or CABG w/i 6 months LBBB or paced rhythm severe CHF cardiogenic shock serious systemic disease Cr >2.5 Use of warfarin, clopidogril or ticlodipine within 3 days Current participation in another investigational study

CONCLUSIONS
Primary end point was 15.9% (early invasive) vs. 19.4% (conservative) (p=0.025) Rate of death or nonfatal MI at 6 months was 7.3% (early invasive) vs. 9.5% (conservative) (p<0.05)

SHORTCOMINGS
Aggressive approach, not feasible at every institution

BOTT OM LINE !!
Use of an early invasive strategy significantly reduced the incidence of major cardiac events

Christopher P. Cannon, M.D., William S. Weintraub, etc. Comparison of Early Invasive and Conservative Strategies in Patients with Unstable Coronary Syndromes Treated with the Glycoprotein IIb/IIIa Inhibitor Tirofiban. N Engl J Med 2001; 344: 1879-1887 50

REPLACE-2 (2002)
Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events

PURPOSE
Compare bivalirudin + provisional GIIb/IIIa vs. heparin + planned GIIb/IIIa with regard to periprocedural ischemia and hemorrhage

METHODS
Randomized, double-blind controlled trial including 6010 patient population undergoing PCI Population consisted of 233 hospitals in 9 countries over a 1 year period

CLINICAL ENDPOINTS
Death MI urgent revascularization in-hospital major bleeding within 30 days

EXCLUSIONS

PCI as reperfusion therapy poorly controlled HTN (BP >180/110) PCI within prior month active bleeding or platelets <100,000 surgery or trauma GI/ GU bleed within 6 weeks Cr> 4mg/dL Actvie warfarin/heparin therapy

CONCLUSIONS
Of patients receiving bilvalirudin, 9.2% were administered Gp IIb/IIIa. Endpoint achieved in 9.2% of bivalrudin group vs. 10.0% heparin + Gp IIb/IIIa (OR 1.09, p=.32) Incidence of MAJOR bleeding was 2.4% of bivalirudin group vs. 4.1% of heparin + Gp IIb/IIIa Incidence of MINOR bleeding was 13.4% of bivalirudin group vs. 25.7% of heparin + Gp IIb/IIIa

Decreased percentage of thrombocytopenia for bivalirudin (0.7% vs 1.7%)

SHORTCOMINGS
The standard use of Gp IIb/IIIa may have altered the outcomes for bilvalirudin group

BOTT OM LINE !!

Bivalirudin with provisional Gp IIb/IIa was noninferior to heparin + Gp IIb/IIIa with regard to suppression of acute ischemia. However, significantly less chance of bleeding event for bilvalirudin when compared to heparin + Gp IIb/IIIa

Lincoff AM, Bittl JA, Harrington RA, for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention REPLACE-2 randomized trial. JAMA. 2003; 289: 853-863.

49

PRISM-PLUS (1998)
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms

PURPOSE
To assess if tirofiban, a glycoprotein IIb/IIIa inhibitor, decreases morbidity and mortality in ACS

METHODS
Studied 1915 patients with prolonged pain or repetitive episodes of angina at rest or during minimal exercise with associated ST or T wave changes or elevation in CK-MB Randomized to 1) tirofiban 2) tirofiban + heparin or 3) heparin alone

CLINICAL ENDPOINTS
Primary Composite of death from any cause, new MI, or refractory ischemia

EXCLUSIONS

Persistent ST elevations Correctable causes of angina Contraindications to anticoagulation

CONCLUSIONS

Tirofiban + heparin group had a reduction in the primary composite end point of death, MI, or refractory ischemia at 7 days and 30 days when compared to heparin alone Study stopped early for tirofiban alone group as they had increased mortality at 7 days compared to heparin alone Major bleeding: 1.4% of tirofiban + heparin vs 0.8% in heparin alone group (NNH 43)
Minor bleeding: 10.5% of tirofiban + heparin vs 8.0% in heparin alone group (NNH 24)

SHORTCOMINGS
Not able to generalize these findings to patients with USA without EKG changes

BOTT OM LINE !!
Tirofiban plus heparin reduces mortality and morbidity in patients with ACS

Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998 May 21; 338(21): 1488-97.

48

PRISM (1998)
The Platelet Receptor Inhibition in Ischemic Syndrome Management

PURPOSE
To assess if tirofiban (glycoprotein IIb/IIIa inhibitor) decreases morbidity and mortality in unstable angina

METHODS

CLINICAL ENDPOINTS

EXCLUSIONS
Thrombolytic therapy within last 48 hrs Cr>2.5 Contraindications to anticoagulation

Studied 3232 patients with CP at rest or Primary composite of death, MI, or refractory accelerating CP with associated EKG changes or elevated enzymes or a history of MI, PCI, ischemia at 48 hrs coronary surgery, positive stress Patients already receiving aspirin randomized to tirofiban OR heparin for 48 hrs

CONCLUSIONS

Tirofiban group with lower incidence of composite end point at 48 hrs compared to heparin At 30 days, two groups had similar composite end points. Trend towards a reduction in the rate of death or MI in the tirofiban group. Mortality was lower in the tirofiban group at 30 days
Major bleeding occurred in 0.4% of both groups

SHORTCOMINGS
Patients only followed for 48 hrs, no long term data available (look to PRISM-plus)

BOTT OM LINE !!
Tirofiban decreases mortality and morbidity in patients with ACS

A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med 1998 May 21; 338(21): 1498-505.

47

CADILLAC (2002)
The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications Trial

PURPOSE

To assess whether platelet glycoprotein IIb/IIIa inhibitors improve outcomes when used in combination with early primary PTCA for acute myocardial infarction

METHODS
2082 patients with AMI randomly assigned to undergo PTCA alone, PTCA plus abciximab, stenting alone with MultiLink stent, or stenting plus abciximab therepy

CLINICAL ENDPOINTS
Primary Composite of death, reinfarction, disabling stroke, ischemia driven revascularization of the target vessel

EXCLUSIONS
Cardiogenic shock History of bleeding diathesis Recent major surgery Cerebrovascular event

CONCLUSIONS

The initial restoration of normal blood flow was the same in all groups At six months, primary end point was significantly lower with stenting, with or without abciximab compared to PTCA alone (10% and 11.5% vs 20%). This difference was entirely the result of a significantly lower need for repeat ischemia-driven revascularization with stenting, with or without abciximab (5% and 8% versus 13.8% and 15.7% percent)
Stenting was also associated with a lower rate of angiographic restenosis (22% vs 41%) and occlusion of the

infarct-related artery (5.7% vs 11%); these benefits were independent of abciximab use

SHORTCOMINGS
This study has been criticized for its bias toward elderly patients. The mean age was 59 yo. This is not

reflective of the STEMI population as a whole.

All high risk patients were excluded.

BOTT OM LINE !!

Stenting with or without abciximab should be considered as the reperfusion therapy of choice when dealing with acute myocardial infarction
46

Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002 Mar 28; 346 (13): 957-66.

PCI-CURE (2001)
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)

PURPOSE
Determining appropriated treatment after PCI with clopidogrel (substudy of CURE trial) Both groups pretreated with clopidogrel prior to PCI Post- PCI: long-term therapy vs. short-term therapy for only 4 weeks

METHODS
Randomized double-blind treatment with clopidogrel vs. placebo of patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study Both groups pretreated with aspirin and study drug for a median of 6 days before PCI during Both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months

CLINICAL ENDPOINTS

EXCLUSIONS

Cardiovascular death contraindications to antithrombotic Myocardial infarction or antiplatelet therapy Target-vessel revascularization high risk of bleeding heart failure within 30 days of PCI If they had undergone PCI or coronary-artery bypass grafting in the previous 3 months G IIb/IIIa inhibitor use

CONCLUSIONS
Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation [4.5% vs 6.4% (p=0.03)] Overall there was a 31% reduction cardiovascular death or myocardial infarction (p=0.002) There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0001) No significant difference in major bleeding between the groups (p=0.64)

SHORTCOMINGS
Same as CURE trial

BOTT OM LINE !!
Clopidogrel decreases cardiovascular events in patients with ACS and patients undergoing PCI

Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527-533. 45

CURE (2000)
Clopidogrel in Unstable Angina to Prevent Recurrent Events

PURPOSE
To investigate the effect of thienopyridines in patients with vascular disease

METHODS
An international, randomized, double-blind trial in which patients with ACS were randomized to receive either a bolus of clopidogrel (300mg) followed by 75mg daily x 3-12 months, or matching placebo

CLINICAL ENDPOINTS
Composite Endpoints CV death, MI, CVA and refractory ischemia

EXCLUSIONS

Both sets of groups also received ASA therapy

Contraindications to antithrombotic or antiplatelet therapy High risk of bleeding Heart failure PCI or coronary-artery bypass grafting in the previous 3 months

G IIb/IIIa inhibitor use

CONCLUSIONS
Clopidogrel group showed a 20% RRR in primary composite outcomelargely due to 23% RRR in MI (ARR ~1.6%) There was also nonsignificant trend of lower mortality rate and fewer strokes in clopidogrel group. This benefit was noted in all subgroups reported Bleeding was significantly higher in clopidogrel group than in placebo The risk of life-threatening bleeds was not significantly increased Rates of neutropenia and thrombocytopenia were similar in both groups

SHORTCOMINGS

Conservative approach not likely used in most hospitals, patients enrolled were at high risk, bleeding increased in clopidogrel group, clopidogrel may delay CABG

BOTT OM LINE !!
Clopidogrel decreases cardiovascular events in patients with ACS
Mehta SR, Yusuf S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. N Engl J Med. 2001;345:494-502

44

TIMI Risk Score (2000)

The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI

PURPOSE
To develop a simple score that helps risk stratify patients with UA/NSTEMI

METHODS
Presentation within 24 hrs of UA/NSTEMI were assigned to 1 of 2 anticoagulation agents in the TIMI 11B and ESSENCE study Patients were followed for 14 days 12 baseline characteristics were evaluated Multivariate logistic regression analysis was done

CLINICAL ENDPOINTS
Primary All cause mortality, new or recurrent MI, or severe recurrent ischemia requiring revascularization

EXCLUSIONS

Planned revascularization in 24 hrs or less Correctable causes of angina Contraindications to anticoagulation

CONCLUSIONS

The 7 characteristics that were found to be statistically significant in predicting increased risk were as follows: age 65, 3 risk factors for CAD, coronary stenosis >50%, ST deviation, 2 anginal events in last 24 hrs, use of aspirin in the last 7 days, elevated serum cardiac markers. Each of these variables is worth one point The TIMI risk score and treatment (unfractionated heparin vs enoxaparin) were significant predictors of all cause mortality, MI, or urgent revascularization

SHORTCOMINGS
The quantitative relationship between release of cardiac biomarkers and prognosis is not accounted for. All variables are equally weighted

BOTT OM LINE !!

The TIMI risk score is a simple tool that can be used during the initial evaluation of patients with UA/NSTEMI to predict the patients risk of death and cardiac ischemic events Increasing TIMI risk scores correlate with increase risk of the primary endpoints above

Antman EM, Cohen M, Bernink P, et al. The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI. JAMA 2000; 284: 834-842.

43

MADIT II (2002)
Multicenter Automatic Defibrillator Implantation Trial

PURPOSE
To investigate if patients with decreased ejection fraction post MI may benefit from prophylactic ICD placement

METHODS
Prospective randomized study of 1232 patients over 4 year period Included EF of 30% or less Divided into 3:2 ratio of ICD: med therapy (meds were not completely standardized and included BB, ACE, lipid lowerers) Did NOT require EP study MI was at least 1 month or more before entry into trial Primary causes

CLINICAL ENDPOINTS
death from all

EXCLUSIONS
Patients already with indications for ICD NYHA class IV CABG within 3 months MI within 1 month Severe CVD fertile women not on contraception High comorbidities

CONCLUSIONS
There was a 5.6% absolute risk reduction in mortality in ICD group (hazard ratio 0.69)

SHORTCOMINGS
Medical regimen was not standardized only 70% were on BB, even less on ACE, some on diuretics, etc.

BOTT OM LINE !!
ICDs reduced mortality rate in patients with ischemic cardiomyopathy

Moss AJ; Zareba W; Hall WJ; etc. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002 Mar 21;346(12):877-83. Epub 2002 Mar 19.

42

MADIT (1996)
Multicenter Automatic Defibrillator Implantation Trial

PURPOSE
Investigate if ICDs decrease mortality in patients with prior MI and LV dysfunction

METHODS
Prospective 5 year study enrolling 196 patients with NYHA 1-3 with prior MI, LVEF of <35% Prior history of NSVT and inducible VT on EP study Group 1 ICD, Group 2 med therapy (any antiarrythmic) Primary causes

CLINICAL ENDPOINTS
death from all

EXCLUSIONS
Previous cardiac arrest VT with syncope without history of MI Symptomatic hypotension MI within 3 weeks CABG within 2 months PTCA within 3 months Severe CVD Fertile women not on contraception High comorbidities

CONCLUSIONS
In this high-risk population, prophylactic therapy with ICD led to improved survival Reduction in overall mortality by 54% and arrhythmic mortality by 75%

SHORTCOMINGS
Industry sponsored trial

BOTT OM LINE !!
ICDs reduced mortality rate in patients with ischemic cardiomyopathy and NSVT with positive EP study
Moss AJ; Hall WJ; Cannom DS; etc. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996 Dec 26; 335(26): 1933-40. 41

SCD-HEFT (2005)
Sudden Cardiac Death in Heart Failure

PURPOSE
Investigate conventional medications vs [meds+amiodarone] vs [meds+ICD] in the setting of severe CHF

METHODS
Randomized, prospective study of 2521 patients with NYHA class II / III LVEF of 35% or less (ischemic and nonischemic) NO NEED for EP study or prior VT Three groups 1) conventional med+placebo 2) conventional med+amiodarone 3)conventional med+ICD conventional meds included: BB+ACE, aldosterone antagonists, aspirin and statins Primary

CLINICAL ENDPOINTS
death from all causes

EXCLUSIONS

Cardiac arrest or sustained VT Cardiomyopathy or myocarditis Age <18 years Current antiarrhythmic medications Creatinine >2.5

CONCLUSIONS
There was no significant change in mortality with amiodarone compared to standard medications There was a 7.2% absolute risk reduction in 5 yrs with ICD group compared to medications ARR demonstrated in ischemic and nonischemic CM, but did vary according to NYHA class

SHORTCOMINGS
Study focused both on ischemic vs. nonischemic and found that both groups benefit. Prior studies were more concerned with ischemic group

BOTT OM LINE !!
ICDs reduced mortality rate and amiodarone was no better than placebo

Bardy GH; Lee KL; Mark DB; etc. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005 Jan 20; 352(3): 225-37. 40

COMPANION (2004)
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure

PURPOSE

Investigate if cardiac resynchorinzation therapy (CRT) with Bi-V pacer may reduce risk of death and hospitalization in advanced CHF with IV conduction delay

METHODS
1520 patients randomly assigned to 1:2:2 of optimal med therapy alone, med+pacer, and med+ICD+Bi-V pacing. (Meds=ACE, diuertic, BB, spironolactone) NYHA Class 3 & 4 CHF QRS interval of at least 120 msec

CLINICAL ENDPOINTS
Primary All-cause mortality or first hospitalization

EXCLUSIONS
None significant

CONCLUSIONS
Risk of combined endpoint of death or hospitalization for heart failure reduced by 34% in Bi-V pacer group and 40% in pacer-ICD group Secondary endpoint of death from any cause by 24% in pacer group 36% in pacer+ICD

SHORTCOMINGS
Industry sponsored trial

BOTT OM LINE !!
CRT is useful in patients with residual symptoms despite aggressive medical therapy
Bristow MR; Saxon LA; Boehmer J; Krueger S; Kass DA; De Marco T; Carson P; DiCarlo L; DeMets D; White BG; DeVries DW; Feldman AM Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004 May 20; 350(21): 2140-50 39

CAST (1991)
Cardiac Arrhythmia Suppression Trial

PURPOSE

Investigate weather suppressing ventricular ectopy with antiarrhythmics (encainide, flecainide or moricizine) after myocardial infarct decreases morbidity and mortality

METHODS
A total of 1498 patients were randomly assigned to receive either encainide or its placebo vs. flecainide or its placebo

CLINICAL ENDPOINTS
Primary death or cardiac arrest from arrhythmia Secondary all death, all cardiac arrest, vtach, syncope, pacemaker implantation, MI, CHF, angina, revascularization

EXCLUSIONS

Proarrhythmia Prolonged QT Mobitz II or third degree block new/worsening CHF Patients on aniarrhythmic treatments

CONCLUSIONS
Patients for followed up for 10 months. Patients on encainide or flecainide associated with poorer outcomes Significant increase in death from arrhythmia in medication group (43 vs. 16 patients, p=0.0004) Nonlethal events were equally distributed between medication and placebo groups

SHORTCOMINGS
Use of encainide and flecanide were discontinued secondary to increased mortality Medications have proarrhythmic properties side effects

BOTT OM LINE !!
There is no benefits to prophylactic antiarrhythmic therapy following myocardial infarct There is increased rate of mortality with antiarrhythmic therapy !!

Echt DS; Liebson PR; Mitchell LB; Peters RW; Obias-Manno D; Barker AH; Arensberg D; Baker A; Friedman L; Greene HL; et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991 Mar 21; 324(12): 781-8

38

AFFIRM (2002)
Atrial Fibrillation Follow-Up Investigation of Rhythm Management

PURPOSE
Compare treatment of atrial fibrillation: cardioversion (with antirrhytmics) vs. rate control (but allowing atrial fibrillation to persist) In both approaches, the use of anticoagulant drugs is recommended

METHODS
Randomized, multicenter comparison enrolling a total of 4060 patients Patient morbidities included a history of hypertension, coronary artery disease, left atrial enlargement and depressed left ventricular function

CLINICAL ENDPOINTS

EXCLUSIONS

Primary mortality Age <65 years Secondary death, stroke, Nonrecurrent a-fib encephalopathy, major bleeding and cardiac arrest

CONCLUSIONS
Rhythm-control strategy offers no survival advantage over the rate-control strategy Lower risk of adverse drug effects with the rate-control strategy Anticoagulation should be continued in this group of high-risk patients to prevent formation of thrombus

SHORTCOMINGS
Risk of adverse drug effects from antirrhytmics medications caused higher hospitalization rate

BOTT OM LINE !!
Rhythm-control strategy offers no survival advantage over the rate-control strategy

Wyse DG; Waldo AL; DiMarco JP; Domanski MJ; Rosenberg Y; Schron EB; Kellen JC; Greene HL; Mickel MC; Dalquist JE; Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002 Dec 5; 347(23): 1825-33 37

MIRACL (2001)
Myocardial Ischemia Reduction with Acute Cholesterol Lowering trial

PURPOSE
Investigate if intensive lowering of cholesterol with (atorvastatin 80 mg/day) initiated 24-96 hours after an acute coronary syndrome would reduce the incidence of death and adverse cardiac events

METHODS
3086 patients with unstable angina or non-Q-wave infarction were randomized to placebo or to atorvastatin (80 mg/day) within 2496 hours of admission to hospital

CLINICAL ENDPOINTS
Primary Time to death, myocardial infarction, resuscitated cardiac arrest, or worsening angina with new objective evidence of myocardial ischemia requiring urgent rehospitalization All endpoints were followed over 4 months

EXCLUSIONS

Planned revascularization Total cholesterol > 270 Contraindication to statin therapy

CONCLUSIONS
The overall composite endpoint was reduced from 17.4% to 14.8% Most significant single endpoint reduction was a 26% relative decrease in worsening angina with objective evidence of myocardial ischemia requiring urgent rehospitalization Stroke, a secondary endpoint, was reduced from 1.6% to 0.8%

SHORTCOMINGS

Baseline lipid panels drawn during ACS may not have been accurate, lipid levels during treatment were drawn at 6 weeks at which point most events had already occurred The study was not powered to make meaningful conclusions about the subgroups but only the composite endpoint of them all

BOTT OM LINE !!

There was an association with decreased cardiac events with aggressive short-term use of atorvastatin administered shortly after ACS

Schwartz GG; Olsson AG; Ezekowitz MD; Ganz P; Oliver MF; Waters D; Zeiher A; Chaitman BR; Leslie S; Stern T. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001 Apr 4; 285(13):1711-8 36

PROVE-IT (2004)
Pravastatin or Atorvastatin Evaluation and Intensive Therapy

PURPOSE
To determine what the how aggressive to be with lowering LDL cholesterol post ACS

METHODS
4162 patients ( 18 yo) hospitalized for ACS: MI ST elev, or UA in preceding 10d, stable, enrolled after PCI if planned TC 240 in past 6mo, if on previous lipid lowering agents than TC<200 Already on standard treatment for ACS Randomized to atorvastatin 80mg, pravastatin 40mg, or placebo. (pravastatin was increased to 80 if LDL>125)

CLINICAL ENDPOINTS
Primary death by any cause, MI, hospitalization for UA, PCI, or CABG within 30 days, stroke Secondary risk of death from CHD, nonfatal MI, CABG > 30d

EXCLUSIONS

Comorbid conditions with survival <2yrs High-Dose statins, concurrent niacin or fibrates CYP450 3A4 inhibitors PCI in last 6 mo, CABG in last 2 mo, planned CABG, QT prolonged, liver disease, CK>3x uln, Cr>2.0

CONCLUSIONS
Significant reduction in LDL, atorvastatin on average to 62, pravastatin to 95. For primary endpoints, there was 16% RRR between the two groups in support of atorvastatin (pravastatin 26.3% vs 22.4% for atorvastatin) For secondary endpoints, risk reduction was not significant but it favored atorvastain group

SHORTCOMINGS
Not an ideal study given that comparison between different doses of atorvastatin would be the best study. The majority of the patients were Caucasian

BOTT OM LINE !!

Patients benefit from intensive lipid lowering therapy with Atorvastatin in the context of lowering the risk of all cause death or major cardiac events EARLY and AGGRESSIVE treatment with statins post ACS reduces the risk of recurrent UA and repeat PCI

Cannon CP; Braunwald E; etc. Pravastatin or Atorvastatin Evaluation and Intensive Therapy: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004 Apr 8; 350(15): 1495-504 35

DIG Trial (1997)

Digoxin Trial

PURPOSE
To assess the affect of digoxin on mortality and hospitalization

METHODS
6000 patients with clinical signs or symptoms of HF LVEF 45% Already on diuretics and ACEI Randomly assigned to digoxin or placebo (eligible for the study whether or not already on digoxin)

CLINICAL ENDPOINTS
Primary all cause mortality Secondary mortality from CV causes, death from worsening HF, all cause hospitalizations

EXCLUSIONS
LVEF > 45%

CONCLUSIONS
No significant difference in mortality (34.8% digoxin group vs. 35.1% in placebo) Digoxin group had trend towards decrease risk of death attributed to worsening HF Digoxin decreases rate of hospitalization

SHORTCOMINGS
Did not largely represent women (only 22.3%) Only 2% of pts were in NYHA class IV

BOTT OM LINE !!
Digoxin DID NOT reduce overall mortality in patients already receiving diuretics and ACEI Digoxin DID reduce the rate of hospitalizations both overall and for worsening HF

Garg R, Gorlin, R, Smith T, and Yusuf S. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 336: 525-33 34

VHeFT II (1991)
Heart Failure Trial

PURPOSE
To investigate if ACE inhibitors are superior to hydralazine and nitrates in CHF

METHODS
806 men with NYHA class II-III CHF Patients assigned to enalapril 20mg daily plus hydralazine/ISDN vs. hydralazine/ISDN

CLINICAL ENDPOINTS
All-cause mortality

EXCLUSIONS
None significant

CONCLUSIONS

There was significantly less mortality in enalapril arm vs. hydralazine/ISDN arm at 2 years (18% vs. 25%, p=0.016) Later, SOLVD trial showed an ARR 5% in 2500 people and CONSENSUS 18% at 1yr and 16% at 2 yrs in 353 NYHA Class 3-4 patients Both groups significantly improved LVEF

SHORTCOMINGS
Incidence of hypotension and cough significantly higher in enalapril arm Incidence of headache significantly higher in hydralazine/ISDN arm

BOTT OM LINE !!
In patients with CHF, enalapril proved superior to hydralazine/ISDN in reducing mortality Both enalapril and hydralazine/ISDN improved cardiac function

Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991, 325: 303-310 33

VHeFT (1986)
Heart Failure Trial

PURPOSE
Mortality benefit of vasodilator therapy in CHF when added to digoxin and diuretics

METHODS
Included 642 VA patients Required cardiac:diaphragm ratio > 0.55, LV internal diameter >2.7, or EF <45% w/decreased exercise tolerance Assigned to hydralazine/ISDN 75/40 QID, prazosin or placebo Mortality

CLINICAL ENDPOINTS

EXCLUSIONS
Exercise tolerance limited by chest pain MI within 3 mos Patinets on BB, CCB or long acting nitrate

CONCLUSIONS
Demonstrated ARR 7% at 1 yr and 10% at 3yrs EF increased by 4% at 1yr no change in BP (don't be afraid of hypotension)

SHORTCOMINGS
19% had side effects, mostly HA, dizziness, or GI Interesting point that prazosin group did same as placebo alpha blockers DID NOT help in HF Doxazosin later proven to increase mortality

BOTT OM LINE !!
Hydralazine/nitrates improve mortality in CHF

JN Cohn, DG Archibald, S Ziesche, JA Franciosa, WE Harston, FE Tristani, WB Dunkman, W Jacobs, GS Francis, KH Flohr, and et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986, 314: 1547-1552

32

AHeFT (2004)
African - American Heart Failure Trial

PURPOSE

Investigate if hydralazine/nitrate provide additional benefit beyond ACEI for afterload reduction and increasing survival in African CHF pateints Theory not only based on vasodilation, but also donation of nitric oxide by nitrates and antioxidant effect of hydralazine, thereby neurohormonally inhibiting effects of CHF, remodeling, endothelial dysfunction, and reducing oxidative stress

METHODS
1050 black pateints with CHF NYHA class III & IV already on standard CHF therapy (i.e. BB, ACE/ARB, dig, aldactone) for at least 3 months Randomized to isordil/hydralazine (20mg tid/75mg tid) or placebo

CLINICAL ENDPOINTS
Death from any cause First hospitalization for CHF in 18 months Change in quality of life after 6 months

EXCLUSIONS

MI, ACS, stroke, PCI, or cardiac surgery within 3 months Valvular, hypertrophic, or restrictive disease Uncontrolled HTN inotropes within month

CONCLUSIONS

Significantly HIGHER mortality in the placebo group compared to hydralazine/nitrates group!! Trial stopped early because of this Survival benefit started at 180 days, 10.2% mortality in placebo vs. 6.2% in study group (ARR of 4%, RRR of 43%)

SHORTCOMINGS

Cannot generalize these findings to patients that are not AA At 6 months, BP in study group fell by a mean of 1.9/2.4 mmHg, whereas it increased in the placebo group. Thus, some of the benefit may be due to BP reduction. However, other trials that decrease BP alone (prazosin and amlodipine in HF) have not shown improvement in outcomes

BOTT OM LINE !!
Hydralazine/nitrates decrease mortality in AA pts with HF

Anne L. Taylor, M.D., Susan Ziesche, R.N.,etc. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. N Engl J Med 2004, 351: 2049-2057 31

Peri-OP Bisoprolol (1999)

PURPOSE
To assess the effect of Bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery

METHODS
112 high risk patients (those with presence of both clinical risk factors and posistive DSE) undergoing major vascular surgery (elective AAA repair or infrainguinal artery reconstruction) Randomized to bisoprolol vs standard care peri-op . Average start of bisoprolol was 37 days pre-op Followed for 30 days post-op

CLINICAL ENDPOINTS
Primary death from cardiac causes and nonfatal MI

EXCLUSIONS

Extensive wall-motion abnormalities on DSE Asthma Strong evidence during DSE of LM or severe three vessel disease Patients on BB

CONCLUSIONS

Reduced incidence of death from cardiac causes and nonfatal MI in the bisoprolol group (34% in the standard-care group vs. 3.4% in the bisoprolol group)

SHORTCOMINGS
The study was not blinded!! Attending physicians knew which treatment had been prescribed

BOTT OM LINE !!
High risk pts undergoing major vascular procedures SHOULD be on a BB peri-operatively!!

Poldermans, D, Boersma, E, Bax, JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999; 341:1789. 30

Peri-OP Atenolol (1996)

Effect of Atenolol on Mortality and Cardiovascular Morbidity after Noncardiac Surgery

PURPOSE
To assess the effect of peri-op atenolol on overall survival and cardiovascular morbidity

METHODS
200 patients with CAD or at risk for CAD (at least 2 of the following age>65, HTN, smoker, HL, DM) undergoing elective noncardiac surgery requiring general anesthesia Randomized to receive IV atenolol vs placebo before and after surgery and then oral atenolol for duration of hospitalization

CLINICAL ENDPOINTS
Overall mortality and cardiac related mortality Combined cardiac events (combo of MI, UA, need for CABG, CHF)

EXCLUSIONS

Patients without risk for CAD

CONCLUSIONS

Overall mortality, mortality secondary to cardiac events, length of time to first event and event free survival were all significantly improved in the atenolol group, particularly at 6-8 mo post op

SHORTCOMINGS
Nothing significant

BOTT OM LINE !!
Patients at risk or with CAD undergoing noncardiac surgery SHOULD be on BB peri-operatively!!

Mangano, DT, Layug, EL, Wallace, A, et al for the Multicenter Study of Perioperative Ischemia Research Group. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 1996; 335: 1713.

29

COPERNICUS (2002)
Cardvedilol Prospective Randomized Cumulative Survival Study

PURPOSE

To see if BB improve functional status and reduce mortality in severe HF (already been shown to benefit patients with mild-moderate HF)

METHODS
2289 euvolemic pateints with NYHA class III & IV (HF at rest or w/ minimal exertion) AND EF 25% Randomized to carvedilol or placebo

CLINICAL ENDPOINTS
All cause morality All cause hospital admissions

EXCLUSIONS

EF > 25% HF pts that were bed bound or end of life

CONCLUSIONS
Risk of death or hospitalization for any CV reason reduced by 27% (RRR) and 12% (ARR) Combined risk of death or hospitalization for HF reduced by 31% (RRR) Patients spent 27% fewer days in the hospital for any reason and 40% fewer days for HF Carvedilol patients with less episodes of ADHF, SCD, cardiogenic shock or VT and they felt better

SHORTCOMINGS
Nothing significant

BOTT OM LINE !!
Carvedilol decreases mortality in patients with severe HF

Packer, M, Fowler, MB, Roecker, EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study. Circulation 2002; 106: 2194.

28

COMET (1996-2002)
Carvedilol or Metoprolol European Trial

PURPOSE
To compare the effects of carvedilol versus metoprolol tartrate Study use metoprolol tartrate whereas metoprolol succinate used in MERIT-HF

METHODS
3029 patients with NYHA class II-IV HF with at least one admission for CV diagnosis in preceding 2 years and followed for 5 years LVEF 35% and already on diuretics and ACEI Randomized to carvedilol (target dose 25mg BID) or metoprolol (target dose of 50mg BID)

CLINICAL ENDPOINTS All cause mortality All cause admissions

EXCLUSIONS

UA, MI, PCI, or CVA within 2 months Recent use of amiodarone, CCB, antiarrhythmics, or investigational drug pregnancy, sustained VT

uncontrolled HTN, valvular disease,

CONCLUSIONS

Carvedilol arm had a significantly lower rate of all-cause mortality (34% vs. 40%) Extrapolation of the survival curves demonstrate longer estimate of median survival to the carvedilol group (8 yrs vs 6.6 yrs). Thus in terms of survival, this study suggested that carvedilol is superior to metoprolol (not exactly true however see below)

SHORTCOMINGS
The degree of beta blockade seems to be unequal between the two arms the carvedilol arm had significant greater reductions in HR and SBP than the metoprolol arm Metoprolol goal dose substantially lower than the goal in MERIT-HF

BOTT OM LINE !!
Carvedilol is superior to metoprolol tartrate

Poole-Wilson, PA, Swedberg, K, Cleland, JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilo Or Metoprolol European Trial (COMET): randomized controlled trial. Lancet 2003; 362:7.

27

CIBIS-II (1997)
The Cardiac Insufficiency Bisoprolol Study II

PURPOSE
To assess the survival benefit of Bisoprolol

METHODS
2647 pts (age 18-80) with symptomatic NYHA class III-IV LVEF 35% Already receiving standardized therapy w/ diuretics and ACEI Allocated to bisoprolol or placebo

CLINICAL ENDPOINTS
Primary All cause mortality Secondary All cause hospital admissions, CV mortality, CV hosp admissions

EXCLUSIONS

NYHA class IV LVEF>35% pts with HF after early AMI, and Symptomatic patients with normal LVEFs

CONCLUSIONS
Significant reduction in all cause mortality All cause mortality 11.8% in bisoprolol group vs. 17.3% in placebo Fewer CV deaths and reduction in admissions Decrease in sudden cardiac deaths by 44%

SHORTCOMINGS BOTT OM LINE !!

Bisoprolol decreases mortality in HF

Several categories not included as mentioned before. Elderly patients not largely represented - mean age was 61, which is at least a decade less than the mean age in clinical practice

Lechat P, Brunhuber KW, Hofmann R. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomised trial. Lancet. 1999; 353: 913

26

MERIT-HF (1998)
The Metoprolol CR/XL Randomized Intervention Trial in CHF

PURPOSE
To assess the survival benefit of metoprolol succinate

METHODS
3991 patients (40-80 yo) with symptomatic HF (NYHA class II-IV) for at least 3 months LVEF 40% Patients initially stabilized with standard treatment (diuretics + ACEI) Pateints allocated to metoprolol CR/XL vs placebo

CLINICAL ENDPOINTS
Total mortality Any hospitalization Number of hospitalizations for worsening HF Change in NYHA class Change in quality of life

EXCLUSIONS

Severe HF confined to bed LVEF > 40% HF 2/2 recent AMI Symptomatic pts with normal LVEF

CONCLUSIONS
All cause mortality and hospitalizations reduced by 19% Total deaths or hospitalizations 2/2 worsening HF reduced by 31% A 34% relative risk reduction in all cause mortality Improvement in NYHA class Improvement in quality of life

SHORTCOMINGS
Several categories of patients were not included as mentioned above: NYHA class IV not largely represented. Elderly pts not largely represented

BOTT OM LINE !!
Metoprolol XL decreases mortality in HF

Hjalmarson A, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA March 8, 2000; 283: 1295-302. 25

HOPE (2000)
Heart Outcomes Prevention Evaluation Study

PURPOSE
To investigate if ramipril decreases the incidence of vascular events in patients at high risk for HF or LV dysfunction

METHODS
9000 high-risk patients with vascular disease or diabetes + additional cardiac RF without HF or known LV dysfuntion randomly assigned to ramipril 10mg daily or placebo for 5 yrs Patients also randomized to Vitamin E 400 IU daily or placebo

CLINICAL ENDPOINTS
Primary CVD MI, stroke, or death from

EXCLUSIONS
LVEF < 40% MI or CVA in past month

CONCLUSIONS
Ramipril signficantly reduced rate of death, MI and stroke in these high risk patients without evidence of LV dysfuntion or CHF Vitamin E showed no benefit towards primary endpoints

SHORTCOMINGS
There was a significant increase in hyperkalemia in the study group

BOTT OM LINE !!
ACE-I reduce morbidity and mortality as primary prevention in patients at high risk for cardiovascular events

The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145-53.

24

ELITE (1997)
Evaluation of Losartan in the Elderly Study

PURPOSE
Could ARBs be better than ACE-Is? Losartan vs Captopril

METHODS
Total 722 patients, Age >65, NYHA 2-4, EF <40%, ACE-I nave patients Double-blinded, prospective 48 week follow-up period

CLINICAL ENDPOINTS
Primary persisting increase in serum creatinine Secondary composite of death and/or hospital admission for CHF

EXCLUSIONS

Prior ACE-I use BP <90 or uncontrolled HTN Recent MI, certain recent surgical interventions-CABG, ICD, etc Constrictive pericard, active myocarditis, Valvular disease, symptomatic tachycardia

CONCLUSIONS
No statistically significant difference in incidence of increased serum creatinine No statistical difference between compositive dead and/or hospital admission for CHF
Losartan showed a trend towards fewer deaths compared to captopril, but no difference in CHF hospitalizations

SHORTCOMINGS
Only 48 week follow-up period Not powered well for sub-group analysis (example, most patients were men, not enough women to compare mortality)

BOTT OM LINE !!

Losartan has at least equal (if not better) mortality benefit & equal hospitalization benefit compared to captopril in CHF patients

Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997 Mar 15;349(9054):747-52.

23

CHARM (1999)
Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity

PURPOSE
Investigate if the angiotensin-receptor blocker (ARB) candesartan could reduce mortality and morbidity

METHODS
Parallel, randomized, double-blind trial compared candesartan with placebo 7601 patients were randomly assigned candesartan (n=3803) titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years

CLINICAL ENDPOINTS
Primary all-cause mortality cardiovascular death or hospital admission for CHF
Secondary

EXCLUSIONS

Cr>3.0, K>5.5 MI or CVA in past month Bilateral renal artery stenosis

CONCLUSIONS

Candesartan, given in titrated doses as tolerated, can prolong survival, particularly in patients with LVEF of 40% or less Candesartan provided clinical benefits for patients with symptomatic heart failure, including reductions in hospital admissions for heart failure and prevention of diabetes Fewer cardiovascular deaths (691 [18%] vs 769 [20%], and hospital admissions for CHF (757 [20%] vs. 918 [24%], p<00001) in the candesartan group

SHORTCOMINGS
There was a significant increase in hyperkalemia in the study group This was an industry sponsored trial

BOTT OM LINE !!
ARBs reduce morbidity and mortality
Swedberg K, Pfeffer M, Granger C, Held P, McMurray J, Ohlin G, et al for the CHARM-Programme investigators. Candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM): Rationale and design. J Card Fail 1999; 5: 276-82 22

EPHESUS (2003)
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

PURPOSE
To assess the effect of eplerenone (a selective aldosterone blocker) on morbidity and mortality

METHODS
6632 pts with AMI with clinical signs of HF LVEF 40% Randomly assigned to eplerenone 25mg qd (titrate to 50) or placebo in addition to optimal medical therapy

CLINICAL ENDPOINTS
Primary time all cause mortality and time to death from CV cause or first hospitalization for a CV event (HF, recurrent AMI, stroke, vent arryhythmia). death from CV causes and all cause mortality
Secondary

EXCLUSIONS
Cr>2.5, K>5

CONCLUSIONS
The study group had decreased death from CV events and decreased hospitalizations from CV causes. Reduction in the rate of sudden death from cardiac causes.

SHORTCOMINGS
There was a significant increase in hyperkalemia in the study group

BOTT OM LINE !!
Addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with AMI complicated by LV dysfunction

Pitt B, Remme W, Zannad F, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309-1321. 21

RALES (1999)
Randomized Aldactone Evaluation Study

PURPOSE
To assess the affect of spirinolactone on mortality

METHODS

CLINICAL ENDPOINTS
Primary all cause mortality

EXCLUSIONS

1633 patients with NYHA class III - IV HF LVEF 35% Already being treated with ACEI, diuretics, and in most cases dig Randomly assigned spirinolactone 25mg qday or placebo

Primary operable valvular disease Congenital heart disease UA Primary liver failure Heart transplant patients Cr > 2.5 or K > 5

CONCLUSIONS

Trial discontinued because spirinolactone was found to decrease mortality (46% placebo vs. 35% spirinolactone group) Study group also had decreased frequency of hospitalizations for worsening HF. Patients in study group also had improvement in their symptoms

SHORTCOMINGS

Lower doses of ACEI used than currently recommended for CHF (average daily doses used - lisinopril 14mg and captopril 63mg) In real practice, you have higher rates of hyperkalemia with this studies dose of aldactone on top of high ACEI doses. Also, elderly pts and diabetics already at higher risk for hyperkalemia Patients not optimally medically managed on other drugs BB used in only 11% at start of study Increased risk of gynecomastia from spirinolactone

BOTT OM LINE !!
Spirinolactone decreases mortality in pts with CHF

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2; 341(10): 709-17. 20