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List of Cardiology Trials
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This List of Cardiology Trials is a collection of some of the important cardiology trials. This list is organized based on topics for simplicity. Atrial Fibrillation, Stroke AFFIRM - no statistical difference in mortality between rate and rhythm control, however, increased mortality in rhythm control in older patients, those with CAD, those without CHF; DIAMOND Study - Dofetilide is a safe and efficacious antiarrhythmic drug in patients with afib/aflutter and a depressed ejection fraction. Torsade de pointes occurred in 3.3% of patients in dofetilide group (75% of TdP occurred in the first 3 days; RACE II - Lenient ( resting <110) vs. strict (resting < 80 ) HR control in patients with AFib - lenient rate control was as effective as strict and required fewer office visits; RE-LY - In patients with Afib, Both doses of Dabigatran are non-inferior to warfarin in preventing stroke and systemic embolism with lower major bleeding profile; slight increase in GI bleeding; ESPS-2, ESPRIT: Aggrenox BID is more effective for secondary prevention of stroke in patients with ischemic stroke/TIAs; SPAF I, SPAF II, SPAF III - Warfarin > ASA > placebo in reducing stroke events in AFib. For high risk patients with Afib, Warfarin INR 2-3 is more effective than low intensity warfarin (INR 1.2-1.5) dosing plus ASA 325 (1.9% vs. 7.9% stroke rates respectively). For low risk patients, ASA 325 has acceptable low risk of stroke < 3%. Sub-study of SPAF III established high risk factors of the CHADS2 risk score; ARISTOTLE - Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.; ROCKET-AF - Rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Coronary Artery Disease COGENT - use of plavix in patients with ACS, DES placed, on PPI who have risk of GI bleeding related to NSAID use or positive for H. pylori - When used with plavix, PPI reduces rate of GI outcomes without change in cardiovascular events. Weak recommendation in patients without risk of GI bleed; Important to note that the study did not have adequate power, did not include patients with high risk bleeding; TRITON-TIMI 38 - Used universal definition of MI. In patients with moderate-severe unstable angina, NSTEMI, and STEMI, Prasugrel (loading 60 then 10 daily) reduced CV death, nonfatal MI, nonfatal stroke compared to clopidogrel (loading 300 then 75 daily) at 1, 6, and 15 months; additionally, there’s reduced stent thrombosis in prasugrel group. Similar bleeding profiles; - 19% reduction in CV death, MI or stroke compared with clopidogrel in patients undergoing PCI for ACS. PLATO - patients with ACS, with or without ST elevation, ticagrelor reduces death from vascular, MI, and CVAs; slight increase non-procedural related, i.e. fatal intracranial bleeding, but fewer other types of fatal bleeding; GUSTO-I : In patients with acute MI, Accelerated t-PA plus IV Heparin has lower mortality although higher bleeding than streptokinase and standard therapy. Older age, Anterior MI, increased Killip class lower systolic BP ( < 110) and increased HR (> 90) predictive of 4 time more higher 30 day mortality ; also, lower TIMI flow grade in infarct artery, renal dysfunction, arrhythmias are factors; CAPRIE - In patients with CAD, plavix was slightly better than aspirin in reducing primary endpoints of MI, CVA, and vascular death; conferred benefit for CVA and PAD; no benefit in patients with previous MI; CAST - flecanide and encanide increased mortality (relative risk 2.5) in patients with post-MI asymptomatic or mildly symptomatic ventricular arrhythmias; ISIS II - ASA lowers CV death, Recurrent MI, CVA when given to patients with acute MI; COMMIT - Plavix plus ASA reduces 30 day mortality (0.6% ARR), BB good after MI if patients do not have heart failure/cardiogenic shock; HORIZONS - AMI - Bivalirudin reduced bleeding and death compared to Heparin plus Glycoprotein IIb/IIIa inhibitor in 30 days; increased <24 hr in stent thrombosis with bivalirudin but offsetted between 24 hrs to 30 days; TACTICS - TIMI 18 - GpIIb/IIIa inhibitor plus invasive strategy in patients with moderate-high risk UA/NSTEMI is better than conservative management; CURE - plavix in addition to aspirin in patients with non-STEMI ACS reduces risk of CV death, MI, and CVAs by 20%; 2002 CLARITY - TIMI 28 - In STEMI patients, plavix in addition to aspirin plus thrombolysis reduced CV death, occlusion of infarct-related artery, re-MI and by 20% at 30 days; 2005 ISIS-4 - In patients with suspected or acute MI, Captopril reduced all cause mortality at 5 wks and long term follow up; increased rate of hypotension and/or renal dysfunction in patients with captopril warranting termination; no benefit conferred by magnesium sulfate or isordil; 1995 GISSI 3 - Lisinopril, when given < 24 hrs in patients with acute MI, reduced mortality and severe LV diastolic dysfunction (EF < 35%); 1994 Norwegian Timolol Study - In patients who survive acute MI, Beta blockers reduce all cause mortality, sudden death, and reinfarction; 1981 Heart Failure Tele-HF - Follow up with telemonitoring in patients with CHF, does not improve mortality or readmission rate; only 55% 6-month pt compliance rate for using the telemonitoring system; 2010 AIRE - In patients with non severe HF, significant relative reduction in all cause mortality by 23% when ramipril started 3-10 days after MI, benefit noticeable as early as 30 days, reduction in progression to heart failure; no reduction in reinfarction or stroke; 1993 CAPRICORN - Carvedilol decreases cardiovascular and all cause mortality in post- infarction patients with EF < 40% ; 2001 MERIT-HF - Metoprolol XL when used on top of ACE-I reversed ventricular remodeling as shown by decreased LV- EDV and ESV by cardiac MRI and decreases all cause mortality when started in patients with CHF; SAVE (captopril, 1992), TRACE (trandolapril, 1995), SOLVD (enalapril, 1991) - ACEI reduces all cause mortality (~ 20%), remodeling, and decreased risk of worsening heart failure (37%) when started 2-10 days after MI, and in patients with CHF (EF < 35%) VALIANT RCT of valsartan, captopril, or both in patients with MI complicated by left ventricular systolic dysfunction, heart failure, or both with primary outcome of all cause mortality at two years. Found that while valsartan is noninferior to captopril, the combination of captopril and valsartan did not reduce mortality and was associated with increased rate of side effects; side note: Angiotensin type 1 receptor blockers ( ARBs) have increased stimulation of angiotensin type 2 receptors, which have protective effect of decreased remodeling; RESOLVD - enalapril plus candesartan combination was more beneficial in preventing LV dysfunction (reduced ESV and EDV), compared to either drug alone ; 1999 CHARM Overall - candesartan addition to concurrent BB and/or ACEI therapy - trend toward significance in reducing all cause mortality; significant reduction in CV death or hospital admission for CHF (16%); NNT is 23 in 1 year OPTIMAAL - ARB vs. ACEI - In patients with acute MI or heart failure/LV dysfunction, Losartan had no additional benefit compared to captopril, but was better tolerated; 2002 CIBIS II - in patients with EF < 35% and NYHA class III or IV, B1 blocker bisoprolol significantly reduced all cause mortality, sudden death, and all cause hospitalizations from CHF; 1999 CONSENSUS - in patients with severe CHF (class IV), addition to diuretics and digoxin, enalapril reduces mortality by 27% and reduces progression of CHF; no change in sudden death; 1987 V-HEFT (Vasodilator (enalapril vs. hydralazine/nitrate)-Heart Failure Trial) - patients with CHF on digoxin and diuretic; enalapril has greater reduction mortality compared to combination for at least 2 years, likely due to lower incidence of sudden death; both increase LV EF, combination > enalapril, combination increased O2 consumption at peak exercise at 1 year; 1991 I-PRESERVE - Irbesartan did not improve mortality or CV outcomes in patients with HF symptoms (Class II-IV) and preserved EF > 45%; Most patients (63%) had HF due to hypertensive heart disease; 2008 COPERNICUS - RCT comparing standard therapy plus carvedilol to standard therapy (at least Ace/ARB) in patients with class III or IV HF and (EF < 25%) to assess the primary outcome of all-cause mortality and secondary outcome of combined risk of death or hospitalization for any reason. There was a 7.1% absolute risk reduction in all cause mortality at 1 year and an 11.4% absolute risk reduction in combined outcome of mortality or hospitalization for cardiovascular reason at 1 year. During initiation and up-titration of carvedilol (8 weeks) there was not an increased risk of worsening heart failure, pulmonary edema, cardiogenic shock, or death, but was a trend toward a reduction in mortality with carvedilol. In the subgroup of high-risk patient's, the carvedilol group showed a significant reduction in all-cause mortality and combined outcome of death, hospitalization, or carvedilol withdrawal. High risk patients included those with signs of HF at randomization, at least 3 hospitalizations for HF in the previous year, hospitalization at randomization, or EF ≤15%; RALES - Spironolactone 25 mg in addition to standard therapy reduces mortality and risk of sudden death in patients with severe CHF (EF < 35, Class 3-4); RRR 30%; 1999 EPHESUS - Eplerenone in addition to standard therapy reduces mortality in patients with severe CHF; 2001 Lipids JUPITER - Rosouvastatin reduced primary endpoint (CV death, MI, CVA, unstable angina, revascularization) in women > 60 and men > 50, LDL < 130 - low normal, elevated hsCRP > 2 by 44%, 20% reduction in total mortality, NNT is 95 in 2 yrs, slightly higher incidence of diabetes; 17K total number of patients; 2008 CRP Genetic loci analysis in patients with CAD - mendelian randomization study showed no effect of CRP levels and loci on CAD; JAMA July 2009 TNT - Intense lipid lowering therapy in patients with CAD (prior MI +/- revascularization, stable angina) - high dose (80 mg) vs. low dose (10 mg) Lipitor - high dose has significantly lowerLDL and total cholesterol levels, and reduced risk of major CV event and death from coronary heart disease and stroke; 2005 A to Z - NSTEMI, STEMI … 2% reduction in CV death, MI and readmission for ACS reduced in pt receiving aggressive zocor (40 initially then 80 mg) vs. placebo then 20 mg zocor after 2 years. Effects occur primarily after 4 months of treatment. Significant decrease in CV death and CHF; 2004 CARDS - Atorvastatin 10 mg daily reduces risk of major cardiovascular events including stroke in patients with DM2; relative risk reduction of 37% and benefits emerge after 1 yr on therapy, favorable trend with regards all cause mortality; 2004 CARE - pravastatin reduces risk of major cardiovascular events in patients (both gender and over and under 60) with average cholesterol and previous MI by 24%; lowers total cholesterol, LDL, and triglycerides by 20%, 285, and 14% respectively, and increases HDL by 5%; 1996 WOSCOPS - patients hyperlipidemia and no hx of MI, pravastatin reduced CV deaths (RRR 30%) and need for revascularization (RRR 37%); 1995 CURVES - Atorvastatin of all doses is more potent in reducing cholesterol levels than simvastatin, pravastatin, lovastatin and fluvastatin; 1998 LIPID - Pravastatin reduced mortality from all causes and CV events in patients with acute MI or unstable angina and cholesterol 155-271; 1998 4S - Among patients with cholesterol 210-310 mg/dl and either stable angina or previous MI (> 6 months), simvastatin reduced all cause mortality, future coronary events and need for CABG/PCI; 1994 PROVE IT - Liberal versus intensive control of lipids following ACS, 80 mg Atorvastatin better than 40 mg Pravachol. Interventional STICH RCT to determine whether medical therapy or medical therapy plus CABG in patients with EF of ≤35% reduces primary outcome of all-cause mortality or secondary outcomes of cardiovascular mortality or all-cause mortality plus hospitalization for any cause. Found no difference of primary outcome of all-cause mortality, however CABG arm did show reduced rates of both secondary outcomes. Even after substudy using SPECT or dobutamine echo, viability was not associated with significant difference in mortality between medical and medical plus CABG arm after controlling for baseline variables. PARTNER cohort A - 699 elderly patients (median age 84.1) with severe aortic stenosis were randomized to either TAVI or surgery. TAVI was just as good as surgery in surgery-eligible patients for the primary end point of mortality. More stroke/TIA, vascular complications seen in TAVI group but more major bleeds in surgery group. Better symptomatic improvement in TAVI. NORDISTEMI - Early invasive strategy in patients with STEMI has significant reductions in primary outcomes (death, stroke, reinfarction) at 30 days, but at 12 months, reductions were nonsignificant, but trended towards significance as invasive group had less incidence of death, strokes, reinfarction at 12 months; 2010 BARI 2D - In patients with DM2, stable CAD, no significant difference in mortality between prompt revascularization ( surgery or angioplasty) vs. medical therapy; or between insulin sensitization (metformin, TZDs) vs. insulin provision therapy (sulfonylurea, insulin); 2009 CURRENT - OASIS 7 - double dose plavix loading dose plus 150 a day for 1 week then 75 daily is beneficial mainly in subgroup of patients undergoing PCI by reducing stent thrombosis; 2008 GUSTO -IIB - PTCA has better outcomes than thrombolysis in patients with AMI. lowest 30 day mortality when D2B time < 60 minutes (1%), 60-90 minutes (4%), > 90 minutes (6.5%) SYNTAX - PCI vs. CABG in patients with severe CAD - At 1 yr, CABG group had lower rates of major cardiac or cerebrovascular events (12% vs. 18%) and repeat revascularization (6% vs. 14%); however, there was increase in rate of strokes (2.2% vs. 0.6%). Conclusion - CABG should be standard of care in patients with severe 3 vessel or left main disease; 2009 SHOCK - In patients with cardiogenic shock due to acute MI, early revascularization vs. medical stabilization does not improve 30 day mortality but does improve 6-month and 12-month mortality, especially in patients < 75; 1999 COURAGE - Compared with optimal medial therapy(OMT), PCI plus OMT in stable CAD did not reduce all cause mortality, non-fatal MI, and other major CV events; however, there was reduction in reoccurrences of angina symptoms in PCI + OMT group; 2008 CARP - In patients with stable CAD, coronary artery revascularization prior to elective major vascular surgery, s.a. expanding AAA, PVOD of legs, does not improve outcomes; 2004 ERACI, GABI, BARI, CABRI, RITA, EAST - PTCA and CABG have similar rates of survival and avoidance of MI and similar long term health care costs; PTCA group had increased rates of recurrent angina and revascularization; nearly ¼ of PTCA patients required CABG; At 10 year follow up some studies showed that Diabetics and patients > 65 yrs have slightly decreased mortality with CABG; Subset of CABRI trial - patients with multi-vessel or chronically occluded major vessel disease had better outcomes with CABG; 1994, 1994, 1996, 1995, 1998, 1999 SoS (Stent or Surgery) - PCI is associated with higher rates of repeat revascularization compared to CABG; similar incidence of q-wave MI; fewer deaths in CABG group; 2002 FRISC-II, RITA-3 - At 5 year follow up, in moderate-high risk patients with ACS without ST elevation, early invasive intervention strategy has improved outcomes in terms of death/MI; 2005, 2006 PRAMI - Preventive Angioplasty in Acute Myocardial Infarction. In patients undergoing emergency PCI for acute STEMI, with multiple vessel atherosclerotic disease, performing preventive PCI in non-infarct vessels with stenosis ≥ 50% significantly reduces risk of composite endpoint (cardiac death, nonfatal MI, refractory angina) RR 0.35. Pacemaker MADIT-CRT - CRT+ICD vs ICD: Among patients with ischemic or nonischemic heart failure (EF < 30%, NYHA Class I or II) and wide QRS > 130ms, CRT + ICD therapy compared to ICD alone resulted in 8.9% ARR in heart failure events over 2.4 years. Most benefit in reducing HF events in patients with QRS > 150; Echo evidence of decreased LV EDV /ESV and improved EF at 1 year; 2009 SCD-HeFT - Amio vs. placebo, ICD vs. placebo for CHF - In patients with mild-moderate CHF, EF <35, shock only ICD reduced risk of death (ARR 7.2% at 5 years), main effects in patients with Class II symptoms, minimal effect in Class III; Amio showed no benefit in Class II, but reduced survival in Class III; 2005 REVERSE - CRT reverses remodeling in systolic LV dysfunction, patients with asymptomatic to mild HF or wide QRS, EF < 40 - significant improvement in reverse LV remodeling seen by measures of LVESV and LVEDV along with EF after 6 months in patients with CRT with further improvement overtime; there was significant decrease in morbidity and mortality; 2009 AVID - ICD is more effective than antiarrythmic drugs in reducing arrhythmia related cardiac deaths. 1999 Preventative Cardiology ACCORD - increased mortality from any cause with aggressive glycemic control hgba1c < 6 vs. 7-7.9 in diabetic patients, NNH is 95 in 3.5 yrs; 2008 ACCORD BP - intensive bp control < 120 vs. < 140 systolic in diabetics did not reduce fatal and nonfatal CV events; 2010 BEAUTIFUL - ivabradine (selective sinus node inhibitor - reduced SA node pacemaker current (If)) addition to standard therapy of BB, etc. in patients with CAD and LVF < 40% showed no reduction in mortality or admissions for new onset of HF, however, in patients with HR > 70 bpm, reduction in fatal and nonfatal MI 36%, coronary revascularization by 30%, and HR reduction by 6 bpm ; 2009 SHIFT - ivabradine outcomes in chronic HF stage 2 -4, HR > 77 bpm - reduction in hospitalization or CV death from heart failure. Drug side effects, bradycardia and visual side effects; 2010 WHI (Women’s Health Initiative) - post menopausal women on combined hormonal therapy is associated with increased risk of CAD, PE, CVA and invasive breast cancer but decreased risk of hip fractures and colorectal cancer; absolute risk excess was 19 per 100,000 person-years; 2002 VALUE - Valsartan vs. Amlodipine in HTN control: Amlodipine has better HTN control in first few months, but equal efficacy at 6 years; Valsartan group had greater incidence of MI and Amlodipine group had greater incidence of new onset diabetes; 2004 UKPDS (HTN in Diabetes study) - BP control < 130/85 in patients with HTN and Diabetes with ACEI or BB, plus additional meds if needed, reduces risk of diabetic related complications and death related to diabetes (MI, PV0D, renal disease, CVA, sudden death) along with decrease in progression of neuropathy and retinopathy; 1998 ONTARGET - ARB vs. ARB plus ACEI - patients with CAD/MI high risk diabetes, without heart failure - Telmisartan is equally efficacious as ramipril, but better tolerated, yet had higher rates of hypotension; combination therapy conferred no benefit in preventing cardiovascular mortality/morbidity; 2008 HOPE - in patients with known vascular disease or diabetes plus at least one cardiovascular risk factor, ramipril reduced risk of death, MI, stroke, and revascularization, along with diabetic complications; new diagnosis of diabetes significantly lower in ramipril group; Vitamin E did not lower the risk of CAD; 2000 GISSI-HF - polyunsaturated fatty acids (PUFA) 1g/day associated with decreased mortality and hospital admission in patients with symptomatic HF( Class II-IV); NNT 56 over 4 years; Rosouvastatin in patients with symptomatic HF does not improve mortality or hospital admissions, etc. it may be prescribed for patients with indication for statin i.e. CAD, but not just for HF; 2008 ALLHAT - thiazide vs. CCB vs. ACEI - No significant difference in all cause mortality, fatal or nonfatal coronary heart disease (CHF). Thiazide type diuretics (chlorthalidone) are superior at preventing 1 or more forms of CVD and should be first line of therapy; amlodipine higher 6 yr rate of HF and lisinopril had higher 6 yr rates of CHD, stroke, and HF; 2002 Framingham Heart study - high levels of LDL, Hypertension, cigarette smoking, obesity, elevated blood sugar levels, stress, lack of exercise, menopause, ECG abnormalities increase risk of coronary heart disease; 1984 LIFE - Losartan vs. atenolol - losartan shows reduction in CV deaths (MI and stroke) compared to atenolol, and losartan in better tolerated with similar BP reduction; reduction in new onset diabetes in losartan group; 2002 ELITE I, ELITE II - Losartan was not superior to captopril, only better tolerated. 1997, 2000 See Also
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