Table 2.
Pharmacological and Non-Pharmacological Clinical Trials for HF.
| Clinical Trial Name | Drug Class | Drugs | Condition | Phase | No. of Patients | Date | Outcome | References |
|---|---|---|---|---|---|---|---|---|
| CONSENSUS | ACE inhibitors (ACEis) | Enalapril vs. placebo | Severe congestive heart failure | Double-blinded multi-center RCT | 253 | 1987 | ACEi improved symptoms, reduced HF progression in NYHA IV and mortality | [80] |
| SOLVD | ACE inhibitors (ACEis) | Enalapril vs. placebo | Heart failure with ejection fractions of 0.35 or less and on drugs other than an angiotensin-converting enzyme inhibitor | Double-blinded multi-center RCT | 4228 | 1992 | ACEi in an asymptomatic LV dysfunction reduced incidence and hospitalization for HF | [81] |
| RALES | Aldosterone antagonists | Spironolactone vs. placebo | CCF (NYHA III and IV) | Double-blinded multi-center RCT | 1663 | 1999 | Spironolactone reduced hospitalization (35%), mortality (30%) and symptoms in NYHA III/IV | [82] |
| CIBIS-II | Beta blockers | Bisoprolol vs. placebo | HF (NYHA Classes III–IV) | Double-blinded multi-center RCT | 2647 | 1999 | All-cause mortality hospitalizations and sudden cardiac death were reduced by 50%. | [83] |
| ValHeFT | Angiotensin receptor blockers (ARBs) | Valsartan vs. placebo | Heart failure (NYHA II–IV) | Multicenter, double-blinded, parallel-group, placebo-controlled RCT | 5010 | 2001 | Valsartan improved symptoms and mortality in NYHA II+; no benefit when added to ACEi | [84] |
| VMAC | Recombinant form of human B-type natriuretic peptide Vs nitrates | Intravenous nesiritide vs. nitroglycerin vs. placebo | Acute decompensated HF | Randomized, double-blind trial | 489 | 2002 | Nesiritide improved hemodynamic function as assessed by measuring reduced pulmonary capillary wedge pressure (PCWP) | [85] |
| COMET | Beta blockers | Carvedilol vs. metoprolol | Heart failure (EF < 35%; Stage II–IV) | Multicenter, double-blind, parallel-group, RCT | 3029 | 2003 | Carvedilol decreased all-cause mortality by 6% as compared to metoprolol | [86] |
| CHARM (includes CHARM added/alternative/preserved) | Angiotensin receptor blockers (ARBs) | Candesartan +/− ACEis vs. placebo | Heart failure (EF < 40%; Stage II or IV); (EF < 40% on ACEi for added); (EF < 40% intolerant of ACEi for alternative); EF > 40% for preserved |
Double-blinded multi-center RCT | 4576/2448 for added/2028 for alternative/30,233 for preserved | 2003 | Candesartan reduced death in HF; had added benefit in the presence of ACEi irrespective of ACEis dose; no benefit in preserved LV dysfunction | [87,88,89] |
| EVEREST | Vasopressin antagonists | Tolvaptan vs. placebo | Decompensated HF | Multi-center, double-blind, parallel-group, randomized controlled trial | 4133 | 2007 | Significant benefit on dyspnea, edema, body weight and serum sodium, but no improvement in cardio-vascular mortality or HF hospitalization | [90] |
| VERITAS | Endothelin receptor antagonist | Intravenous tezosentan vs. placebo | Acute HF | Randomized, double-blind trial | 1435 | 2007 | Tezosentan failed to improve symptoms or clinical outcomes in patients with acute heart failure | [91] |
| CORONA | Statin | Rosuvastatin vs. placebo | Congestive Cardiac Failure (CCF) (EF < 40%, NYHA II) | Multicenter, double-blind, randomized placebo-controlled trial | 5011 | 2007 | Rosuvastatin in statin-naive CCF patients reduced admissions, but not mortality | [92] |
| ACCLAIM | Device-based non-specific immuno-modulation therapy (IMT) | Celecade vs. placebo | NYHA II–IV HF | Double-blind, placebo-controlled study | 2426 | 2008 | Failed to demonstrate reduction in hospitalization or mortality, but proposed to be beneficial for the early stages of HF | [93] |
| SHIFT | Specific inhibitor of current in the sinoatrial node | Ivabradine vs. placebo | HF with LVEF 35% or lower with heart rate >70 in sinus rhythm | Double-blinded multi-center RCT | 6558 | 2010 | Ivabradine reduced CCF admissions and deaths, especially those with higher HR | [69] |
| EMPHASIS-HF | Aldosterone antagonists | Eplerenone vs. placebo | CCF (NYHA II and EF < 35%) | Double-blinded multi-center RCT | 2737 | 2011 | Eplerenone reduced mortality by 7% and symptoms in NYHA II | [70] |
| ASCEND-HF | Recombinant form of human B-type natriuretic peptide | Nesiritide infusion vs. placebo | HF | Double-blinded multi-center RCT | 7141 | 2011 | Improved the symptom of dyspnea, but no change in mortality | [72] |
| RELAX | cGMP-specific phosphodiesterase type 5 inhibitor | Sildenafil vs. placebo | Diastolic HF with NYHA II–III (LVEF > 50%) |
Double-blinded multi-center RCT | 216 | 2012 | No improvement in health outcomes and exercise ability | [94] |
| ASTRONAUT | Renin inhibitor | Aliskiren vs. placebo | Decompensated HF | Multicenter, double-blind, randomized placebo-controlled trial | 1639 | 2013 | No additional benefit from the drug to standard therapy | [95] |
| ATOMIC-AHF | Cardiac-specific myosin activator | Omecamtiv mecarbil vs. placebo | ADHF with LVEF ≤ 40% | Multicenter, double-blind, randomized placebo-controlled trial | 614 | 2013 | Safe, but no change in the dyspnea symptoms | [96] |
| RELAX-AHF | Vasoactive peptide hormone | Serelaxin, recombinant human relaxin-2 vs. placebo | Acute HF | Randomized, placebo-controlled trial | 1161 | 2013 | Dyspnea relief and other symptoms of HF, but had no effect on hospital readmissions | [97] |
| PARADIGM-HF | Combination of ARB, valsartan and a neprilysin inhibitor prodrug sacubitril | Valsartan/sacubitril (LCZ696) vs. enalapril | NYHA functional Class II–IV (HFrEF and HFpEF) | Randomized study | 8442 | 2014 | Significant reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization | [72,98] |
| SOCRATES, including SOCRATES-REDUCED for LVEF ≤ 45 SOCRATES-PRESERVED for LVEF ≥ 45 | Oral cyclic guanosine monophosphate (cGMP) stimulator | Oral (cGMP) stimulator vericiguat (BAY 1021189) vs. placebo | HF with LVEF ≥ 45 and ≤ 45 | Double-blinded multi-center RCT | 456 | 2014 | Study completed, results awaited | [99] |
| NCT01919177 | Inorganic nitrates | Beet root vs. placebo | Heart failure with normal ejection fraction | randomized, double-blind, | 17 | 2015 | Increased exercise capacity by increasing exercise vasodilatory and cardiac output reserves | [3] |
| Defibrillator-based clinical trials | ||||||||
| SCD-HeFT | ICD vs. drug | ICD vs. amiodarone vs. placebo | CCF (NYHA II/III; LVEF < 35) |
Double-blinded multi-center RCT | 2521 | 2005 | ICD significantly increased survival by 23%; amiodarone had no effect | [100] |
| MADIT-CRT | CRT | CRT with and without ICD | HF (NYHA I–II; EF < 30%; QRS > 130 ms) |
Double-blinded multi-center RCT | 1820 | 2009 | CRT (added to ICD) slows the progression of heart failure in high-risk (QRS ≥ 130 ms, EF ≤ 3 0%), mildly symptomatic patients (NYHA I/II) | [75] |
| PARTNERS HF | HF device | Combined heart failure (HF) device guided diagnostic data to predict clinical deterioration of HF | CRT implantable cardioverter-defibrillators in HF patients | Observational study | 1024 | 2010 | Identifies patients at a higher risk of HF hospitalizations | [101] |
| Stem cell-based clinical trials | ||||||||
| TOPCARE-CHD | Bone marrow-derived mononuclear cells | intracoronary injection of functional BMMC vs. placebo | Ischemic HF | Single-center study randomized | 121 | 2007 | Improved cardiac function and suppression of NT-proANP and proBNP with BMMC, especially with cells with high functional capacity determined with the colony forming unit assay | [102] |
| SCIPIO | Cardiac stem cells | Intracoronary injection of in vitro expanded c-Kit+ CSC from myocardium vs. placebo | Ischemic HF with LVEF < 40% | Single-center study | 18 | 2011 | Significant improvement in myocardial performance, scar tissue reduction and LV systolic function | [103] |
| TAC-HFT | MSCs and BMMCs | Trans-endocardial injection of culture-expanded MSCs vs. whole BMMC vs. placebo | Ischemic cardio-myopathy with LVEF < 50% | Randomized, blinded, placebo-controlled study | 65 | 2011 | MSCs and BMMC were safe, but MSCs better for scar reduction and improved myocardial function than BMMCs | [104] |
| FOCUS-CCTRN | Bone marrow-derived mononuclear cells | Trans-endocardial injection of BMMC vs. placebo | Ischemic HF/NYHA II–III with LVHF < 45% | Randomized double-blind, placebo-controlled trial | 153 | 2012 | Failed to improve LVESV, maximal oxygen consumption or reversibility on SPECT | [105] |
| POSEIDON | Mesenchymal stem cells | Allogenic vs. autologous trans-endocardial injection of MSCs | Chronic ischemic left ventricular dysfunction with LVHF < 50% | Single-center study | 31 | 2012 | Both allo- and auto-MSCs were safe, reduced infarct size and improved ventricular remodeling | [106] |
| CADUCEUS | Cardiosphere-derived cells | Intracoronary administration of autologous CDCs vs. placebo | Ischemic HF, NYHF I with LVEF between 25% and 45% | Single-center study | 17 | 2012 | Safe and decreased scar size, increased viable myocardium and improved regional function of infarcted myocardium, but no significant improvement in EF | [107] |
| NOGA-DCM | Bone marrow-derived CD34+ cells | Trans-endocardial CD34+ vs. placebo | Non-ischemic cardiomyopathy with NYHA III and LVHF < 40% | Single-center study randomized | 33 | 2014 | Improved left ventricular function, decreased N-terminal pro-BNP and better exercise capacity with infusion of a high number of cells | [108] |
| PROMETHEUS | Mesenchymal stem cells | Intra-myocardial injection of autologous MSCs | Chronic ischemic cardiomyopathy undergoing CABG | Single-center study | 6 | 2014 | Scar reduction, improvement in myocardial perfusion, regional function and LVEF in patients undergoing CABG | [109] |
| CHART-1 | Cardiopoietic stem cells | bone marrow-derived and lineage-directed autologous cardiopoietic stem cells | Ischemic HF | Randomized, sham-controlled multicenter study | 240 | 2015 | Under progress | [110] |
| Gene therapy-based clinical trials | ||||||||
| CUPID-Phase I | Gene therapy | Antegrade epicardial coronary artery infusion of gene SERCA2a via an adeno-associated viral (AAV) vector | Advanced HF-NYHF III/IV (LVEF ≤ 30%) | Single-center study | 9 | 2008 | Safe and improvement in various parameters, such as exercise tolerance, LVEF, reduction of BNP levels | [78] |
| CUPID-Phase II | Gene therapy | Intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca2+-ATPase vs. placebo | Advanced HF-NYHF III/IV (LVEF ≤ 30%) | Randomized, double-blind, placebo-controlled | 39 | 2011 | Improvement in various parameters, such as exercise tolerance, LVEF, reduction of BNP levels | [79] |