Q-Symbio

Last updated

The Q-Symbio study was an international multi-center clinical trial that was reported in the Journal of the American College of Cardiology: Heart Failure in September 2014. [1]

Contents

Professor Mortensen and a team of researchers enrolled 420 patients with moderate to severe chronic heart failure. Half of the patients received a Coenzyme Q10 treatment of 100 milligrams three times daily for two years. The other half of the patients got inactive placebo capsules daily for two years. All of the patients continued their standard heart failure medications. [1]

Not until the end of the clinical trial did the researchers and the patients find out which patients were receiving the active Coenzyme Q10 treatment and which patients were receiving the placebo treatment.

The patients in the Coenzyme Q10 treatment group had significantly reduced risk of heart disease death and death from all causes and significantly fewer hospital stays for heart failure complications. [1]

A later sub-analysis including only the European segment of the Q-Symbio Study showed that the Coenzyme Q10 therapy was also positively associated with a significant improvement in ejection fraction. The results of the Coenzyme Q10 treatment were even more impressive in the European sub-study. Treatment with Coenzyme Q10 300 milligrams per day in addition to conventional heart failure medications was safe, well tolerated, and effective at reducing symptoms and improving survival rates of chronic heart failure patients. [2]

Purpose

The Q-Symbio study was a multi-center randomized placebo-controlled double-blind clinical trial that was reported in the Journal of the American College of Cardiology: Heart Failure in September 2014. [1] The purpose of the study was to assess the effect of the adjuvant therapy drug Coenzyme Q10 on several short-term and long-term endpoints in a total of 420 chronic heart failure patients enrolled in 17 cardiology centers in Europe, Asia, and Australia from 2003 to 2010.

The trial name Q-SYMBIO reflects the focus on the following elements in the clinical trial: Q = Q10 and SYMBIO = SYMptoms, BIomarker status [Brain-Natriuretic Peptide], and long-term Outcome [hospitalizations/mortality].

Professor Mortensen and a team of researchers assigned 420 patients with moderate to severe chronic heart failure to Coenzyme Q10 100 milligrams three times daily or matching placebos in addition to the patients' standard heart failure therapies for two years. [1]   The patients in the Coenzyme Q10 adjunctive treatment group had significantly fewer major adverse cardiovascular events, significantly reduced risk of cardiovascular death and all-cause death, and significantly fewer hospital stays for heart failure complications. [1]

Dosage

The dosage of CoQ10 administered to the active treatment arm of the Q-SYMBIO trial was 100 milligrams three times daily, a dosage large enough to raise blood serum levels of Q10 significantly. [3]

Patients

The patients were selected for the Q-SYMBIO trial if they had chronic heart failure in New York Heart Association functional classes III (marked limitation of physical activity) or IV (unable to carry out any physical activity without discomfort).

The age of the patients in years was 62.3 +/- 12. The ratio of male patients to female patients was roughly three to one.

The mean duration of heart failure was around three years in both arms of the trial, and the baseline ejection fraction and six-minute-walking-time distances were equal between the groups.

90% of the patients in the study were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and 75% of the patients in the study were receiving beta-blockers.

The dosages of the medications were only infrequently modified during the trial, so it is unlikely that minor changes in medication should have influenced the outcome of the trial.

Short-Term Effects (16 weeks of treatment)

At week 16, there were improvements in NYHA classification, VAS score, and 6MWT (6-Minute Walk Test) in both treatment groups, but there were no significant differences between the groups. There was a trend with a 20% reduction of NT-proBNP in the CoQ10 group and a proportional rise of 12% in the placebo group.

Retrospectively, at this time cardiovascular deaths were already significantly lower in the CoQ10 group, but this was not a pre-specified endpoint at week 16.

Long-Term Effects (106 weeks of treatment)

Major Adverse Cardiovascular Events

The number of Major Adverse Cardiovascular Events (MACE), which was the primary long-term endpoint in the trial, was statistically significantly fewer (p < 0.005) in the Q10 treatment arm (N = 30, 15%) than in the placebo arm (N = 57, 26%), corresponding to a 42.3% relative reduction in risk of MACE events.

Cardiovascular Mortality

The total number of cardiovascular deaths during the 106 weeks of the study was statistically significantly lower (p = 0.026) in the Q10 treatment arm (N = 18, 9%) than in the control arm (N = 34, 16%), a relative reduction of 43.8% in risk of cardiovascular death.

All-cause Mortality

Altogether, there were statistically significantly fewer (p = 0.018) deaths from all causes in the Q10 treatment arm (N = 21, 10%) than in the control arm (N = 39, 18%), a relative reduction of 44.4%.

Hospital Stays for Heart Failure

The number of hospital stays for heart failure during the 106 weeks was statistically significantly lower (p = 0.033) in the Q10 treatment arm (N = 17, 8%) as compared to the control arm (N = 31, 14%), a relative reduction of 42.8%.

Discussion of the Results

Mortensen et al. hypothesize that the dosage (100 mg three times daily) and the formulation of the Q10 used in the Q-SYMBIO clinical trial may have resulted in the patients reaching a required "therapeutic threshold in serum and tissue of CoQ10" needed to reduce the number of major adverse cardiovascular events. [1]

The formulation used in the trial has been demonstrated to have good bio-availability in controlled studies. [2] [4]

In 2019, AL Mortensen, FL Rosenfeldt, and KJ Filipiak evaluated the treatment effect of Coenzyme Q10 adjuvant treatment in the European sub-population of the Q-SYMBIO clinical trial. In the European sub-group, ejection fraction and NYHA classification improved significantly, and both all-cause and cardiovascular mortality decreased significantly. [5]

The researchers concluded that the evidence from the European sub-group analysis re-affirms the evidence of the therapeutic efficacy of the CoQ10 adjuvant therapy despite the greater adherence to guideline-directed therapy in the European sub-group than in the entire group of chronic heart failure patients.

The European sub-group study provides confirmatory evidence that the treatment with 300 mg/day of Coenzyme Q10 in additional to conventional heart failure therapy is safe, well tolerated, and effective in improving the symptoms and survival of chronic heart failure patients.

The Morisco Clinical Trial

The results of the Q-SYMBIO clinical trial build on the earlier results from the multi-center randomized placebo-controlled double-blind clinical trial that was reported in 1993 [6] by Morisco et al. That study enrolled 641 congestive heart failure patients (again, patients classified NYHA III and IV) randomly in a placebo arm and in a Q10 treatment arm in which the patients received a daily dosage of 2 mg per kilogram of body weight for the period of a year. The study focused on the need of hospitalization and on the incidence of life-threatening arrhythmias, pulmonary edema, and cardiac asthma. [6]

The number of patients in the Morisco study who required hospitalization for worsening heart failure was significantly smaller (p < 0.001) in the Q10 treatment arm (n = 73, 22.8%) than in the control arm (n = 118, 36.6%), a relative reduction of 37.7% in required hospitalizations. [6]

Moreover, in the Morisco study, the number of the episodes of pulmonary edema (20/319, 6.3% versus 51/322, 15.8%) and cardiac asthma (97/319, 30.4% versus 198/322, 61.5%) was significantly reduced (p < 0.001) in the Q10 arm as compared to the control arm. [6]

The Morisco study authors concluded that their results demonstrated that adjuvant treatment with CoQ10 in addition to conventional therapy significantly reduced the number of hospitalizations for worsening of heart failure and the incidence of serious complications in patients with chronic congestive heart failure.

Meta-analyses of the Efficacy of Q10 in Heart Failure

Altogether, meta-analyses by Soja et al., [7] Sander et al., [8] and Fotino et al. [9] have found significant improvements in ejection fraction. A total of 21 placebo-controlled trials have evaluated the efficacy of CoQ10 in heart failure, including Q-SYMBIO. Only three of these studies did not find any effects, and the outcome in those three trials could possibly be attributed to low compliance rates in the treatment arm or to flaws in the study design.

Senior Citizens

It is known that the ability of the human body to synthesize CoQ10 declines with age [10] and that it may therefore be necessary to supplement the diet of senior citizens with Q10. Alehagen et al. have reported on the results of the Kisel-10 study, a five-year prospective randomized double-blind placebo-controlled trial among Swedish citizens aged 70 to 88. [11] 443 participants given combined supplementation of selenium and CoQ10 or a placebo.

There was a significant reduction (p = 0.015) of cardiovascular mortality in the Q10 treatment arm as compared with the placebo group (5.9% vs. 12.6%, a relative reduction of 53%). [11] The long-term supplementation with a combination of 200 mg/day of CoQ10 capsules (Bio-Quinone 100 mg twice daily) and 200 μg/day of organic selenium yeast tablets (SelenoPrecise 200 μg) reduced cardiovascular mortality. The positive effects could also be seen in N-terminal pro b-type natriuretic peptide (NT-proBNP) levels and on echocardiography. [11]

The significantly reduced mortality from heart disease associated with the combined Coenzyme Q10 and selenium treatment, compared to the placebo treatment, persisted during 12 years of follow-up. [12] Professor Alehagen and his co-researchers carried out a number of sub-studies to investigate the mechanisms by which the combined supplementation reduced the risk of heart disease. They identified reduced bio-markers of oxidative stress, inflammation, and fibrosis as possible mechanisms explaining the study results. [12]

Individuals Taking Statins

Statins are known to block the biological pathway that produces both cholesterol and CoQ10. Oral Coenzyme Q10 supplements replace the lost CoQ10. [13]

Biological Mechanisms Explaining the Improvement of Heart Failure Symptoms

Mortensen et al. posit four explanations for the effect of Q10 on the improvement of symptoms and survival of chronic heart failure patients:

  1. Additional available Q10 may improve the respiratory rate in heart cells. [13]
  2. Additional available Q10 may increase energy production in the heart muscle cells, thus impeding the "vicious metabolic cycle" in heart failure. [14]
  3. Additional available Q10 may increase the stability of the "mitochondrial permeability transition pore" and thereby protect the heart muscle against apoptotic cell death. [15]
  4. Additional available Q10 may improve endothelial function [16] and may protect the heart muscle against ischemic damage [17]

Related Research Articles

Scandinavian Simvastatin Survival Study

The Scandinavian Simvastatin Survival Study, was a multicentre, randomized, double-blind, placebo-controlled clinical trial, which provided the initial data that supported the use of the cholesterol-lowering drug, simvastatin, in people with a moderately raised cholesterol and coronary heart disease (CHD); that is people who had previously had a heart attack or angina. The study was sponsored by the pharmaceutical company Merck and enrolled 4,444 people from 94 centres in Scandinavia.

Heart Protection Study

The Heart Protection Study was a randomized controlled trial run by the Clinical Trial Service Unit, and funded by the Medical Research Council (MRC) and the British Heart Foundation (BHF) in the United Kingdom. It studied the use of the cholesterol lowering drug, simvastatin 40 mg and vitamin supplementation in people who were at risk of cardiovascular disease. It was led by Jane Armitage, an epidemiologist at the Clinical Trial Service Unit.

Candesartan

Candesartan is an angiotensin receptor blocker used mainly for the treatment of high blood pressure and congestive heart failure.

Perindopril High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

Ivabradine heart medication

Ivabradine, sold under the brand name Procoralan among others, is a medication used for the symptomatic management of stable heart-related chest pain and heart failure not fully managed by beta blockers.

Bivalirudin

Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).

Celacade was a non-drug, device-based treatment also known as Immune Modulation Therapy (IMT), developed by the Canadian-based biotherapeutics company Vasogen, Inc. for chronic heart failure and peripheral artery disease. Blood was piped through the device, where it was exposed to heat, ultraviolet light, and ozone, in the hope that this oxidative stress would trigger an anti-inflammatory immunomodulation response.

Dronedarone

Dronedarone, sold under the brand name Multaq, is a medication by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. In the United States, the FDA approved label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in patients with moderate to severe CHF.

Dapagliflozin Diabetes medication

Dapagliflozin, sold under the brand name Farxiga among others, is a medication used to treat type 2 diabetes and, with certain restrictions, type 1 diabetes. It is also used to treat adults with certain kinds of heart failure.

Pharma Nord is an international pharmaceutical company with corporate headquarters in Vejle, Denmark and manufacturing facility and research laboratories in Vojens, Denmark. Pharma Nord has 25 daughter companies throughout Europe, Asia, North America and the Middle East. Pharma Nord is a privately owned limited company.

Ticagrelor

Ticagrelor, sold under the brand name Brilinta among others, is a medication used for the prevention of stroke, heart attack and other events in people with acute coronary syndrome, meaning problems with blood supply in the coronary arteries. It acts as a platelet aggregation inhibitor by antagonising the P2Y12 receptor. The drug is produced by AstraZeneca.

Management of heart failure requires a multimodal approach. It involves a combination of lifestyle modifications, medications, and possibly the use of devices or surgery.

Sacubitril/valsartan Chemical compound

Sacubitril/valsartan, sold under the brand name Entresto, is a fixed-dose combination medication for use in heart failure. It consists of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. It is recommended for use as a replacement for an ACE inhibitor or an angiotensin receptor blocker in people with heart failure with reduced ejection fraction.

Ischemic cardiomyopathy Medical condition

Ischemic cardiomyopathy is a type of cardiomyopathy caused by a narrowing of the coronary arteries which supply blood to the heart. Typically, patients with ischemic cardiomyopathy have a history of acute myocardial infarction, however, it may occur in patients with coronary artery disease, but without a past history of acute myocardial infarction. This cardiomyopathy is one of the leading causes of sudden cardiac death. The adjective ischemic means characteristic of, or accompanied by, ischemia — local anemia due to mechanical obstruction of the blood supply.

Remote ischemic conditioning (RIC) is an experimental medical procedure that aims to reduce the severity of ischaemic injury to an organ such as the heart or the brain, most commonly in the situation of a heart attack or a stroke, or during procedures such as heart surgery when the heart may temporary suffer ischaemia during the operation, by triggering the body's natural protection against tissue injury. Although noted to have some benefits in experimental models in animals, this is still an experimental procedure in humans and initial evidence from small studies have not been replicated in larger clinical trials. Successive clinical trials have failed to identify evidence supporting a protective role in humans.

Stefan D. Anker

Stefan D. Anker is Head of Field “Tissue Homeostasis and Cachexia" at Charité University, Berlin, Germany. Previously, he was Professor of Innovative Clinical Trials at University Medical Center Göttingen in Germany. The main focus of the Innovative Clinical Trials department was research in the field of chronic heart failure, including the development and clinical testing of new therapies.

Svend Aage Mortensen, M.D., Sc.D. was a Danish cardiologist at Rigshospitalet in Copenhagen, Denmark. Rigshospitalet was until February 2017 the largest hospital in Denmark; only surpassed by Skejby Sygehus, however, Rigshospitalet is a flagship in the Danish health care system. From 1990 until his death in 2015, Mortensen was the medical director of the heart transplantation unit at Rigshospitalet. He was a fellow of the European Society of Cardiologists. Mortensen is best known as the chief researcher and the leading author for the Q-Symbio study of the “Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure.”

William V. Judy, Ph.D. is an American author, clinical researcher, clinical trial consultant, and retired professor of physiology and biophysics. He was first introduced to the field of Coenzyme Q10 clinical research by Dr. Karl Folkers, the American bio-chemist who determined the structure of the Coenzyme Q10 molecule. 

International Coenzyme Q10 Association

The International Coenzyme Q10 Association is a nonprofit association based in Ancona, Italy. Since its establishment in 1997, it has promoted biochemical and clinical research on the substance Coenzyme Q10 in an attempt to increase the body of knowledge about the preventive and therapeutic health effects of Coenzyme Q10.

Plácido Navas Lloret Spanish Professor of Cell Biology

Plácido Navas Lloret is a Spanish Professor of Cell Biology in the Andalusian Center for Developmental Biology at the Pablo de Olavide University in Sevilla, Spain. From 2002 to 2012, Professor Navas served as a board member of the International Coenzyme Q10 Association; since 2013, he has been the chairman of the association.

References

  1. 1 2 3 4 5 6 7 Mortensen, S.A.; Kumar, A. (2014). "The Effect of Coenzyme Q10 on Morbidity and Mortality in Chronic Heart Failure: Results From Q-SYMBIO: A Randomized Double-Blind Trial". Journal of the American College of Cardiology, Heart Failure. 2 (6): 641–9. doi: 10.1016/j.jchf.2014.06.008 . PMID   25282031.
  2. 1 2 Folkers, K.; Moesgaard, S.; Morita, M. (1994). "A one year bioavailability study of coenzyme Q10 with 3 months withdrawal period. Molecular Aspects Of Medicine". Molecular Aspects of Medicine. 15 Suppl: s281-5. doi:10.1016/0098-2997(94)90039-6. PMID   7752840.
  3. ↑ Morrill, RL. (2019). "Coenzyme Q10 adjuvant therapy for chronic heart failure". Q10facts.com.
  4. ↑ Weis, M.; Mortensen, S.; Rassing, M.; Møller-Sonnergaard, J.; Poulsen, G.; Rasmussen, S. (1994). "Bioavailability of four oral coenzyme Q10 formulations in healthy volunteers". Molecular Aspects of Medicine. 15 Suppl: s273-80. doi:10.1016/0098-2997(94)90038-8. PMID   7752839.
  5. ↑ Mortensen, A.L.; Rosenfeldt, F.; Filipiak, K.J. (March 5, 2019). "Effect of Coenzyme Q10 in Europeans with Chronic Heart Failure: A Sub-Group Analysis of the Q-SYMBIO Randomized Double-Blind Trial". Cardiology Journal. 26 (2): 147–156. doi: 10.5603/CJ.a2019.0022 . PMC   8086660 . PMID   30835327.
  6. 1 2 3 4 Morisco, C. (1993). "Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study". The Clinical Investigator. 71 (8 Suppl): S134-6. doi:10.1007/bf00226854. PMID   8241697. S2CID   26973909.
  7. ↑ Soja, A.; Mortensen, S. (1997). "Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials". Molecular Aspects of Medicine. 18 Suppl (18): 159–168. doi:10.1016/s0098-2997(97)00042-3. PMID   9266518.
  8. ↑ Sander, S.; Coleman, C.; Patel, A.; Kluger, J.; White, C (2006). "The impact of coenzyme Q10 on systolic function in patients with chronic heart failure". Journal of Cardiac Failure. 12 (6): 464–72. doi:10.1016/j.cardfail.2006.03.007. PMID   16911914.
  9. ↑ Fotino, A.; Thompson-Paul, A.; Bazzano, L.; Kluger, J.; White, C (2013). "Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis". The American Journal of Clinical Nutrition. 97 (2): 268–75. doi:10.3945/ajcn.112.040741. PMC   3742297 . PMID   23221577.
  10. ↑ Kalén, A.; Appelkvist, E.; Dallner, G. (1989). "Age-related changes in the lipid compositions of rat and human tissues". Lipids (24(7) ed.). 24 (7): 579–584. doi:10.1007/BF02535072. PMID   2779364. S2CID   4052688.
  11. 1 2 3 Alehagen, U.; Johansson, P.; Björnstedt, M.; Rosén, A.; Dahlström, U. (2013). "Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens". International Journal of Cardiology (167(5) ed.). 167 (5): 1860–1866. doi:10.1016/j.ijcard.2012.04.156. PMID   22626835.
  12. 1 2 Alehagen, Urban; Aaseth, Jan; Alexander, Jan; Johansson, Peter (2018). "Still reduced cardiovascular mortality 12 years after supplementation with selenium and coenzyme Q10 for four years: A validation of previous 10-year follow-up results of a prospective randomized double-blind placebo-controlled trial in elderly". PLOS ONE. 13 (4): e0193120. Bibcode:2018PLoSO..1393120A. doi: 10.1371/journal.pone.0193120 . PMC   5894963 . PMID   29641571 – via e0193120.
  13. 1 2 Littarru, G.P. (1994). "Location and function of Coenzyme Q in the respiratory chain. In Energy and Defense: Facts and Perspectives on Coenzyme Q10 in Biology and Medicine". Roma: Casa Editrice Scientifica Internazionale: 14–22. ISBN   88-86062-24-9.
  14. ↑ Opie, L. (2004). "The metabolic vicious cycle in heart failure". Lancet (364(9447) ed.). 364 (9447): 1733–1734. doi:10.1016/S0140-6736(04)17412-6. PMID   15541431. S2CID   45301156.
  15. ↑ Haas, R. (2007). "The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease". Mitochondrion (7 ed.). 7 Suppl: 136–145. doi:10.1016/j.mito.2007.03.008. PMID   17485245.
  16. ↑ Belardinelli, R.; Muçaj, A.; Lacalaprice, F.; Solenghi, M.; Seddaiu, G.; Principi, F.; Littarru, G. (2006). "Coenzyme Q10 and exercise training in chronic heart failure". European Heart Journal (27(22) ed.). 27 (22): 2675–2681. doi: 10.1093/eurheartj/ehl158 . PMID   16882678.
  17. ↑ Rosenfeldt, F.; Marasco, S.; Lyon, W.; Wowk, M.; Sheeran, F.; Bailey, M.; Pepe, S. (2005). "Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue". The Journal of Thoracic and Cardiovascular Surgery (129(1) ed.). 129 (1): 25–32. doi: 10.1016/j.jtcvs.2004.03.034 . PMID   15632821.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.