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CompletedNCT03350737CARHEXAUpdated May 13, 2020

Coronary Arteriogenetic Heparinized Exercise

An interventional study of Physical rehabilitation and Heparin in Refractory Angina and Chronic Stable Angina, sponsored by Clinical Centre of Serbia. Completed at 1 site in Serbia. Per ClinicalTrials.gov, last updated 2020-05-13.

Sponsored by Clinical Centre of Serbia · Not applicable, Interventional, and Treatment

Phase
Not applicable
Study type
Interventional
Enrollment
32
Allocation
Randomized
Sex
All
01

Study summary

This study evaluates the addition of heparin to a 2-week cycle of physical rehabilitation in the treatment of refractory angina. Half of the patients will undergo heparin-primed physical rehabilitation, while the other half will undergo only physical rehabilitation.

Read the detailed description

Our approach is based on the combination of pharmacological stimuli (with heparin) on top of a 2-week cycle of physical rehabilitation. The rationale for this chemical-physical cocktail stems from the fact that increase in shear stress (achieved with exercise), or heparin (when used alone) have no significant effect on coronary arteriogenesis. Nevertheless, when the two stimuli are coupled coronary arteriogenesis is consistently present, and clinically significant.

The basic principle of heparin treatment is to potentiates angiogenic growth factors, which are over expressed by increased shear stress at the site of pre-existing collateral vessels as a result of exercise or pacing. Although the precise mechanisms by which heparin potentiates arteriogenesis remain to be completely elucidated, heparin administration combined with exercise has great potential in treating patients with effort angina who are not indicated for conventional revascularization therapy.

02

Conditions studied

  • Refractory Angina
  • Chronic Stable Angina

Keywords

  • No-option patients
03

Who can participate

Ages eligible
Child (0–17), Adult (18–64), Older adult (65+)
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Patients with documented coronary artery disease not amenable of future treatment and belonging to "no-option" category with symptoms consistent with angina pectoris

Exclusion criteria

Exclusion Criteria:

  • Patients with unstable angina, recent myocardial infarction, uncontrolled hypertension, hemodynamically valvular heart disease, bronchial asthma, and neurologic and/or orthopedic illnesses that limit exercise capacity .
  • Patients receiving vitamin K antagonist.
  • Patients actively involved in programmes of cardiac rehabilitation or exercise training.
04

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
32 participants (actual)

Study arms

  • Experimental
    Heparin-primed physical rehabilitation

    2 exercise sessions per day for 5 days a week for 2 weeks with 100 IU/kg of Heparin i.v. (up to a maximum of 5000 IU) 10 minutes prior to exercise

    Other: Physical rehabilitation · Drug: Heparin

  • Placebo comparator
    Placebo-primed physical rehabilitation

    2 exercise sessions per day for 5 days a week for 2 weeks with placebo (2 ml of Sodium Chloride 0.9% i.v.) 10 minutes prior to exercise

    Other: Physical rehabilitation · Other: Placebo

Interventions

  • OtherPhysical rehabilitation

    Standard treadmill exercise session

    Also known as: E

  • DrugHeparin

    Heparin i.v.

    Also known as: H

  • OtherPlacebo

    Sodium Chloride 0.9% i.v.

    Also known as: P

05

What researchers measure

Primary outcomes

  1. Change from Baseline Canadian Cardiovascular Society (CCS) angina severity class at 2 weeks

    CCS class ranging from 1 (mild) to 4 (severe) before and after the 2-week physical rehabilitation.

    Time frame: 2 weeks

Secondary outcomes

  1. Change from Baseline peak stress wall motion score index (WMSI) at 2 weeks

    Peak WMSI at stress echocardiography before and after 2-week physical rehabilitation at . Wall motion score index is assessed by using 17- segment model of left ventricle (1=normal, 4=dyskinetic).

    Time frame: 2 weeks

  2. Change from baseline peak stress global longitudinal strain (GLS) at 2 weeks

    Peak stress GLS assessed by echocardiography before and after the 2-week physical rehabilitation.

    Time frame: 2 weeks

Other outcomes

  1. Change from Baseline Coronary Collateral Circulation (CCC) at 2 weeks

    CCC score assessed by multi dimensional computed tomography (CT) before and after 2-week physical rehabilitation. Distal filling of the epicardial segment is semiquantitatively classified by using a four-point scale according to patterns at coronary CT angiography (CTA) (0 = absence of distal filling; 1 = partial distal filling, with a length less than one-third of the segment; 2 = partial distal filling, with a length between one-third and two-thirds of the segment; 3 = complete or partial distal filling, with a length longer than two-thirds of the segment). A coronary CTA scores correspond fully to Rentrop classification (coronary CTA score of 0 or 1 to Rentrop 0 or 1, coronary CTA score of 2 or 3 to Rentrop 2 or 3). Coronary CTA score of 3 is indicative of well-developed collaterals, contrary to scores of 0-2 (poorly developed). Also we look for change in growth of baseline bridging antegrade collaterals at 2 weeks (0= not present, 1= present)

    Time frame: 2 weeks

  2. Change from Baseline Stable Angina questionnaire (SAQ) at 4 weeks

    19-item Seattle SAQ that assesses angina frequency, angina stability, physical limitations, treatment satisfaction, and disease perception/QoL

    Time frame: 2 weeks to one month

06

Study locations

1 site
  • Clinical Centre of Serbia
    Belgrade, 11000, Serbia
07

References and documents

Publications

  • Barron HV, Sciammarella MG, Lenihan K, Michaels AD, Botvinick EH. Effects of the repeated administration of adenosine and heparin on myocardial perfusion in patients with chronic stable angina pectoris. Am J Cardiol. 2000 Jan 1;85(1):1-7. doi: 10.1016/s0002-9149(99)00596-2. PubMed 11078227 ↗
  • Bolognese L, Carrabba N, Parodi G, Santoro GM, Buonamici P, Cerisano G, Antoniucci D. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction. Circulation. 2004 Mar 9;109(9):1121-6. doi: 10.1161/01.CIR.0000118496.44135.A7. Epub 2004 Feb 16. PubMed 14967718 ↗
  • Bombardini T, Picano E. The coronary angiogenetic effect of heparin: experimental basis and clinical evidence. Angiology. 1997 Nov;48(11):969-76. doi: 10.1177/000331979704801106. PubMed 9373049 ↗
  • Buschmann I, Schaper W. Arteriogenesis Versus Angiogenesis: Two Mechanisms of Vessel Growth. News Physiol Sci. 1999 Jun;14:121-125. doi: 10.1152/physiologyonline.1999.14.3.121. PubMed 11390835 ↗
  • Fujita M, Sasayama S, Asanoi H, Nakajima H, Sakai O, Ohno A. Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina. Circulation. 1988 May;77(5):1022-9. doi: 10.1161/01.cir.77.5.1022. PubMed 2834115 ↗
  • Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O'Rourke RA, Pasternak RC, Williams SV, Gibbons RJ, Alpert JS, Antman EM, Hiratzka LF, Fuster V, Faxon DP, Gregoratos G, Jacobs AK, Smith SC Jr; American College of Cardiology; American Heart Association Task Force on Practice Guidelines. Committee on the Management of Patients With Chronic Stable Angina. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation. 2003 Jan 7;107(1):149-58. doi: 10.1161/01.cir.0000047041.66447.29. No abstract available. PubMed 12515758 ↗
  • Mannheimer C, Camici P, Chester MR, Collins A, DeJongste M, Eliasson T, Follath F, Hellemans I, Herlitz J, Luscher T, Pasic M, Thelle D. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J. 2002 Mar;23(5):355-70. doi: 10.1053/euhj.2001.2706. No abstract available. PubMed 11846493 ↗
  • Meier P, Gloekler S, de Marchi SF, Indermuehle A, Rutz T, Traupe T, Steck H, Vogel R, Seiler C. Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation. 2009 Oct 6;120(14):1355-63. doi: 10.1161/CIRCULATIONAHA.109.866269. Epub 2009 Sep 21. PubMed 19770393 ↗
  • Picano E, Alaimo A, Chubuchny V, Plonska E, Baldo V, Baldini U, Pauletti M, Perticucci R, Fonseca L, Villarraga HR, Emanuelli C, Miracapillo G, Hoffmann E, De Nes M. Noninvasive pacemaker stress echocardiography for diagnosis of coronary artery disease: a multicenter study. J Am Coll Cardiol. 2002 Oct 2;40(7):1305-10. doi: 10.1016/s0735-1097(02)02157-5. PubMed 12383579 ↗
  • Picano E, Michelassi C. Chronic oral dipyridamole as a 'novel' antianginal drug: the collateral hypothesis. Cardiovasc Res. 1997 Mar;33(3):666-70. doi: 10.1016/s0008-6363(96)00262-3. PubMed 9093537 ↗
  • Picano E; PISA (Persantin In Stable Angina) study group. Dipyridamole in chronic stable angina pectoris; a randomized, double blind, placebo-controlled, parallel group study. Eur Heart J. 2001 Oct;22(19):1785-93. doi: 10.1053/euhj.2001.2623. PubMed 11549300 ↗
  • Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985 Mar;5(3):587-92. doi: 10.1016/s0735-1097(85)80380-6. PubMed 3156171 ↗
  • Schirmer SH, van Nooijen FC, Piek JJ, van Royen N. Stimulation of collateral artery growth: travelling further down the road to clinical application. Heart. 2009 Mar;95(3):191-7. doi: 10.1136/hrt.2007.136119. PubMed 19144878 ↗
  • Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, Voigt JU, Zamorano JL; European Association of Echocardiography. Stress Echocardiography Expert Consensus Statement--Executive Summary: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur Heart J. 2009 Feb;30(3):278-89. doi: 10.1093/eurheartj/ehn492. Epub 2008 Nov 11. No abstract available. PubMed 19001473 ↗
  • Tateno S, Terai M, Niwa K, Jibiki T, Hamada H, Yasukawa K, Honda T, Oana S, Kohno Y. Alleviation of myocardial ischemia after Kawasaki disease by heparin and exercise therapy. Circulation. 2001 May 29;103(21):2591-7. doi: 10.1161/01.cir.103.21.2591. PubMed 11382729 ↗
  • Traupe T, Gloekler S, de Marchi SF, Werner GS, Seiler C. Assessment of the human coronary collateral circulation. Circulation. 2010 Sep 21;122(12):1210-20. doi: 10.1161/CIRCULATIONAHA.109.930651. No abstract available. PubMed 20855668 ↗
  • Williams B, Menon M, Satran D, Hayward D, Hodges JS, Burke MN, Johnson RK, Poulose AK, Traverse JH, Henry TD. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter Cardiovasc Interv. 2010 May 1;75(6):886-91. doi: 10.1002/ccd.22431. PubMed 20432394 ↗
  • Wykrzykowska JJ, Henry TD, Lesser JR, Schwartz RS. Imaging myocardial angiogenesis. Nat Rev Cardiol. 2009 Oct;6(10):648-58. doi: 10.1038/nrcardio.2009.157. Epub 2009 Sep 8. PubMed 19736553 ↗

Study documents

  • Protocol and statistical analysis plan · Dec 25, 2012

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — De-identified individual participant data for all primary and secondary outcome measures will be made available.

Supporting information: Study protocol, Sap

08

Registry details

Key details

Study ID
NCT03350737
Lead sponsor
Clinical Centre of Serbia
Collaborators
Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy
Responsible party
Branko Beleslin (Clinical research, Clinical Centre of Serbia) — Principal investigator
First posted
Nov 22, 2017
Start date
Feb 1, 2013
Primary completion
Dec 31, 2019
Completion
Dec 31, 2019
Last update
May 13, 2020

Study contacts

Branko Beleslin, MD, PhD
principal investigator · Clinical Centre of Serbia
Ana Djordjevic-Dikic, MD, PhD
study director · Clinical Centre of Serbia
Eugenio Picano, MD, PhD
study chair · Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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