The Coronary Slow Flow Phenomenon and Coronary Artery Spasm

The enigma of angina in the absence of significant epicardial CAD has puzzled cardiologists since the advent of invasive coronary angiography. The challenge for clinicians and researchers investigating these patients is to identify when the chest pain is cardiac in origin. The approach used to define and diagnose syndrome X, as it has been called, is a positive exercise stress test. However, this would not necessarily identify all patients with coronary microvascular dysfunction, since most clinical cardiologists have endured the frustration of finding a patient with severe CAD despite a normal stress test.

An alternative approach to identifying patients with coronary microvascular dysfunction is to evaluate coronary angiographic blood flow during diagnostic angiography. The coronary slow flow phenomenon (CSFP), first proposed by Beltrame et al. as a distinct clinical entity, is a coronary microvasculature disorder angiographically-defined as the delayed passage of contrast within the epicardial arteries despite the absence of obstructive CAD. Several approaches have been used to define this disorder, but all embrace the concept of impaired angiographic contrast flow due to increased coronary microvascular resistance.¹

Beltrame and others have demonstrated that this microvascular dysfunction differs from many other coronary microvascular disorders. Coronary hemodynamics studies have demonstrated increased resting microvascular resistance, preserved vasodilator capacity (i.e., coronary flow reserve), and dynamic microvascular dysfunction as vasodilator therapy acutely improves the angiographic phenomenon. Furthermore, as it differs hemodynamically from other primary coronary microvascular disorders, it warrants consideration as a novel form of primary microvascular angina.

Two approaches have been used by investigators to define the threshold contrast flow that constitutes ‘slow flow.’² The Thrombolysis in Myocardial Infarction (TIMI) flow grade scores epicardial artery contrast flow from TIMI 0 (no flow) to TIMI 3 (normal flow). TIMI 2 flow involves delayed filling of the distal vessels and is considered present when three or more beats are required to opacify the distal vasculature. This approach is frequently used in diagnosing the no-reflow phenomenon and has also been used to diagnose the CSFP.

An alternative assesses the number of cine frames required to opacify the distal vasculature, with a reference value of 21 ± 3 frames established by Gibson et al.³ Thus, some researchers have defined the CSFP as any frame account above the baseline threshold, while others have used a threshold of more than two standard deviations above this reference value.

In order to define a population of patients with primary microvascular dysfunction, John F. Beltrame, MBBS, PhD, FACC, a professor of medicine at the University of Adelaide, Australia, notes that other causes of the angiographic phenomenon must be considered.² For example, inadvertent injection of microbubbles during the angiographic procedure will impede the microcirculation, producing a transient CSFP. Similarly, the no-reflow phenomenon arises from distal embolization of an atherosclerotic lesion, as well as the release of vasoactive substances, resulting in the angiographic appearance of the CSFP. Large ectatic coronary arteries may give rise to the appearance of the CSFP because of a capacitance effect of filling the large vessels. When defining a primary coronary microvascular condition, Beltrame emphasizes that these secondary causes must be excluded.

Mechanisms Unclear (Opaque Even)

While increased coronary microvascular resistance has been well documented in patients with CSFP, the mechanisms responsible for this particular microvascular dysfunction are more elusive.

Beltrame and colleagues took an elegant plasma proteomic approach in one study that implicated an inflammatory/oxidative stress process in the pathogenesis of the acute coronary syndrome (ACS) presentation associated with the CSFP.⁴ However, subsequently he and his team reported a clinical study of endothelial function, oxidative stress, and inflammation in chronic coronary slow flow phenomenon patients.⁵ They found no differences between CSFP and controls in response to salbutamol (endothelium-dependent) or glyceryl trinitrate (endothelium-independent), nor were there any differences in various biomarkers of inflammation (myeloperoxidase and hs-CRP) and oxidative stress (malondialdehyde and homocysteine).

Most patients with CSFP do exhibit ST/T wave changes during an ACS presentation. The strong association with T wave changes raises the possibility that the T wave may be a marker of microvascular dysfunction.⁶

Considering the evidence, not only have a number of investigators suggested that CSFP should be considered a specific disease entity, some suggest it should be referred to as ‘syndrome Y.’ The evidence base for CSFP does seem to be expanding and Beltrame thinks it may be soon considered a clinical syndrome rather than a phenomenon.

However, if this field of research is to advance, he said, a consensus statement to formalize the angiographic definition of the CSFP is required.

His own suggestions² are that angiographic evidence of CSFP should be defined by:

• No evidence of obstructive epicardial CAD (i.e., no angiographic lesions ≥40%)
• Delayed distal vessel contrast opacification as evidenced by either:
• TIMI 2 flow (i.e., requiring ≥3 beats to opacify the vessel) or
• corrected TIMI frame count >27 frames (images acquired @ 30 frames/s)
• The delayed distal vessel opacification is in at least one epicardial vessel
• Exclusion of secondary causes of the CSFP, including
• No-reflow phenomenon
• Coronary emboli
• Coronary ectasia
• Exogenous vasoconstrictor administration (e.g., cocaine)

References

1. Beltrame JF, Cutri N, Kopetz V, et al. Coron Artery Dis. 2014;25:187-9.
2. Beltrame JF. Circ J. 2012;76(4):818-20.
3. Gibson CM, Cannon CP, Daley WL, et al. Circulation. 1996; 93: 879-88.
4. Kopetz VA, Penno MA, Hoffmann P, et al. Int J Cardiol. 2012;156:84-91.
5. Kopetz V, Kennedy J, Heresztyn T, et al. Cardiology. 2012;121(3):197-203.
6. Cutri N, Zeitz C, Kucia AM, B, et al. Int J Cardiol 2011;146:457-8.

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Slipping into Reverse
New agents under study for reversing target-specific oral anticoagulants

The direct thrombin inhibitor dabigatran as well as the anti-factor Xa (fXa) agents rivaroxaban, apixaban, and edoxaban (listed in order of U.S. approval for stroke prevention in nonvalvular atrial fibrillation [AF] patients), are a new generation of oral anticoagulants that are transforming clinical practice. While these target-specific oral anticoagulants (TSOAs) overcome some of the difficulties associated with anticoagulation with vitamin K antagonists, one reason for a slower than-expected uptake in clinical practice may be the absence of specific reversal agents.

Serious bleeding events are low, and the need for reversal of any anticoagulant is relatively rare: over a 12-month period ending in June 2013, there were about 6.8 million patients taking anticoagulants in the United States, of whom approximately 345,000 (5.1%) presented to the emergency room with a bleeding event.¹ Approximately 228,000 of those patients warranted hospital admission.

Also, the rapid offset of the TSOAs (half-life of rivaroxaban is 4 to 9 hours and 12 to 17 hours for dabigatran and apixaban) obviates the need for reversal in most situations, although antidotes for these agents would be beneficial to manage patients who require urgent surgery or interventions and to treat individuals with life-threatening bleeds.

In the summer of 2015, Mark Crowther, FRCP, MD, a professor of medicine at McMaster University, Canada, published a review of the anticoagulants, their current use, and future potential.² Unlike the anti-fXa agents, the absorption of dabigatran can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis.

Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is largely based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these approaches is the most suitable for emergency reversal.

Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

Universal Antidote for Factor Xa Inhibitors

Recently, Crowther presented the results of a phase III clinical trial of Andexanet alfa (PRT064445), a universal antidote for fXa inhibitors. An FDA-designated breakthrough therapy, this protein acts as a decoy for direct fXa inhibitors, binding to anti-fXa agents in a dose-dependent manner, preventing them from acting on the coagulation cascade. The new agent is being studied with all of the direct fXa inhibitors: apixaban, rivaroxaban, and edoxaban. It is also being studied as an antidote for patients on enoxaparin, a low-molecular-weight heparin (LMWH) and indirect fXa inhibitor. The drug does not seem to be effective against the factor IIa inhibitor dabigatran.

The trial is known as ANNEXA (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors) with ANNEXA–A referring to the specific apixaban study (presented at AHA.14) and ANNEXA–R referring to the rivaroxaban study (data presented at ACC.15).

In ANNEXA–A, 33 healthy volunteers were given apixaban 5 mg twice daily for 4 days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg intravenous (IV) bolus (n = 24) or to placebo (n = 9). The new agent was well-tolerated and met all pre-specified primary and secondary efficacy endpoints with p < 0.0001. Fully 100% of andexanet-treated participants had ≥ 90% reversal of anti-fXa activity and restoration of thrombin generation to baseline (pre-anticoagulant) levels. Andexanet produced near complete normalization of all coagulation parameters measured within 2 minutes of infusion completion and the effect lasted 1-2 hours with bolus dose.

A second part of ANNEXA was presented at the June 2015 International Society on Thrombosis and Haemostasis Congress in Toronto, Canada. This analysis included 31 healthy volunteers also given apixaban 5 mg twice daily for 4 days and both the original 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n = 23) or to placebo (n = 8). The agent has a very short half-life, so in order to get continuing effect, it needs to be delivered as a continuous infusion. Andexanet acts as a ‘decoy,’ so the fXa inhibitor binds to the decoy and is unable to maintain an anticoagulant effect as it is removed from the body. Again, the second part of ANNEXA–A study achieved all primary and pre-specified secondary endpoints with high statistical significance.

Specifically, the anticoagulant activity of apixaban, as measured by anti-factor Xa activity, was reversed by 93.5% (p < 0.0001 versus placebo). Following completion of the 2-hour continuous infusion of andexanet alfa, the anticoagulant activity of apixaban remained significantly reversed, by 92.7% (p < 0.0001). These two endpoints demonstrate that andexanet alfa produced rapid reversal of the anticoagulant effect of apixaban, which was sustained for the duration of the infusion. Andexanet alfa significantly reduced the level of free unbound apixaban in the plasma and restored thrombin generation to normal. The new agent was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported.

It should be noted that data have not been reported yet evaluating these agents in the setting of active bleeding. Crowther explains that in the case of an individual with an upper gastrointestinal bleed due to an ulcer, from what is known now a single bolus of andexanet alfa might be sufficient, which would provide a 30- to 60-minute window to allow an interventionalist to perform a procedure without any anticoagulant effect. On the other hand, in the event of a patient requiring a longer surgical procedure, then it likely would be necessary to utilize prolonged infusion rather than a single bolus of andexanet.

What about the rivaroxaban study? In the first part of ANNEXA–R, 41 healthy volunteers were given rivaroxaban 20 mg once daily for 4 days to steady state. They were then randomized in a 2:1 ratio to receive either andexanet administered as an 800 mg IV bolus (n = 27) or placebo (n = 14).

For the primary endpoint, andexanet alfa reduced the anti-fXa activity of rivaroxaban from baseline to nadir by >90%, a highly significant difference (p < 0.0001). For the secondary endpoints:

• Significantly more andexanet alfa subjects (26 of 27) than placebo subjects (0) had a 90% or greater reduction in anti-Factor Xa activity from baseline to nadir (p < 0.0001).
• The free (unbound) rivaroxaban concentration from baseline to nadir was reduced significantly by andexanet compared with placebo
  (p < 0.0001).
• Endogenous thrombin potential significantly increased from baseline to peak in andexanet subjects compared with the placebo volunteers (p < 0.0001).
• Finally, 26 of 27 andexanet alfa subjects returned to the normal range of thrombin generation within 10 minutes of the end of the bolus administration.
• The second part of the ANNEXA-R study is expected to be presented soon in these healthy volunteers who, after receiving an 800 mg IV bolus, received a continuous infusion of 8 mg/min for 120 minutes or placebo.

Idarucizumab for Dabigatran Reversal

Also in June of 2015, investigators published an interim analysis of a prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in 90 patients who had serious bleeding (group A) or required an urgent procedure (group B).³

Idarucizumab is a humanized MoAb fragment with high affinity for the oral direct thrombin inhibitor dabigatran that selectively and immediately neutralizes its anticoagulant activity.⁴ The data indicate that the antidote effectively and within minutes of administration neutralized the activity of dabigatran with a satisfactory safety profile. Normal hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of idarucizumab. Concentrations of unbound dabigatran remained below 20 ng/ml at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in two patients and one patient, respectively.

In an accompanying editorial, Kenneth A. Bauer, MD, chief of the hematology section, VA Boston Healthcare System, and director, Thrombosis Clinical Research, Beth Israel Deaconess Medical Center in Boston, noted that without a control group, it is difficult to assess the clinical benefit of idarucizumab in patients with dabigatran-related bleeding.⁵ The mortality in the study population was high at 20%; half the deaths occurred more than 96 hours after the administration of the antidote and were attributable to coexisting illness.

Bauer wrote, “Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neutralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures? (The) location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking.”

Finally, perosphere or PER977 is a small, synthetic, water-soluble, cationic molecule that is a nonspecific reversal agent which binds to several of the direct oral anticoagulants by means of electrostatic interactions. In vitro and in vivo studies indicate that PER977 reverses anticoagulation with each of the new oral agents mentioned above. This reversal effect is due to direct binding to the anticoagulant molecule but no binding to blood coagulation factors or to other proteins in the blood.
On April 2, 2015, the FDA granted Fast Track designation for PER977 and phase III trials are in the final planning stages.

References

1. Truven Marketscan® Commercial, Medicare Supplemental, and Medicaid Databases. Time period: January 1, 2012, to June 30, 2013. Extracted April 2014. Unpublished results.
2. Crowther M, Crowther MA. Arterioscler Thromb Vasc Biol. 2015 Jun 18. [Epub ahead of print]
3. Pollack CV Jr, Reilly PA, Eikelboom J, et al. N Engl J Med. 2015 Jun 22 [Epub ahead of print]
4. Glund S, Stangier J, Schmohl M, et al. Lancet 2015 Jun 15. [Epub ahead of print]
5. Bauer KA. N Engl J Med. 2015;373:569-71.

Keywords: CardioSource WorldNews Interventions, Angina Pectoris, Chest Pain, Coronary Angiography, Microvascular Angina, Anticoagulants

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