Dr. Sundeep Mishra, a noted professor of Cardiology, shares his take on 3 therapies- Tafamidis for Transthyretin amyloid cardiomyopathy, Ticagrelor for post-PCI therapy, and oral antibiotics for left-sided endocarditis, all of which were discussed at the ESC annual Meeting held in Munich, 2018.

 

 

ATRR-ACT a Sea Change in Cardiology

Tafamadis reduces mortality in amyloid cardiomyopathy

Transthyretin amyloid cardiomyopathy is an under-diagnosed disease caused by deposition of amyloid fibrils in the myocardium which occurs when wild-type or variant transthyretin becomes unstable and misfold. These mis-folded monomers / oligomers of transthyretin are deposited in the myocardium, leading to cardiomyopathy and symptoms of heart failure; dyspnea, fatigue, orthostatic hypotension, and syncope. Moreover, infiltration of the conduction system can lead to bundle-branch block, AV node block, SA node disease, and AF.

Transthyretin amyloid cardiomyopathy is generally inherited as an autosomal dominant trait (caused by mutations in the transthyretin gene, or from deposition of wild-type transthyretin protein - called senile systemic amyloidosis). It is a late-onset disease, occurring predominantly in men ≥60 years with a very poor prognosis (mean survival is <2.5 years from the time of diagnosis).

As yet, there has been no definite treatment other than supportive care. However, recently there has been a rekindling of hope with several new investigational agents. Patisiran was the first drug approved by the US-FDA for treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis. Patisiran and an antisense oligonucleotide inotersen act by reducing transthyretin production.

Tafamidis is another agent which acts by stabilizing transthyretin, preventing mis-folding and the formation of amyloid. It was approved by EU in 2011 for use in transthyretin familial amyloid polyneuropathy (to slow neurologic progression). Subsequently it has also been approved in Israel, Mexico, Japan, and South Korea for this use. However, its use in cardiomyopathy is not that well established.

ATTR-ACT trial

It was a multicenter, international, double-blind, RCT, enrolling a total of 441 patients randomly assigned in a 2:1:2 ratio to receiving 80 mg or 20 mg of Tafamidis or placebo for 30 months. The study included both patients with the hereditary form of the disease and those with the wild-type form. For the primary endpoint (the hierarchical assessment of all-cause mortality, followed by frequency of cardiovascular-related hospitalizations using the Finkelstein–Schoenfeld method), Tafamidis was superior to placebo over 30 months (P <.001).

• All-cause mortality was reduced by 32% (95% CI 0.51 - 0.96) and rates of cardiovascular-related hospitalizations were reduced by 42% (95% CI 0.56 - 0.81).
• Over 30 months, Tafamidis was also associated with better 6-minute walk distances (P <.001) and a lower rate of decline in quality of life score (P <.001).

The incidence and types of adverse events were similar between the groups, and between 2 doses; mild - moderate in severity, and permanent discontinuation was less common in the Tafamidis groups than with placebo. Both diarrhea and UTI which is common with familial amyloid polyneuropathy per se, were less common in patients who received Tafamidis.

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GLOBAL LEADERS Trial: Ticagrelor fails to become the Whale Rider

Extended Ticagrelor monotherapy after stenting misses endpoint

During the course of stent deployment there is a risk of thrombosis of target vessel due to several reasons- significant trauma and damage to the endothelium can occur during the procedure, subsequent to procedure the struts exposed to lumen could activate platelet activation and aggregation contributing to stent thrombosis (ST).

Potent anti-platelets are required to prevent stent thrombosis. ASA can inhibit both platelet activation and aggregation but alone is not enough to prevent ST; an addition P2Y12 receptor antagonists (clopidogrel, prasugrel and ticagrelor) which bind and inhibit ADP receptors on platelets is mandatory to sufficiently reduce the ischemic risk post-PCI, a strategy called dual-anti-platelet therapy (DAPT). However, the issue is a high bleeding risk with his therapy.

On the other hand, all P2Y12 receptor antagonists are not equal. There is a clear evidence that ticagrelor / prasugrel are much more potent anti-thrombotic agents than clopidogrel (although bleeding risk is also higher) and thus more useful in unstable patients like those with ACS. Since use of DAPT is associated with increased bleeding risk there is a feeling among the experts that a single potent P2Y12 inhibitor could optimize the balance between reduction of the risk of ischemic events and avoidance of bleeding risk on long term basis; a best of both worlds.

With this in view the GLOBAL LEADERS trial was planned to answer 3 questions:

• Can we do without aspirin?
• Can we also give ticagrelor to stable patients (the trial included both stable and unstable patients)?
• Can we extend ticagrelor for 2 years?

GLOBAL LEADERS trial

The study involved ~ 16,000 patients undergoing PCI with a biolimus A9-eluting stent for stable CAD / ACS, randomly assigned to an open-label design to 75 - 100 mg ASA OD + 90 mg ticagrelor BD for 1 month, followed by 23 months of ticagrelor mono-therapy or standard DAPT (75 - 100 mg ASA+ 75 mg clopidogrel daily (for stable CAD) or 90 mg ticagrelor BD (for ACS) for 12 months, followed by ASA mono-therapy for 12 months (control arm).

At the end of 2 years,

• the primary endpoint (a composite of all-cause mortality or new Q-wave MI at 2 years) was 13% lower in ticagrelor arm although it did not reach statistical significance (95% CI 0.75 - 1.01, P= 0.073).
• there was no difference in major bleeding, which was the key secondary safety endpoint. Of note adherence to ticagrelor was an issue, particularly beyond the 1st year of trial (by the end of the 2nd year, 22% of ticagrelor patients vs. 7% of controls had stopped taking ASA which could have contributed to increased ischemic risk in ticagrelor arm).

It was thus felt that maybe 1 year of ticagrelor is enough and after that one could switch to ASA lifelong. A sub-analysis of the trial revealed that if the trial had been stopped at 1 year, the result would have been highly significant in favor of ticagrelor.

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For a POET – Oral (antibiotic) is the Key

Switch to Oral Antibiotics Safe in Left-Sided Endocarditis

Infective endocarditis (IE) is a rare but one of the most serious infectious disease in the field of cardiology with mortality rate ~ 20%. It could be either left sided endocarditis or right sided one (generally because of IV drug abuse). While there is reasonable evidence that right-sided endocarditis due to methicillin-susceptible S. aureus can be treated with oral antibiotics (ciprofloxacin and rifampicin) following IV administration, only a few trials have examined the effectiveness and safety of this strategy for left-sided endocarditis, where the stakes are generally higher.

For left-sided IE, the guidelines recommend treatment with IV antibiotics for at least 4 weeks in the hospital for native vale IE (at least 6 weeks for prosthetic valve IE). However, an in-hospital IV therapy is associated with high in-hospital complication and mortality rates, mainly in the early phase. Furthermore, treating IE with 4 - 6 weeks of intravenous antibiotics not involves hospital stay, a higher cost but also higher chance of developing hospital-acquired infections.

POET Trial

Whether, patients with left-sided IE can also receive predominantly oral therapy (after a short course of IV therapy during hospital admission) was the question asked by the study investigators who (screened 1954 patients referred to a cardiac center in Denmark for suspected IE, from which they) included 400 patients (77% men; mean age, 67 years) treated with IV antibiotics for left-sided IE caused by Streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci. About 1/3rd of patients had prosthetic valves. The patients were randomized if they had received 2 antibiotics IV for a minimum of 7 - 10 days, they were clinically and biochemically stable, and they had undergone TEE to rule out abscess or valve re-infection which would mandate a surgical intervention.

The oral group received oral tablets after mandatory at least 10 days of IV antibiotics (vs. continuous IV antibiotic in the intravenous group). The oral group had a 28% reduction of primary end-point (all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen) which occurred in 9% patients after completion of Rx which was found non-inferior (P<0.001) to the 12.1% in the IV-only antibiotic group (HR 0.72, P=0.40).

• Length of hospital stay, after randomization was 19 days with IV-only antibiotics compared with 3 days in the oral switch group (P < .001). Rates were identical in the two groups for the individual components of unplanned cardiac surgery (6 each), embolic event (3 each), and re-infection (5 each).
• There were fewer deaths in the oral group than in the IV-only group (7 vs. 13), although it is unclear why this happened. The reduction in hospital stay could play at least some part in this because patients who stay in the hospital longer could be at greater risk of events such as hospital-acquired infections.

Notably, patients were selected for oral OPD management only when they had no heart failure, no emboli, no arrhythmia, no complicating co-morbidities, and could be frequently and strictly monitored. It is estimated that about 40% (stable) IE patients can be managed in this manner.

To read Part 2 of the ESC Congress 2018 by Dr. Sundeep Mishra, click Key takeaways & opinions on 3 major studies from ESC Congress 2018 by Dr. Mishra

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a Professor of Cardiology.