Octreotide enables left atrial appendage closure in AF patients with GI bleeding

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Dhanunjaya Lakkireddy

Octreotide therapy has the potential to offer atrial fibrillation (AF) patients with arteriovenous malformations (AVM) related gastrointestinal (GI) bleeding another treatment option. It is a safe way to reinitiate oral anticoagulants (OACs) by bringing down the risk of repeat GI bleeds and enables medical professionals to continue with the appropriate therapy for AF. A large randomised control trial is needed to confirm these findings. The data was presented by Dhanunjaya Lakkireddy (KU Cardiovascular Research Institute, Kansas City, USA)at the AF Symposium (AF Symposium; 11–13 January 2018, Orlando, USA).

The risk of warfarin related GI bleeds can range from between 0.8% and 1.5% in patients on long term anti-coagulation. The risk increases significantly as the number of anti-coagulators a patient is taking goes up.

Some patients with AF also have coronary diseases and may require alternative interventions and some patients need to maintain their long term oral anti-coagulation therapy. This predisposes patients to a significant risk of bleeding.

Warfarin vs NOACs

There have been numerous randomised control trails looking at whether novel oral anticoagulents (NOACs) are better than warfarin. Meta-analyses have shown that the risk of GI bleeding is significantly higher with NOACs than with warfarin.

“This could be because the agents are very effective in terms of anti-coagulating patients and when there is a fixed source of bleeding and there is no fluctuation and variation in the anti-thrombotic levels it is possible that the risk of bleeding is going to be dramatically higher then with warfarin,” said Lakkireddy, “where most of the times people spend 40% of their time in the sub-therapeutic range.”

The ROAR study (replacing warfarin with a novel oral anticoagulant: risk of recurrent bleeding and stroke in patients with warfarin ineligible or failure in patients with atrial fibrillation) looked at patients that had contraindications from warfarin because of bleeding reasons and went on to be treated with NOACs. It was published in the Journal of Cardiovascular Electrophysoiology in 2017. It took 263 patients who, for various reasons, were considered warfarin ineligible. Of those that were warfarin ineligible, in 86% this was due to systemic bleeding and 12% had recurrent transient ischemic attack. Even when these patients were put on a NOAC they still continue to bleed and gastrointestinal bleeding was the most common type. The vast majority of the patients bled back into the same or gan as they were originally bleeding from.

The study showed that NOACs were not superior when compared to warfarin in reducing GI bleeds. This meant there was a need for another way to reduce GI bleeding in patients on OACs.

To do this Lakkireddy and his team looked at what the most common cause of gastrointestinal bleedingwas. They found that in almost 50% it was caused by arteriovenous malformations in the small bowel and that this was the most common cause of bleeding in the subset of patients presenting with recurrent significant anaemia and occult blood positive stools.

Finding a solution

GI bleeding complicates the continued care of patients with AF and puts them at significant risk for of recurrent bleeds and anaemia and could force the withdrawal of OAC treatment, putting these patients at risk for systemic thromboembolism.

It also means that it can be hard to treat AF with ablation or left atrial appendage closure as current regiments mandate that patients are anti-coagulated for at least 6 weeks post treatment.

One possible solution is to treat the bleed directly, by looking for the lesions with endoscopy but they often cannot be found and the risk of intervention has to be taken into account.

Pharmacologic intervention

“Gastroenterologists have looked into this issue and found that using agents like oestrogen, oestrogen and progester­one, octreotide, corticosteroid, prednisolone and cyclo­phosphamide, interferon, danazol, you name it, and every possible agent that was out there has been tested.” Said Lakkireddy, “The problem is that most of them are very small observational studies and people chose them based on their mechanistic properties but the data is all over the place. And of all those what stands out to be more promis­ing is the octreotide.”

Lakkireddy set out to see if octreotide could make a difference. He, and is team screened about 150 patients and after endoscopy 60 of these patients met the criteria. Of these 38 were eligible and these patients were treated with octreotide. The average patient was 70 years of age, and there were more women in the study then men (27/9). The average CHA2D2-VASc score was three and above, the HAS-BLED score was three and there was a wide band of distribution of oral anticoagulants used prior to discontinuation for GI bleed. Warfarin was used most commonly and the most common source of bleeding was the small intestine, which accounted for 42% of cases, with 25% in colon and bleeding coming from an unidentifiable source in 25%.

There are two different formulations available of octreotide, one has a short action time and there is also a long acting monthly injection available but the cost is prohibitive.

Oral anti-coagulation was resumed 24 hours after the octreotide was first given and the patients were assessed for incidences of repeat GI bleeds and drops in Hb levels at one, three and six months. In patients with significant repeat bleeds or perceived risk of increased risk, LAA occlusion was offered.

Mechanism of action

Octreotide is a somatostatin analogue and is used in GI bleeding because it reduces splanchnic arterial blood flow by decreasing smooth muscle tone, it also inhibits growth factors like EGF, FGF, IGF-1 and is responsible for angiogenesis suppression.

The response to treatment is primarily dependent on the different expression of each receptor subtype conditioning the vasoconstrictor, antiangiogenetic, antiproliferative, immunomodulatory and antisecretory effects generated by octreotide in the GI tract.

Of those 30 patients that were enrolled, there were two patients that were subsequently lost to follow up and five patients that opted out of the study and preferred LAA occlusion and three of the received the WATCHMAN atriclip. There was four major GI bleeds requiring transfusions and LAA closure. There were 28 patients that were left for follow up at 3 months and there were no bleeds in about 68% of patients. There were some minor GI bleeds that were easily managed and major bleeds requiring transfusion was about 14% as well. One patients who required a colectomy because of bleeding that could not be contained. Those patients who had major transfusions and colectomy were evaluated too but they were not suitable for any of these treatments, both WATCHMAN as well as LARIAT.

“The take home message from this is that using an agent like OCT gave us the opportunity to minimise or contain the risk of bleeding.” explained Lakireddy, “In our study 68% of patients experienced no GI bleeding and this really helped us to offer LLA occlusion as a subsequent therapy to get them off the OACs. It decreases the need for transfusions and recurrent bleeds at the end of one and two years. It enables re-initiation of OACs and

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