Adding Rivaroxaban to Aspirin in treatment of Indian Stable CAD patients- Analysis of COMPASS trial in India by Dr Prafulla Kerkar Et al

The following article is a critical analysis of the COMPASS trial with respect to benefit-risk assessment using the number needed to treat: Applicability and relevance in Indian patients with stable coronary disease (CAD)

1. Purpose:

Given that coronary artery thrombosis is the main culprit for acute coronary events, antiplatelet agents (single or dual) and anticoagulants, either alone or in combination have been used in the management of coronary artery disease (CAD) {acute coronary syndromes (ACS) as well as stable coronary artery disease} for a long time. Although monotherapy with aspirin is the standard of care for secondary prevention, about 5 to 10% of patients with cardiovascular disease have recurrent events each year. In an attempt to reduce this residual risk, several trials have been by conducted adding a second antiplatelet or an anticoagulant to aspirin monotherapy or by substituting aspirin. The superior efficacy in preventing ischemic events documented in some of these trials has been at the expense of excessive bleeding. Hitting the sweet spot by balancing efficacy and safety has been challenging.

In recent years, we have seen the introduction of newer anticoagulants for secondary prevention. Rivaroxaban, a selective direct Factor Xa inhibitor was tested in patients with stable atherosclerotic vascular disease in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial based on its superior efficacy (albeit with excessive bleeding) in the earlier ATLAS- ACS-TIMI-51 trial of patients with acute coronary syndromes. The COMPASS trial was envisaged to test the hypothesis that Rivaroxaban alone or in combination with aspirin is more effective than aspirin alone in preventing recurrent cardiovascular events with acceptable safety. The trial used three antithrombotic regimens: low dose (100mg once daily) aspirin monotherapy considered to be the control arm, low dose (5mg twice daily) rivaroxaban monotherapy and a combination of low dose aspirin (100mg daily) and very low dose rivaroxaban (2.5 mg twice daily). This combination was clearly superior in reducing the composite primary endpoint of cardiovascular death, myocardial infarction and stroke compared to aspirin monotherapy. This impressive efficacy has resulted in a guideline recommendation of the European Society of Cardiology for Rivaroxaban for secondary prevention in patients with stable atherosclerotic cardiovascular disease.

However, it must be noted that in this trial, the rates of major bleeding events were significantly higher in the rivaroxaban groups than in the aspirin monotherapy group. Thus, clinicians could still be wary of using Rivaroxaban for this indication, more so Indian physicians, given that there were no Indian patients recruited in the COMPASS trial. But, we hypothesised that this concern may not be justified given that the Indian CAD population is younger and therefore possibly less prone to bleeding. It is well- known that In India, CAD occurs a decade earlier than the western population. In the large CREATE Registry of Indian patients with acute coronary syndromes, the mean age of presentation with ACS was 57.5 years as against 68 years in COMPASS trial.

In COMPASS trial, subgroup analysis was available for patients aged less than 65 years and > 65 years which was used as a threshold for younger and older age in our benefit risk analysis.

The COMPASS trial did not enrol Indian patients unlike ATLAS-ACS-TIMI-51 trial which enrolled Indian patients. However, no subgroup analysis was performed for Indian sub set of patients. Thus, we decided to use the COMPASS data of younger patients [less than 65 years] with stable atherosclerotic vascular disease to see if the benefit - risk in them was any different so that this would help decision making about the use of Rivaroxaban among younger Indian patients. We anticipated less bleeding in an younger patient population which is well known.

2. Risk – Benefit metrices used

We used the following two simple metrices for benefit risk assessment – the Number Needed to Treat for benefit (NNT- B) and the Number Needed to Treat for Harm [NNT-H).

The NNT-B is interpreted to mean the following – what is the number of patients that need to be treated with one intervention [rather than another] so as to prevent one adverse outcome or for one patient to benefit? It should thus be as close to 1 as possible.

The NNT- H is interpreted to mean the following – what is the number of patients who need to be treated with one intervention [rather than another] for one patient to be harmed? This number should thus be as far away from 1 as possible.

3. Findings:

In COMPASS trial 4344/18,288 [24%] patients belonged to younger age [less than 65 year] group. The benefit risk metrices were calculated primarily for these subsets of population.

The NNT – B for the overall patient population of the COMPASS trial was 76. This is interpreted to mean that every time 76 patients are treated with a combination of Rivaroxaban + Aspirin, one patient will be prevented from having a major adverse cardiovascular event [MACE]. The NNT- H was 83, interpreted to mean that every time 83 patients are treated with a combination of Rivaroxaban + Aspirin, one patient will develop a bleeding event.

For younger patients [less than 65 years], the NNT-B and NNT-H values were 48 and 500 respectively indicating that the combination had a favourable benefit- risk profile among the less than 65-year- old patients with stable atherosclerotic disease.

4. Major take away:

The favourable benefit–risk profile of the combination of rivaroxaban with aspirin among patients aged less than 65 years (relative to those more than 65 years) may be useful for Indian patients as the Indian stable coronary artery disease patients tend to be younger.

5. Limitations

This post – hoc analysis needs to be confirmed and strengthened through evidence that can be generated in a large randomized controlled trial conducted in Indian population.

The above article is a summary of the review article that was published in the November-December 2018 edition of the Indian Heart Journal. To read the full article, click on the following link

https://doi.org/10.1016/j.ihj.2018.06.006

The article has been jointly contributed by Doctors P. Kerkar, D. Bose, T. Nishandar, G. Sabnis, D. Kumar, U.M. Thatte, N.J. Gogtay

Dr Prafulla Kerkar, MD, DM (Cardiology),FACC,FESC is a renowned Cardiologist and currently the Head of the Department of Cardiology at the King Edward VII Memorial Hospital and the Professor in Cardiology at the Seth G.S. Medical College in Mumbai. D. Bose, T. Nishandar, U.M. Thatte, and N.J. Gogtay are clinical pharmacologists from the Department of Clinical Pharmacology, Seth GS Medical College & KEM Hospital, Mumbai. Dr. G. Sabnis and Dr D. Kumar are cardiologists and assistant professors at Seth GS Medical College & KEM Hospital, Mumbai.