Doctor's Review: Medicine on the Move

October 19, 2017

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Conference Proceedings: 2011 Canadian Cardiovascular Congress

Before the flood – a glimpse over the horizon

Change in most fields of medicine comes in waves. Cardiology is no exception, and one message resounded clearly at the 2011 Canadian Cardiovascular Congress held in Vancouver on October 22-26: big change is coming ... it's just not quite here yet.

Too often in recent years, new cardiology treatments have proliferated without ever proving an overall survival benefit. "Biomarkers often mislead us,” warned San Francisco-based Canadian cardiologist Dr David Waters. “Drugs may affect multiple physiologic systems, may have unrelated harmful effects ... or may not actually impact clinical endpoints." A newfound caution has slowed down the research pipeline. A host of new therapies wait in the wings, but they may have to wait a little longer these days.

“The less you clot, the more you bleed.”

The need to weigh treatment benefit against treatment harm is most acute in the hottest cardiology topic of them all: preventing stroke in atrial fibrillation. The dilemma was summed up by Dr L. Brent Mitchell of the Libin Cardiovascular Institute of Alberta: “The less you clot, the more you bleed.”

This area of medicine was recently up-ended by the arrival of dabigatran (Pradax), heir apparent to the long reign of warfarin. But already dabigatran faces strong challengers in the factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis). All three drugs have shown superiority to warfarin, but in different ways. Dabigatran was shown in the RE-LY trial1 to reduce the number of ischemic and hemorrhagic strokes. Apixaban was shown in the ARISTOTLE trial to further reduce the number of dangerous intracranial bleeds, and while it failed to outperform warfarin in reducing ischemic stroke, the safer bleeding profile plus a lowered rate of MI made it the first anticoagulant to achieve an overall survival benefit over warfarin in AF.2

Rivaroxaban has also gone against warfarin in the ROCKET-AF trial,3 which bravely took on some very sick AF patients. Their poor condition may have blurred the drug's benefits somewhat. It showed similar bleeding rates to warfarin, but the bleeds on rivarobaxan tended to be less severe. As Dr Stuart Connolly of McMaster put it: "Warfarin causes intracranial hemorrhage. Rivaroxaban, and indeed the other agents, don’t." The new anticoagulants aren't stronger than warfarin – but they are safer. "Warfarin would never be approved today in a clinical trial,” said Dr Connolly.

Physicians often ask if the new anticoagulants have an antidote. None does, though all are expected to have one within a year or so. But even without an antidote, noted Dr Connolly, dabigatran caused less bleeding in RE-LY than warfarin. All three drugs make life far simpler than warfarin, because drug interactions are few, dosage is constant and there's no need for routine monitoring of INR. Rivaroxaban holds an edge here with its once-daily dosing. Intriguingly, apibaxan has an almost identical half-life to rivaroxaban, but twice-daily dosing.

Apixaban isn't yet approved in Canada or anywhere else, though it seems certain to be on the market within 2 years. Rivaroxaban has just received Health Canada's approval for stroke prevention in AF.

Most experts agree that new AF patients should start on one of the new anticoagulants. As for patients who are already on warfarin, viewpoints differ – the new agents are pricier. The expert consensus is this: patients on warfarin who fared badly in trials tended to be those with poorly-controlled INR. Patients who are comfortably lodged in the INR sweet spot aren't priorities for switching. Should they ultimately be switched? Pin a cardiologist to the wall, and most will eventually say "yes".

One player who seems sure to be knocked out of the stroke prevention game by recent results is ASA. “There is probably no role for ASA therapy outside some relatively limited situations once apixaban becomes available,” said Dr Connolly.

With legions of Canadians now marching towards retirement age, these improved stroke prevention tools are certainly timely arrivals.

Success in failure

Heart failure is another arena where new entrants wait offstage. A decade-long investigation of aldosterone antagonists began to wind up rather suddenly when the EMPHASIS-HF trial of eplerenone was stopped early due to overwhelming evidence of benefit.4 The treatment brought marked improvement in patients with hard-to-treat milder symptoms, such as NYHA class II, Dr Malcolm Arnold of London Health Sciences Centre told the conference. Patients with preserved ejection fraction may also benefit - the TOPCAT study is looking into that.

Three studies looked at implantable cardioverter-defibrillators (ICD) with cardiac resynchronization therapy (CRT) in patients with mild-to-moderate HF. The mostly Canadian RAFT study5 found a survival benefit in moderate HF, at the price of frequent device malfunctions. But lead RAFT investigator Dr Anthony Tang said the devices studied would be considered primitive and unreliable today. Benefits appeared greatest in patients with left bundle branch block or long QRS duration. ICD use lags in Canada, but Tang predicts it's set to take off.

The shadow of diabetes

Coronary disease is getting diabetes. That is, the number of heart attacks are going down, despite more sensitive detection with troponin. Yet the rate of diabetes is climbing fast, and 8 of 10 diabetic patients will die of heart disease. So acute coronary syndrome is going to be seen increasingly in company with type 2 diabetes which, like kidney disease, changes the treatment equation somewhat. For example, diabetic ACS patients benefit greatly from stents, but diabetes is a risk factor for stent thrombosis.

A Canadian consensus is emerging that prasugrel (Effient) outperforms clopidogrel for secondary protection in diabetic ACS patients. But Dr Lars Wallentin of Uppsala, Sweden told the conference that prasugrel is second choice (and clopidogrel third) in current European guidelines. First place is held by ticagrelor (Brilinta), which was approved in Canada last year. Its rapid onset and offset is most helpful in patients who may need urgent surgery.

The symposium on ACS in diabetes attracted lively interest at CCC 2011, not least because all audience members received an iPod Touch with which they answered case-based questions.

Attacking the roots of heart disease

Our perception of atherosclerosis has shifted. It's increasingly seen as an inflammatory disease not so different from common autoimmune disorders, said Jean-Claude Tardif, director of the Montreal Heart Institute. That explains why low-dose methotrexate is one of at least 5 agents being studied for the direct treatment of atherosclerotic plaques.

Anti-inflammatory serpins released by viruses are also the subject of major research, and 3 studies using reconstituted HDL have already shown sharply reduced atheroma burden; results of a larger study are expected soon. “In the near future,” forecast Tardif, “a direct anti-inflammatory intervention will improve cardiovascular outcomes in patients with atherosclerosis beyond the current standard of care.”

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