ACE inhibitors and angiotensin-receptor blockers have been found to effectively slow progression of kidney disease. It has been theorized that dual blockade of the renin-angiotensin-aldosterone system (RAAS) might prove even more beneficial, but these hopes have not been realized. Now a new trial published in the New England Journal of Medicine throws further cold water on the once-promising hypothesis.
In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, Linda Fried and colleagues randomized type 2 diabetics with proteinuric kidney disease already receiving the angiotensin-receptor blocker losartan to either the ACE inhibitor lisinopril or placebo. The trial was stopped early by the data and safety monitoring committee due to safety concerns and the low likelihood that the trial would be able to yield a significant difference in the primary end point.
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The European Medicines Agency said last week that it was initiating a review of the combined use of agents that block the renin-angiotensin system (RAS). The three classes of RAS-blocking drugs (ACE inhibitors, ARBs, and direct renin inhibitors) are used to treat hypertension and congestive heart failure.
The EMA said that the review was being performed to address concerns that combined RAS-blocking drugs could increase the risk for hyperkalemia, hypotension, and kidney failure when compared with a single agent. A recent meta-analysis of 33 clinical studies published in the British Medical Journal concluded that ”although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events… The risk to benefit ratio argues against the use of dual therapy.”
Franz Messerli, senior author of the BMJ meta-analysis, applauded the EMA action and said that “as usual the FDA is dragging its feet.”
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Giving an ACE inhibitor to people with peripheral artery disease (PAD) and intermittent claudication reduces pain and increases walking time, according to a new study published in JAMA. Currently the pharmacologic options for this patient population are few and have limited efficacy.
Researchers at three Australian hospitals randomized 212 patients with PAD to receive the ACE inhibitor ramipril or placebo for 24 weeks. Compared to the patients on placebo, patients on the ACE inhibitor had a mean 75 second increase in their pain-free walking time (156 seconds in the placebo group versus 229 seconds in the ramipril group, p<0.001) and a 255-second increase in their maximum walking time (259 seconds in the placebo group versus 512 seconds in the ramipril group, p<.001). The ACE inhibitor was also associated with improvements in other secondary measures of walking and physical quality of life.
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The enormous success of ACE inhibitors in hypertension and heart failure spurred hope that adding a second drug to block the renin-angiotensin system would yield improved outcomes. Although definitive evidence supporting dual blockade of the renin-angiotensin system has never been found, more than 200,000 patients in the US currently receive this therapy. Now a large new meta-analysis suggests that dual blockade results in no improvement in mortality but is associated with an increase in important adverse events.
In a paper published online in BMJ, Harikrishna Makani and colleagues at Columbia University and New York University performed a meta-analysis of more than 68,000 patients who were enrolled in clinical trials comparing dual blockade of the renin-angiotensin system with monotherapy. They found no significant difference between the groups for all cause mortality or cardiovascular mortality, although dual blockade was associated with a signifcant 18% reduction in hospital admission for heart failure:
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Adding a non-steroidal anti-inflammatory drug (NSAID) to dual antihypertensive therapy (a diuretic plus either an ACE inhibitor or an angiotensin receptor blocker) is associated with an increase in risk for kidney injury, according to a large new retrospective study published in BMJ.
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Novartis announced today the early termination of the ALTITUDE trial, which was testing the effect of the direct renin inhibitor aliskiren (Rasilez, Tekturna) in type 2 diabetics at high risk for cardiovascular and renal events. The action was based on the recommendation of the independent Data Monitoring Committee (DMC), after it found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months. Patients in ALTITUDE were randomized to receive aliskiren or placebo in addition to an ACE inhibitor or an angiotensin receptor blocker (ARB).
The company is also recommending that physicians not prescribe drugs containing aliskiren with either an ACE inhibitor or an ARB. Patients who are already taking a combination pill should be switched to an alternative anti-hypertensive regimen, according to the company.
The action represents a major setback for a drug that had once been thought to have blockbuster potential. Novartis said it was immediately ceasing all promotion of products containing aliskiren and was talking with health authorities about the implications of the findings.
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