The ability to block the renin-angiotension-aldosterone system (RAAS) is a wonderful advance in the practice of medicine. With two parallel avenues of attack available, the angiotensin converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs), it seems natural to combine them for more effective blockade.

But the ONTARGET trial, which followed hypertensive subjects on an ACE inhibitor (ramipril), on an ARB (telmisartan), and on the combination, has well and truly set the cat among the pigeons. ONTARGET’s finding that ACE inhibitors and ARBs taken together actually increased the composite outcome of dialysis, creatinine doubling, or death has brought a swift reversal in the perception of ACE/ARB combination therapy. The Heart and Stroke Foundation of Canada is now recommending against it, noting that perhaps 175,000 Canadians have been taking such a combination.

But only 30% of patients can be brought down to target with one drug alone. So what is the best combination for significant hypertension?

• First, take ONTARGET’s results with a pinch of salt when it comes to nephropathy. As the authors have acknowledged, ONTARGET’s results are a poor guide to the treatment of hypertensive patients who already have overt nephropathy. These made up just 3% of trial subjects, and they actually showed a nonsignificant trend towards lower renal risk on the combination.
• So for most patients, avoiding the ARB/ACE inhibitor combination is wise, but for the small subgroup with overt nephropathy and albumin excretion > 1 g/day, nephrologists may well continue prescribing both.
• What about the new direct renin inhibitors (DRIs)? Can they be combined with another RAAS blocker? They’ve been shown to lower blood pressure and decrease proteinuria both alone and in combination therapy, but we lack powerful studies combining them with ARBs or ACE inhibitors and looking at renal outcomes as well as vascular protection. For now, pick one RAAS drug at a time.
• One aspect of ONTARGET that’s been little mentioned is the high dropout rate, with 23% of the ramipril group, 24.5% of the telmisartan group, and 29.3% of the combination group discontinuing medication. The most prominent adverse effect was a benign but annoying cough. In fact, about half of Ontario hypertensive patients discontinue therapy. This may be a more powerful argument than kidney risk for keeping treatment simple.
• And yet, we know that most patients’ hypertension isn’t controlled by single therapy. My current three-drug combination for difficult hypertension includes a diuretic with an ACE or ARB, and a long-acting calcium channel blocker.