Combination ACE inhibitor –ARB therapy “TOs and FROs of Researches Vs. Logics in Medicine” when Evidence-based Medicine Contradicts Experience-Based Medicine what should a clinician do ?

The renin-angiotensin-aldosterone system (RAAS) maintains BP via angiotensin II-induced vasoconstriction and aldosterone-mediated sodium retention in the collecting duct. Angiotensin-converting enzyme (ACE) inhibitors interact with the RAAS by inhibiting the formation of angiotensin II, causing vasodilation and decreased BP.

There are 2 important caveats to this observation. First, older patients as well as those with diabetes or chronic kidney disease or who are concurrently taking an ACE inhibitor, ARB, or NSAID are at increased risk for hyperkalemia. Second, if dual therapy consists of an ACE inhibitor plus an ARB (neither with spironolactone added), benefits in BP lowering are not supported by the evidence. Adding non-RAAS blockers to ACE inhibitor or ARB monotherapy lowers BP more effectively than both agents in combination.

Dual RAS blockade was first proposed in the early 1990s as a way to avoid the “escape phenomenon”;Escape phenomenon or aldosterone synthesis escape defined as :

 

  Incomplete suppression of angiotensin II,or The inability of ACE inhibitor therapy to reliably suppress aldosterone release, for example, in patients with heart failure or diabetes, usually manifested by increased salt and water retention, this latter sense may rather be termed refractory hyperaldosteronism) with ACE inhibitor monotherapy. . ARBs were initially developed because ACE inhibitors were associated with “escape.” That is, after initial blockade of the RAAS with ACE inhibitors (at the step of angiotensin I to II conversion), renin levels rebounded, and as a result, so did angiotensin II and aldosterone levels (the latter called aldosterone synthesis escape).

 

Plasma angiotensin II concentrations may increase during combination therapy, both as a result of the reactivation phenomenon described above that is sometimes seen with ACE inhibitors,and because of the reflex increase in angiotensin II seen during treatment with ARBs. However, the effect of such increases is negated by the AT1 receptor-blocking activity of ARBs. Furthermore, combination therapy may reduce the incidence of aldosterone escape associated with ACE inhibition. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), direct renin inhibitors, and aldosterone antagonists—which specifically block the renin-angiotensinaldosterone system (RAAS)—are a valuable adjunct in the treatment of organ pathologies complicated by hypertension, as well as a variety of heart conditions (eg, remodeling and failure) and kidney diseases (eg, diabetic renal disease
A further potential advantage of combination therapy is enhancement of the beneficial effects of kinins, including NO generation, as a result of both inhibition of kinin breakdown by ACE inhibitors and a possible effect of AT2-receptor stimulation during ARB therapy.

The rationale for combination therapy is further strengthened by the differential effects of ACE inhibitors and ARBs on insulin sensitivity. Both agents improve insulin sensitivity by increasing NO generation, which results in increased skeletal muscle blood flow and enhanced insulin signaling. In addition, as described above, certain ARBs can act as partial agonists of PPARgamma, thereby further increasing insulin sensitivity.

Indeed, studies in rats showed a synergistic effect on blood pressure with an ACE inhibitor combined with an ARB, and these results were encouraging enough for the medical community to make a remarkably quick transition to adopting dual RAS blockade in clinical practice.

The concept of dual RAS blockade was so appealing that effects on surrogate end points—lower blood pressure, less protein in the urine, and improved endothelial function—were accepted as free passes, obviating the need for evidence of an effect on hard end points such as lower rates of cardiovascular death or kidney failure. Currently, in the United States, about 1.5% of all patients on RAS blockers are currently receiving both an ACE inhibitor and an ARB.

In heart failure , the outcome benefits of adding the ARB candesartan to an ACE inhibitor  are recognized by  the FDA-approved license . some principles are as follows :
1- addition of a proven ARB such as candesartan or valsartan to established ACE inhibitor  therapy  is associated with improved outcomes in CHF , perhaps by treating  renin-angiotensin system ( RAS) escape from ACE inhibition .
2- Candesartan benefits can be found even in patients who are on higher than average ACE inhibitor  doses . Candesartan can benefits when added to prior Beta-blockade . whereas valsartan lacks such data .
3- In patients with LV systolic dysfunction who remain symptomatic on ACE inhibitors and Beta-blockers, ARBs can give added benefit though as an alternate to the addition of third –line aldosterone blockers .

4- In those patients with LV ejection fraction ≤40% , retrospective analyses  suggest  that candesartan added to prior ACE inhibition , B-blockade and aldosterone blockade could improve all-cause mortality . such “quadruple-therapy” may be offset by a marked increase in advers effects , especially worsening renal function and hyperkalemia and needs prospective trail testing . additionally note that the combination of an ARB with B-blockade has only been trial supported with positive outcome for candesartan .

In chronic renal disease with proteinuria, the combination of an RB with an ACE inhibitor reduces progression of proteinuria better than either drug alone according to an exhaustive review. the accompanying editorial  proposes  that monotherapy with either an ACE inhibitor or an ARB is appropriate for early –stage renal disease , reserving the combination for use when monotherapy fails to decrease proteinuria to less than 0.5. however , safety concern remain , with hyperkalemia the major danger .

No benefit to dual RAS blockade in meta-analysis
Already researches was notorious to stated that The study showed that dual blockade of the RAS improved left ventricular ejection fraction and reduced hospital admissions, but there was no reduction in all-cause mortality, coupled with a high rate of drug discontinuation due to renal effects and hypotension.
A large meta-analysis of randomized trials comparing dual blockade of the renin-angiotensin system (RAS) with ACE inhibitors and angiotensin-receptor blockers (ARBs) failed to show any benefit in terms of reducing mortality compared with monotherapy.

In fact, dual blockade of the RAS was associated with an increased risk of hyperkalemia, hypotension, and renal failure, as well as a significantly increased risk of drug withdrawal due to adverse effects. The 33 trials in the meta-analysis explored RAS blockade in patients with hypertension, diabetes, renal disease, or heart failure. Researchers are hoping their results are the final nail in the coffin when it comes to dual blockade of the RAS.
These are nephrologists that look at proteinuria, and there is no question that proteinuria diminishes when you add an ARB to an ACE inhibitor, although it would probably diminish just as much if you doubled the dose of the ACE inhibitor. For some reason or another, dual blockade of the RAS still has some magic attraction.