High Blood Pressure Patients — Meta-Analysis Shows that Dual Blockade of the Renin-Angiotensin System Does Not Reduce All-Cause Mortality — and Comes at the Price of Subjecting Many Patients to Noticeably Higher Risks for Hyperkalemia, Hypotension, and Renal Failure

29 January 2013

Citation — to the study

Harikrishna Makani, Sripal Bangalore, Kavit A. Desouza, Arpit Shah, and Franz H. Messerli, Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials, British Medical Journal 346: f360, doi: 10.1136/bmj.f360 (early online publication, 28 January 2013)

Who this essay is for

High blood pressure patients:

who are taking two blood pressure reducing drugs,

both of which are aimed at the reducing activity in the body’s “renin-angiotensin” system.

There are reportedly 200,000 of these people in the United States alone.

Medically knowledgeable patients will immediately recognize whether they are in this group. Most people will not. Yet, all patients who fall into this “dual blockade” group need to discuss the study’s results with their doctors.

For the “can’t wait” reader — summary of the study’s conclusion

Based on their meta-analysis of other studies, the authors 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 such as hyperkalaemia, hypotension, and renal failure when compared with monotherapy.

The overall risk to benefit ratio argues against the use of dual therapy.

© 2013 Harikrishna Makani, Sripal Bangalore, Kavit A. Desouza, Arpit Shah, and Franz H. Messerli, Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials, British Medical Journal 346: f360, doi: 10.1136/bmj.f360 (early online publication, 28 January 2013) (at Conclusion) (paragraph split)

What is the renin-angiotensin system — and why do we care?

Wikipedia does an outstanding job of simplifying complicated physiology:

The renin–angiotensin system (RAS) or the renin–angiotensin–aldosterone system (RAAS) is a hormone system that regulates blood pressure and water (fluid) balance.

When blood volume is low, juxtaglomerular cells in the kidneys secrete renin directly into circulation. Plasma renin then carries out the conversion of angiotensinogen released by the liver to angiotensin I.^[2]

Angiotensin I is subsequently converted to angiotensin II by the enzyme angiotensin converting enzyme found in the lungs.

Angiotensin II is a potent vaso-active peptide that causes blood vessels to constrict, resulting in increased blood pressure.

Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which also increases blood pressure.

If the renin–angiotensin–aldosterone system is too active, blood pressure will be too high.

There are many drugs that interrupt different steps in this system to lower blood pressure. These drugs are one of the main ways to control high blood pressure (hypertension), heart failure, kidney failure, and harmful effects of diabetes.^[3]^[4]

We see that “ACE” converts one of the body’s chemicals (angiotensin II) into a molecule that raises blood pressure:

(i) directly — by making the diameter of certain blood vessels smaller

and

(ii) indirectly — by getting the kidneys to produce another chemical that makes the kidneys increase the volume of fluid in the blood vessels.

When we make the blood vessel “hose” narrower, fluid pressure inside will go up.

And when we pump more fluid into the same hose, pressure also rises.

When we do both, blood pressure increases still more.

In people who already have high blood pressure, that is obviously bad.

“How do I recognize whether I am on one or more of these drugs?”

The drugs at issue are called:

(a) angiotensin converting enzyme (ACE) inhibitors

and

(b) angiotensin receptor blockers.

The first prevents or reduces formation of an enzyme called “antiotensin converting enzyme.”

And the second attaches to the cell receptors that ACE is supposed to “hook up” to. With the blocking drug molecule in place on the cell’s receptor, the enzyme cannot latch onto the cell — so it cannot raise your blood pressure.

What is “dual blockade” in the renin-angiotensin context?

Dual blockade, as the study authors use the term, just means that your doctor is using two drugs to attack the pressure elevating components of the renin-angiotensin system.

In most cases, this means that the physician is using an ACE inhibitor and an angiotensin receptor blocker. But some doctors do much the same thing by using (a) two ACE inhibitors, or (b) two angiotensin receptor blockers, or (c) an ACE inhibitor or angiotensin receptor blocker and a renin inhibitor:

The concept of dual blockade of the renin-angiotensin system originated from an experimental model purporting to show a “synergistic” effect between angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers.

Despite a lack of solid evidence on the safety and efficacy of dual blockade of the renin-angiotensin system this type of therapy has been mentioned in several sets of guidelines.

Thus dual therapy was commonly used in patients with hypertension and with diabetes or proteinuria [protein in urine, indicating kidney damage], or both and also to a lesser extent in those with heart failure resistant to treatment.

Even patients with uncomplicated essential hypertension [high blood pressure by itself] were not entirely able to escape this fashionable trend.

In the United States more than 200 000 patients are currently treated with dual blockade of the renin-angiotensin system, most of them by the combination of an angiotensin receptor blocker and ACE inhibitor (70%).

Some other combinations are also used, such as two ACE inhibitors (15%), two angiotensin receptor blockers (5%), and ACE inhibitors or angiotensin receptor blockers in combination with a direct renin inhibitor (8%).

The long term efficacy and safety of dual blockade is not, however, well defined.

Why using “dual blockade” of the renin-angiotensin system seemed like a good idea

Hypothetically, giving high blood pressure patients both of these drugs would provide a “double drug whammy” that should be more effective than using just one drug by itself.

The inhibitor prevents significant amounts of the enzyme from being produced. And, somewhat metaphorically, the blocker prevents what enzyme is left from getting to the cells that evolution “designed it” to control.

To see whether dual blockade works as advertised, the team looked at the statistics uncovered by a host of other studies (meta-analysis)

The team looked at 33 randomized, controlled, and pertinent studies that were published between 1990 and August 2012. These involved 68,405 patients.

However, each of the following questions required culling through these 33 to find the studies that were pertinent to the specific issue.

Findings, 1 versus 2 drugs — all cause mortality (meaning deaths from any cause)

The team wanted to find out whether 2 drug blockade had any advantage over using only 1 drug, with regard to lowering the risk of death from any cause.

They analyzed 7 trials that involved 56,824 patients.

Of these, 21,638 patients had been on 2 drugs — and 3,314 died (15.3 percent).

The remaining 35,186 people had been on 1 drug — and 5,286 died (15.0 percent).

The team concluded that being on 2 drugs (as opposed to 1) did not reduce the risk of dying.

In fact, the risk of dying was slightly elevated (by about 7 percent) in the patients, who did not have heart failure at the start of the studies.

Findings, 1 versus 2 drugs — cardiovascular mortality (meaning deaths from heart attacks and cardiovascular disease)

If there was no difference in deaths attributable to any cause, might 2 drug therapy have had a favorable effect at least on the risk of specifically dying from cardiovascular disease?

No.

Findings, 1 versus 2 drugs — hospital admissions for heart failure

Did 2 drug therapy help reduce the number of hospital admissions for heart failure?

Yes, by 18 percent. With most (but not all) of the effect coming for those who started out with heart failure.

“Okay, Pete, we’ve seen that dual blockade doesn’t help to reduce mortality, but it does reduce hospital admissions for heart failure — what’s the problem?”

Elevated health risks, as a result of using 2 drugs where 1 might do.

Read on.

Safety risks, 2 versus 1 drug — hyperkalemia (too much potassium in the blood)

Hyperkalemia can be deadly.

The team’s meta-analysis of previous studies indicated that dual therapy increased the risk of too much potassium in the blood by 55 percent. And that was true in people with or without heart failure.

Safety risks, 2 versus 1 drug — hypotension (too low blood pressure)

A 2 drug blockade increased the risk of low blood pressure by 66 percent, as compared to using only 1 drug. It didn’t matter whether the patient had heart failure or not.

Safety risks, 2 versus 1 drug — renal failure (kidney failure)

Dual drug therapy elevated the risk of kidney failure by 41 percent in the heart failure group — but not in patients who did not have heart failure.

Safety risks, 2 versus 1 drug — withdrawal from therapy due to side effects

Patients were 27 percent more likely to withdraw from blood pressure treatment, when they were put on 2 drugs as opposed to 1.

Scientific caveats

The authors caution readers that their study suffered from the limitations generally applicable to meta-analyses.

For example, they couldn’t know whether patients had actually done what the individual studies said they did.

And their included studies involved different methodologies, doses, study durations, safety definitions and outcomes, and demographics. Biases in all of these were possible.

Yet:

Despite all the limitations, this is the most comprehensive analysis evaluating the safety and efficacy of dual blockade of the renin-angiotensin system.

Despite significant heterogeneity among the studies, there was no evidence of publication bias visually and by Egger’s test. The results were fairly consistent among various subgroups.

The moral? — What seemed like a good medical idea may not be for large numbers of patients

If you are on two drugs, both aimed at the renin-angiotensin system, you should mention this study to your treating physician:

The overall risk to benefit ratio argues against the use of dual therapy.

The authors’ conclusion emphasizes a point that I repeatedly make. Medicine is frequently (and often unavoidably) unscientific, subject to clinical fashion, and increasingly influenced by varieties of financial and research bias.

Patients who educate themselves are in a better position to interact competently with their medical providers.

Uncertainty is the name of the game, more often than most people suppose.

PeteFree.com

High Blood Pressure Patients — Meta-Analysis Shows that Dual Blockade of the Renin-Angiotensin System Does Not Reduce All-Cause Mortality — and Comes at the Price of Subjecting Many Patients to Noticeably Higher Risks for Hyperkalemia, Hypotension, and Renal Failure