Experts Debate Value of Measuring Renin Levels to Guide Hypertension Therapy

August 19, 2010

August 18, 2010 (New York, New York) — The fact that hypertensive subjects respond differently to the many available classes of blood-pressure–lowering drugs is highlighted in three studies published online August 18, 2010 in the American Journal of Hypertension, which provide new information on this subject [1,2,3]. But how to go about deciding who should get which medicines is still somewhat controversial, as evidenced by two accompanying editorials [4,5].

Sure, you can get a little more prediction with measurement of plasma renin activity, but I don't think it's a big enough bang for the trouble.

One of the reasons for this heterogeneity of response is differing levels of the hormone renin in different patients, something that has been known for 40 years. One of the editorials says information from the new studies points to the need to measure renin levels routinely in all patients, while the other says it has a role to play only in those who are harder to treat. But others still, including the lead authors of two of the new studies, believe renin is too impractical a measure to use at all.

Dr Stephen T Turner (Mayo Clinic, Rochester, MN) told heartwire that he does not believe renin testing is necessary. "The method for measurement of plasma renin is pretty ancient and cumbersome," he said, and "not something you can get an answer to quickly. If all you want to do is predict response [to antihypertensive therapy], race and age are pretty good. Sure, you can get a little more prediction with measurement of plasma renin activity, but I don't think it's a big enough bang for the trouble."

Four Major Types of Hypertension; Renin Levels Predictive of Response

It has been known for many years that people with hypertension respond differently to blood-pressure–lowering drugs, based on the landmark work of Dr John H Laragh (Weill Cornell Medical College, New York, NY) and colleagues during the 1970s, Turner explained. Based on this research, there appear to be four major types of hypertension defined by their pathophysiology: low-renin hypertension, constituting around a third of hypertensives; medium/high-renin hypertension, representing more than a third of all those with hypertension; "resistant" hypertension, requiring more than three antihypertensive drugs; and secondary hypertension, occurring in renovascular and endocrine conditions.

It was Laragh et al who first advocated the measurement of plasma renin activity to match the characteristics of an individual's hypertension, an idea that was largely rejected by practicing physicians at the time, Turner says. Low-renin hypertension usually responds favorably to sodium volume-depleting drugs such as thiazide diuretics, while medium/high-renin hypertension responds very well to agents such as ACE inhibitors, angiotensin-receptor blockers (ARBs), and beta blockers, all of which block plasma renin activity.

In his new paper, Turner and his colleagues have evaluated predictors of blood-pressure response in 363 men and women with primary hypertension; race, age, plasma renin activity, and other characteristics were assessed to quantify their contributions to prediction of BP response. They show, for the first time, that renin levels after treatment with monotherapy were still predictive of response, something that had not been appreciated before.

"It used to be thought that renin levels were only informative in 'virgin' patients who had never been treated," says Turner, "but most people who walk into my office are on one drug and it's not working. However, our data say that yes, renin levels can still help you."

They also showed that plasma renin activity consistently contributed to prediction of systolic and diastolic BP responses to each drug administered as monotherapy and add-on therapy and that the predictive effects were independent of race, age, and other characteristics.

Nevertheless, Turner maintains that routine renin testing is unwarranted. "Why do you need to measure renin when you can just look at somebody and note their birth date? Any additional benefit would be marginal. Academic doctors might think this is pretty cool, but I'm not sure it would cut it with third-party payers. It becomes an issue of whether you really need this, and I don't think there is any consensus committee worldwide that has said you need to make this measurement," he adds.

"Remarkable" Observations of Pressor Responses to Drugs

In the second paper, Dr Michael H Alderman (Albert Einstein College of Medicine, Bronx, New York, NY) and colleagues assessed pressor responses to different types of antihypertensive drugs when 945 patients were given either a diuretic or calcium-channel blocker (CCB) (n=537) or a beta blocker or ACE inhibitor (n=408). Plasma renin activity was categorized by low, middle, and high tertiles, and a systolic blood-pressure rise of 10 mm Hg or greater was considered a pressor response.

Prescription of the 'wrong' drug, eg, a renin blocker, for low-renin patients, could trigger a pressor response that could undermine the whole premise of antihypertensive treatment.

They showed that a pressor response to antihypertensive monotherapy is not rare and is not the result of chance alone; rather, patients with the lowest plasma renin activity are at the highest risk of a pressor response when prescribed an antirenin drug (ie, beta blocker or ACE inhibitor). But it is also important to appreciate that a 10-mm-Hg or greater increase in systolic BP can occur with any antihypertensive drug and at any level of plasma renin activity, they note.

In one of the editorials, Dr Curt Furberg (Wake Forest University School of Medicine, Winston-Salem, NC) says these observations "are quite remarkable. We urgently need to understand the clinical relevance of this observation. Prescription of the 'wrong' drug, eg, a renin blocker for low-renin patients, could trigger a pressor response that could undermine the whole premise of antihypertensive treatment." And Furberg wonders, "Does this pressor response increase the risk of stroke, myocardial infarction, and congestive heart failure?"

Will This Affect the Use of Fixed-Dose Combinations?

Furberg also questions the rationale of initiating treatment using fixed-dose combinations of antihypertensives, which he says may be "of limited value" in the wake of the findings by Alderman et al. "A pressor response to one of the components might interfere with the antihypertensive effect of the other, leading to the further addition of unnecessary drugs."

But Turner questions this assumption, "It's a theory and it's plausible, but it's kind of a hard sell. What's the evidence for that?"

And the lead author of the third study, Dr Ajay K Gupta (Imperial College London, UK), also takes issue with Furberg's stance on this: "I think this is a very far-fetched statement. Fixed-dose combinations are the future," Gupta told heartwire , stating that it has been "clearly shown" that they improve compliance, resulting in further blood-pressure lowering that is "very significant."

But Furberg commented to heartwire : "Why did drug companies come up with fixed-drug combinations? It's a commercial issue. Stepped care has always been the recommended approach for any medical condition. You don't start with multiple drugs--although there are exceptions such as AIDS--but here you start with one. If you don't take the renin [level] before treatment and you get a good response, then you don't need to worry about renin. If the BP is not lowering or is going up, you obviously picked the wrong one and then you can switch. But if you start with a fixed-drug combination, you have lost the opportunity to tailor treatment to the underlying condition."

Also, he says, "I'm looking at it from a cost-effectiveness point of view. You should start by picking the right drug to help keep costs down and then you don't need fixed-dose combinations. The cost of a renin test is a fraction of what the drug cost is. A renin-test–guided treatment is rational and shows that better BP control can be achieved without increasing the number of antihypertensive agents."

Ethnic Differences in Response in ASCOT-BPLA

Gupta's new paper examines the role of ethnicity in predicting BP response to both first- and second-line antihypertensives, based on data from the ASCOT-BPLA study. This is one of the first attempts to look extensively at differences in response among different ethnic groups to second-line therapy, Gupta says.

BP response to atenolol and amlodipine monotherapy differed among the three ethnic groups studied: Europeans, black Africans, and South Asians. For the first time, Gupta et al showed that South Asians had a greater response to adding perindopril to amlodipine as second-line therapy compared with whites, while black patients had a lesser response.

Our paper shows that ethnicity does provide a parameter to personalize medicine for the majority of individuals; it should not be discounted.

"Our paper shows that ethnicity does provide a parameter to personalize medicine for the majority of individuals; it should not be discounted," Gupta told heartwire . "We found important differences in BP responses among ethnic groups to both first- and second-line antihypertensives."

Gupta says he would start with a CCB in black patients, then add in a diuretic before further adding an ACE inhibitor. In South Asians, an ACE inhibitor followed by a CCB would be his choice for therapy, while in whites it would be the other way around. "Having said that, most people need two medicines," he says.

Turner agrees: "Most people will require two drugs to optimally control their blood pressure: one should be a diuretic and one should be some other drug, and those other drugs are generally ones that inhibit the renin-angiotensin [RAS] system, so it becomes somewhat moot [to test renin]."

But Is Renin Still Needed? Opinion Is Divided

In his editorial, Furberg says the findings of Gupta et al "indirectly support the Laragh classification." African Americans have, on average, lower renin compared with whites and increased salt sensitivity. But he maintains that the reliance on ethnicity for selection of antihypertensive agents "appears limited. A more productive method would be to stratify hypertensive patients based on their plasma renin levels."

New national and international treatment guidelines should recommend stratification of hypertension based on plasma renin activity, preferably prior to the start of treatment, states Furberg.

Would [renin] be a good enough marker for all people, everywhere in the world? I don't know. The studies need to be done.


But Gupta contests this conclusion. "Ethnicity may be a crude marker, and renin may be more specific, but there is a cost involved to testing renin. Would it be a good enough marker for all people, everywhere in the world? I don't know. The studies need to be done."

In response, Furberg told heartwire : "Of course when you question the way people have practiced medicine for years, they get defensive. Also, many doctors are close to industry. I'm not saying we have to accept renin testing tomorrow, but it should be considered, so let's discuss it."

In the other editorial accompanying the new studies, Dr Morris J Brown (University of Cambridge, UK) argues that the role of renin measurement may be reserved "to detect the extremes and to reach rational treatment in those not controlled by standard combination."

Brown says the heterogeneity of response to antihypertensives "is not in doubt," but given that most people lie between the extremes of good and poor response to individual drugs, the interesting question now is "whether routinely to start with combination in order to preempt compensatory responses; unpublished data suggest 'yes,' " he concludes.

Turner and colleagues and Alderman and colleagues declare no conflicts of interest. Gupta declares no conflicts of interest; disclosures for the coauthors are listed in the paper. The editorialists declare no conflicts of interest.