Hypertension Insights With Drs. Messerli and Watson

Franz H. Messerli, MD; Karol E. Watson, MD, PhD


May 23, 2014

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Renal Denervation Dashed Hopes

Franz H. Messerli, MD: Good morning. I'm Franz Messerli, here in Washington, DC, at the American College of Cardiology (ACC) Scientific Sessions. I am Director of the Hypertension Program at Mount Sinai Roosevelt Hospital in New York and Professor of Medicine at the Icahn School of Medicine. Here with me is Karol Watson. Karol, why don't you introduce yourself?

Karol E. Watson, MD, PhD: I am Dr. Karol Watson. I am Co-Director of Preventive Cardiology at University of California at Los Angeles and also Director of the Barbra Streisand Women's Heart Center.

Dr. Messerli: The SYMPLICITY HTN-3 trial was just reported in the New England Journal of Medicine[1] and was also reported here at ACC.[2] That has kind of dashed our hopes -- has it not, Karol?

Dr. Watson: It has. Some of us were less optimistic, some more, but what it has done is shown that renal denervation did not significantly lower blood pressure, but it was safe. That is what I took away from it. What about you, Franz?

Dr. Messerli: That is very important. Safety certainly was documented. It was a bit surprising that heart rate did not move at all, and to my way of thinking, we have to question whether renal denervation actually happened in these patients.

Dr. Watson: Right -- heart rate did not fall, nor did blood pressure. It suggests that there was no real denervation.

Dr. Messerli: There should be a way to measure effectiveness and to characterize the patients a little better. There is also an issue with the standard deviations: They were tremendous.

Dr. Watson: Yes, they were big.

Dr. Messerli: We probably could design a study that would be more straightforward. As you may have heard, Medtronic is committed to continuing the program, and that should tell us something.

Dr. Watson: We could either take it as though renal denervation was shockingly ineffective or that sham control was shockingly effective. It does suggest that really good attention to blood pressure management with medications actually can get you a lot of blood pressure reduction.

Dr. Messerli: Most of these patients were on 4 or 5 medications, and as we both know, compliance is not easy to achieve. We do not know how many of these patients actually took their medicine throughout the trial. Even if they said they did, we know that this is not always the case.

Dr. Watson: Correct.

A Flurry of New Guidelines

Dr. Messerli: That is one issue, and another issue in hypertension has been the new guidelines. What is your take there, Karol?

Dr. Watson: A flurry of guidelines was released, some within weeks or days of each other, with some contradictions and some similarities. Now we have guidelines throughout the world. The Europeans,[3] the British,[4] the Canadians,[5] the Americans[6] have guidelines, and in general, they are similar. However, there are some key differences. One is the first recommendation of the new 2014 Eighth Joint National Committee[6] (formerly JNC 8) which said that we should loosen blood pressure goals in what they describe as the elderly (older than 60 years). Most of us take a bit of a different tack in terms of loosening blood pressure control and use the age of 80 as a cut-off. Doing it in patients older than 60 years doesn't make sense. What do you think?

Dr. Messerli: We have to give the committee some credit, though. When you look strictly at the evidence, we do not have good evidence that the blood pressure should be lowered to that extent. Nevertheless, we have solid evidence that blood pressure should be below 160 mm Hg. There is no question about that. That has been shown in the SHEP study,[7] the HYVET study,[8] and the Syst-Eur study.[9] There is rock-solid evidence for this, but how low we should go, and the age limit for when we can ease up a bit, has not been well documented. The Europeans say more than 80 years.

Dr. Watson: The Canadians say the same, and it makes sense because as you get older, several things happen. There is a much higher incidence of orthostatic hypotension. As we get older, our systolic blood pressure keeps going up, but after about age 55, our diastolic pressure starts going down. If the diastolic pressure is too low, it starts to compromise coronary perfusion. Many times when you are trying to drive down that systolic blood pressure in an elderly patient, you dramatically drive down the diastolic pressure as well. There is reason to believe that once the physiology is different, we should aim for looser goals, but that shift probably does not take place as early as age 60.

Dr. Messerli: There is absolutely no question. As you pointed out, there is a J-shaped curve, and if there is a J-shaped curve, it is much more pronounced for diastolic pressure and coronary perfusion than for stroke. For stroke you probably can go down to 120 mm Hg and still reduce the risk somewhat, but not for coronary heart disease. That is a very important issue here.

Dr. Watson: Exactly.

Dr. Messerli: The European Guidelines still promote the use of beta-blockers as first line therapy in all patients with hypertension. You can use an angiotensin receptor blocker (ARB), an angiotensin-converting enzyme (ACE) inhibitor, a calcium antagonist, a diuretic, or a beta-blocker as the first step. What do you think, Karol?

Dr. Watson: That was taken out of the British guidelines a while ago. Now it is no longer listed in the current American guidelines as a first step. There are some reasons for that -- some you may agree with and some you may not. The fact that the new guidelines have broadened our choice of initial antihypertensive therapy makes a lot of sense. They still endorse the use of beta-blockers as second- or third-line therapy if you need it, but they have not put them in the category of initial antihypertensive choices.

Dr. Messerli: That makes sense. Having said this, you want to consider patients who have ischemic heart disease, in whom you may use a beta-blocker. If such a patient has hypertension, then you could consider a beta-blocker as initial therapy, although I think we should not do a "2-for-1." You should treat ischemic heart disease on one hand and hypertension on the other, with drugs that have been shown to reduce morbidity and mortality for each condition.

Dr. Watson: We agree on the morbidity and mortality reduction.

The Demise of Dual RAAS Blockade?

Dr. Messerli: That is a very important issue. One thing that was in fashion over the past few years was dual renin-angiotensin-aldosterone system (RAAS) blockade. What do you think about that?

Dr. Watson: Several trials have looked at dual RAAS blockade with an ACE inhibitor plus an ARB, and although the initial enthusiasm was for the reduction in proteinuria,[10] the more recent trials have shown that the overall outcomes are equivalent and the adverse effects are greater.[11] We have not seen the benefits we had hoped for from dual RAAS blockade, and so the new guidelines suggest that we should not use an ACE and an ARB together.

Dr. Messerli: That is another good example of surrogate endpoint failure, right? Proteinuria goes down, but if anything, the rate of renal failure is higher in these patients.

Dr. Watson: It has gotten worse.

Dr. Messerli: We have to be careful with surrogate endpoint data.

Dr. Watson: Absolutely.

Dr. Messerli: In contrast, dual calcium channel blockade, in certain situations, is acceptable. We did an analysis of the data,[12] and you can use a dihydropyridine and a non-dihydropyridine under certain circumstances -- when, for instance, you have to avoid an ACE inhibitor or an ARB because of potassium issues. Dual calcium channel blockade is acceptable, but this is located at the surrogate endpoint (ie, blood pressure) and we do not have any outcome data.

Dr. Watson: Correct.

Dr. Messerli: We have to be very cautious here.

Which Drugs Are "No Longer in Fashion"?

Dr. Watson: The other thing that was surprising to some people about the new guidelines was that ACE inhibitors and ARBs were no longer recommended in patients with diabetes. The new guidelines say that in patients with chronic kidney disease, an ACE inhibitor or an ARB should be part of your antihypertensive regimen, but they no longer say that for diabetes.

Dr. Messerli: That is correct, and one can agree or disagree, but when you look at the ALLHAT study,[13] there was no nephroprotective effect with lisinopril. It is not an unreasonable decision if there is no hypertensive kidney disease or minimal kidney disease; then all the drugs are about the same. One more issue is that in black patients, ACE inhibitors are no longer in fashion.

Dr. Watson: That is correct. The new guidelines say that in non-black patients, your initial choice of antihypertensive therapy can include an ACE inhibitor, ARB, calcium blocker, or thiazide-type diuretic. In black patients, they say that the initial choice should be a thiazide-type diuretic or a calcium blocker. They have taken out the ACE inhibitor and the ARB. That might be a little premature. We know that in combination with diuretics, ACE inhibitors and ARBs are very effective in black patients, and they may have some potential nephrotoxic prevention benefits. There are certainly benefits in terms of coronary heart disease. I am not sure whether that alone should be taken into account. Certainly, the data on combining an ACE inhibitor or an ARB with a thiazide diuretic are very good. What do you think?

Dr. Messerli: I partially agree with the issue, insofar as ACE inhibitors cause angioedema rarely. Angioedema risk is distinctly higher in the black population so I would probably not start an uncomplicated black patient on an ACE inhibitor. I would consider an ARB in combination with a diuretic. That is still an excellent and efficacious combination in that population.

Dr. Watson: I agree with you.

Dr. Messerli: Karol, it has been a pleasure. There are a few fascinating issues in hypertension, and we will continue to explore them. Thank you so much.

Dr. Watson: I look forward to it.


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