Circulation January 9, 2018 Issue

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Dr. Carolyn Lam: Welcome to "Circulation on the Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke‐National University of Singapore. Our featured discussion this week focuses on the new 2017 ACC/AHA high blood pressure guidelines, and the potential impact of these guidelines on the U.S. population. A must listen, coming right up after these summaries.

The first original paper this week provides insights into how extracellular matrix remodeling contributes to in‐stent restenosis and thrombosis. First author, Dr. Suna, corresponding author, Dr. Mayr, and colleagues from King's College London, implanted bare metal and drug‐eluting stents in pig coronary arteries with an overstretch and then harvested the stented segments up to 28 days poststenting for proteomics analysis of the media and neointima.

The authors found significant differences by proteomics in the extracellular matrix of coronary arteries after stent implantation. Most notably, an upregulation of aggrecan, a major extracellular matrix component of cartilaginous tissues that confers resistance to compression. In fact, this study provided the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting. This opens a door to consideration of aggrecanase activity as new drug targets that may alter extracellular matrix remodeling in the vasculature.

The next paper tells us that empagliflozin could address a significant unmet need in patients with chronic kidney disease. First and corresponding author, Dr. Wanner, from Wurzburg University Clinic in Germany investigated the effects of empagliflozin on clinical outcomes in patients with chronic kidney disease in the EMPA‐REG OUTCOME trial, where patients with type 2 diabetes, established cardiovascular disease, and an eGFR above 30 at screening were randomized to receive empagliflozin or placebo, in addition to standard of care.

In the current study, prevalent kidney disease was defined as an eGFR of less than 60 or urine albumin/creatinine ratio of more than 300 at baseline. In these patients, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo, reduced the risk of all‐cause mortality by 24%, and reduced the risk of hospitalization for heart failure by 39%, and the risk of allcause hospitalization by 19%.

The effects of empagliflozin on these outcomes were independent of renal function or albuminuria status at baseline. Furthermore, the adverse event profile of empagliflozin was similar across subgroups by renal function at baseline. Adverse events of particular concern in this population, such as urinary tract infection, acute renal failure, hypokalemia or fractures, lower limb amputations or hypoglycemia were not increased with empagliflozin compared to placebo.

The next study provides mechanistic insights into exercise intolerance in heart failure with preserved ejection fraction or HFpEF. First author, Dr. Houstis, corresponding author, Dr. Lewis and colleagues from Massachusetts General Hospital, investigated the mechanism of exercise intolerance in 79 patients with HFpEF and 55 controls referred for cardiopulmonary exercise testing who were also studied with invasive monitoring to measure hemodynamics, blood gases and gas exchange during exercise.

These measurements were used to quantify six steps of oxygen transport and utilization in each HFpEF patients, identifying the defective steps that impaired each one's exercise capacity. The authors then quantified the functional significance of each pathway defect by calculating the improvement in exercise capacity that a patient could expect from correcting the defect.

The authors found that the vast majority of HFpEF patients harbored defects at multiple steps of the pathway, the identity and magnitude of which varied widely. Two of these steps, namely, cardiac output and skeletal muscle oxygen diffusion were impaired relative to controls by an average of 27% and 36% respectively. Due to interactions between a given patient's defects, the predicted benefit of correcting any single defect was often minor. At the individual level, the impact of any given pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects.

The authors concluded that a personalized pathway analysis could identify patients most likely to benefit from treating a specific defect. However, the system properties of oxygen transport favor treating multiple defects at once, such as, with exercise training.

What are the potential benefits or risks of intensive systolic blood pressure lowering in individuals with a low diastolic blood pressure? Well, the final paper today tells us. In this study by first and corresponding author, Dr. Beddhu, and colleagues from Salt Lake City in Utah, a post hoc analysis of the SPRINT trial was performed. Remember that the SPRINT trial was a randomized control trial that compared the effects of intensive versus standard systolic blood pressure control in older adults with high blood pressure at increased risk of cardiovascular disease. The current post hoc analysis examined whether the effects of the systolic blood pressure intervention differed by baseline diastolic blood pressure.

The authors found that there were U‐shaped relationships of baseline diastolic blood pressure with the primary cardiovascular disease outcome and all‐cause death. However, the beneficial effects of intensive systolic blood pressure lowering on the primary cardiovascular disease outcome in all‐cause death were not modified by baseline level of diastolic blood pressure.

Increased risk of kidney events and serious adverse effects of the intervention were consistent across baseline diastolic blood pressure quintals. Therefore, there was no evidence that the benefit of intensive systolic blood pressure lowering differed by baseline diastolic blood pressure levels.

These findings suggest that the reason for the observed associations of worse outcomes with lower diastolic blood pressure was due to underlying processes, such as increased arterial stiffness that lead to a decline in diastolic blood pressure, rather than the level of diastolic blood pressure per se. Furthermore, lower levels of diastolic blood pressure within the ranges examined in SPRINT, should not be an impediment to intensive treatment of hypertension, at least in those without diabetes or stroke.

Well, that wraps it up for our summaries. Now for our feature discussion. The ACC/AHA guidelines for the management of hypertension in adults has really been a hot topic. Just published this year, and it really updates the seventh JNC report, which was published in 2003. Well, today's feature paper deals directly with a comparison of these two guidelines and how it may impact our practice.

I'm so pleased to have with us today the first and corresponding author of this paper, Dr. Paul Muntner, from University of Alabama at Birmingham and a very familiar wonderful voice, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome!

Dr. Paul Muntner: Hi. Thank you for having me.

Dr. Wanpen Vongpatanasin: Hi, Carolyn.

Dr. Carolyn Lam: Paul, could I ask for you to start by painting the differences between the 2017 ACC/AHA guidelines and the JNC 7? We understand you were part of writing the guidelines, so who better than to draw our attention to the main differences.

Dr. Paul Muntner: I think that the new guideline, the ACC/AHA guideline, it was fairly comprehensive included 15 chapters, so there's a lot of new information in the guideline, everything from a dedicated section on the measurement of blood pressure to aspects of patient care.

The manuscripts featured in "Circulation" in this issue is focused on, in the past, there's different blood pressure thresholds in the guideline for defining hypertension, as well as recommendations for antihypertensive medication treatments, as well as blood pressure goals.

As everyone probably knows form JNC 7, hypertension was defined as a systolic blood pressure greater than or equal to 140 mmHg and/or a diastolic blood pressure greater than or equal to 90 mmHg, versus in the 2017 ACC/AHA guideline, these were lowered to 130/80.

In terms of treatment recommendations, there's really a fundamental shift with the new guideline, where the new guideline focuses not just on blood pressure levels, but also on overall cardiovascular disease risk. So going to the new guideline, people are recommended treatment if their blood pressure is above 140/90 but also there's a group with a blood pressure in the 130 to 139 range for systolic blood pressure, of 80 to 89 mmHg for diastolic blood pressure, who are recommended treatment if they have a high cardiovascular disease risk.

Finally, I'll just finish with this last note is that blood pressure control for people taking antihypertensive medication is now 130/80 so a goal blood pressure for people taking antihypertensive medication is systolic blood pressure less than 130 mmHg, and a diastolic blood pressure less than 80 mmHg.

Dr. Carolyn Lam: That was beautifully explained. Paul, I just really loved table 1 of your paper, and I want to refer our audience to it. It so nicely summarizes the differences between the 2017 guidelines and JNC 7. At risk of oversimplifying, when you compare the two in this approach, it's sort of comparing using a cardiovascular risk in conjunction with blood pressure‐type approach with a blood pressureonly number approach, isn't it?

Dr. Paul Muntner: Right. I think that's a key important piece of the new guideline and really CVD risk is used in conjunction with blood pressure levels to guide the recommendation to initiate antihypertensive medication. This decision was based on a wide variety of data from randomized trials, observational studies, as well as simulation or economic analyses that consistently showed the benefits of considering an individual's overall cardiovascular disease risk and providing effective and efficient treatment for lowering blood pressure.

Dr. Carolyn Lam: Right. And you analyzed the impact of this in the NHANES data in today's paper. Could you tell us a bit more about that?

Dr. Paul Muntner: The U.S. National Health and Nutrition Examination Survey, or NHANES, provides an opportunity to generate national representative point estimates on the prevalence of hypertension and treatment recommendations. So we're able to use data on about 9500 U.S. adults. Each person came in for a clinic examination where they had their blood pressure measured three times, and they were asked about their use of antihypertensive medication. What we found was the prevalence of hypertension, or the percentage of U.S. adults with hypertension according to the new guideline, is about 46%, which compares to 32% according to the JNC 7 guideline, so really a big increase in the prevalence of hypertension of about 14%. However, by using the combination of risk and blood pressure, we're not recommending treatment for everyone with hypertension but rather people with hypertension with very high blood pressure as well as those at high cardiovascular disease risk.

So antihypertensive treatment, pharmacological antihypertensive treatment, is now being recommended for about 36% of U.S. adults compared to 34% of U.S. adults according to JNC 7. The rest of the people with hypertension are recommended nonpharmacological therapies; exercise, diet, alcohol reduction, weight loss for people who are overweight and obese.

Really, it's an opportunity to treat people with pharmacological therapy if they're high risk. Then for people who aren't high risk, there's an opportunity for nonpharmacological therapies, so they can, hopefully, prevent the need for further treatment.

Overall, this equates to about 103 million U.S. adults with hypertension, so it's a very large number. However, only about 82 million of these individuals are recommended pharmacological antihypertensive treatment, so there's a big portion of the U.S. population who have hypertension, have high blood pressure, yet we think would benefit from nonpharmacological therapy.

Dr. Carolyn Lam: Wanpen, could I get you to chime in on what you think of the clinical implications of today's paper?

Dr. Wanpen Vongpatanasin: I think that this paper gives us at least reassurance that although we have 30 million more people with hypertension now, not all of them have to be started on medication right away. But it also put an emphasis on cardiovascular risk assessment, which we as the cardiologist are already doing this on a regular basis. It is a major step forward to incorporate cardiovascular risks as another way to gauge how people should be treated intensively, which we like that aspect of it.

Dr. Carolyn Lam: I agree. I think it's reassuring because most people think, "Oh, my goodness. We have got so much more hypertensives to manage." But then it tells us that a restratified approach really keeps it manageable, I suppose. But Wanpen, did you have some specific concerns or questions?

Dr. Wanpen Vongpatanasin: We look at the people who by JNC 7 calls prehypertension, which it's now some of them turn out to be a stage 1 hypertension. The question I have for Paul is that even though guidelines call for nonpharmacologic treatment first, the guidelines said give a try from three to six months, but what happens after that if they're still not reaching the goal?

Would people on the guidelines propose drug treatment eventually because, as you know, nonpharmacology treatment is easier said than done. Even though you might be able to tackle some aspect of it, but I doubt you can tackle everything; exercise, diet, sodium, weight loss all at the same time in a three to six month period.

Dr. Paul Muntner: It's a great question and it's something that the guidelines really spent a lot of time considering and reviewing the evidence. First, what the recommendation is that we recommend nonpharmacological intervention as you mentioned and the re‐evaluation. If the person's blood pressure remains in the stage 1 hypertension range and they're not a high cardiovascular disease risk, then they are recommended to continue attempts at the nonpharmacological interventions.

I've been asked several times since the guideline has been published, "What, are we supposed to just wait until people become high risk?" And my viewpoint on this is, it's hard enough to get people to adhere to their medications currently, let's be judicious about this, focus on the high‐risk people, and maybe if we can communicate with people that have high‐risk for cardiovascular disease, we can work with patients to improve medication adherence and really focus on the low‐risk people in preventing the need for lifelong therapy.

Dr. Wanpen Vongpatanasin: That's great, I think that's really helpful in clarifying this point. Because even if you say that 30 million doesn't need to be started on the drug right away, that eventually have to be started on drug in six months, I think that doesn't really give us a reassurance but, obviously, we still have to continue to

work on these patients who are on the fence of needing pharmacology intervention.

Dr. Paul Muntner: Right. I think what's interesting here is a lot of people since the guideline has been published have said to me, "Now this is done." I said, "No. Now we're really just starting. Now is the most important part of the guideline, which is implementation." And how are we going to implement the guideline, which, as we were just discussing, isn't just about initiating pharmacological therapy, but it's also about the nonpharmacological therapies as well as medication adherence and all these other issues that are in the guideline, proper measurement of blood pressure, etc.

I think that now is going to be the most important time to really have a big impact on our patients' lives by really using the evidence and now that it's in the guideline, we're using the evidence to direct treatment appropriately.

Dr. Carolyn Lam: Indeed, Paul. Just one thing. Along the lines of implementation, how about the issue of the lower target BP, to treat to? What did your study from NHANES show about that, numbers reaching targets, and do you see that as an issue?

Dr. Paul Muntner: It's an interesting question because the findings from our study found that it's currently over half of U.S. adults according to the new guideline, over half of U.S. adults on antihypertensive medication, have blood pressure above the goal in the new guideline. So in our study, 53% of U.S. adults taking antihypertensive medication had a blood pressure above 130/80. This represents an increase from the JNC 7 guideline of people with blood pressure above 140/90, of course, of about 14.4%. According to our estimates, there are about 8 million U.S. adults who are going to be recommended more intensive antihypertensive medication.

The blood pressure of less than 130/80 is a uniform goal for all people taking antihypertensive medication. This comes from several meta‐analyses that have consistently shown the cardiovascular and mortality risk reduction associated with achieving a blood pressure of less than 130/80. I think there's very firm evidence to stand on.

One interesting thing from the guidelines, it's in one of the tables, and I think it's a very important point to make, is that a lot of people who have above goal blood pressure, according to the new guideline, they're only taking one or two classes of antihypertensive medication. The vast majority of them are not taking multiple classes of antihypertensive medication, so we feel that these therapies can be optimized and we're not going to be pushing people into antihypertensive polypharmacy but rather they can receive substantial risk reductions without really giving them too many additional pills.

Dr. Carolyn Lam: Wow. Really about implementation. Wanpen, did you have any other comments before we close?

Dr. Wanpen Vongpatanasin: Yes, I think that is really interesting to see also with these guidelines how is this going to be embraced to the rest of the world. Actually, prior to this guideline, at least hypertension control rate in the U.S. is better than most countries, European countries, as well as in Asia. But now even lowering the bar, we use the same criteria for the rest of the world, that would be a lot worse control rate than now. I think it will be challenging, not only in this country but throughout the world.

Dr. Paul Muntner: That's a great point. Obviously, these guidelines are U.S. guidelines, however, new European guidelines should be coming out in 2018, is what I've heard. I think that even though these guidelines were developed by the American College of Cardiology and the American Heart Association, the data that we're using really comes from worldwide evidence. The evidence didn't stop at the borders. A lot of the evidence that was used in choosing the blood pressure levels to define hypertension, the blood pressure levels to recommend pharmacological interventions, as well as the blood pressure goals do come from other countries. A lot of data from Asia, Europe, Australia, so I think that the data used in these guidelines should be generalized when it's out of the United States.

I think there may be challenges with implementing these guidelines in different settings, and, obviously, a lot of things will have to be tailored to where they will be implemented. However, the overall goal is to reduce the burden of cardiovascular disease and renal disease related to hypertension and, hopefully, that can be a worldwide goal.

Dr. Carolyn Lam: What a great reminder. It is worldwide data, worldwide evidence for a worldwide problem. Well, listeners, you heard it right here on "Circulation on the Run." Thank you so much for joining us today and don't forget to tune in again next week.

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