DR. IZZO: Another point worth making about risk reduction is related to the geometric nature of risk and risk reduction and the “20/10 rule.”8 At a systolic BP of 170 mm Hg, the overall cardiovascular disease risk is about 4x greater than a systolic of 130 mm Hg. Reducing the systolic from 170 to 150 mm Hg has the potential to reduce the relative risk by 50% (to 2x); going from 150 to 130 mm Hg lowers the risk to 1x overall, a 75% risk reduction from the 170 mm Hg baseline in this example. In this sense, the main benefit is getting the person out of the higher risk category, Stage 2 hypertension. The first few millimeters of mercury are the most important. Maybe this justifies the higher targets a little bit too but it’s hard to argue against the principle of “lower is better.”
DR. MOSER: We have discussed treatment targets and it appears that we disagree generally with the change from 140 to 150 mm Hg as a target in the elderly. We seem to have decided that the target BP of 140/90 mm Hg is reasonable, and perhaps the change in targets in treating the diabetic might also be reasonable, although if you could get to 130/80 mm Hg, that’s fine. I agree with Dr. Izzo, the lower the better.
I think now we probably ought to address how to get there. If you look at the JNC 8 protocol of both the treatment of lower and the high-risk patient, it’s almost exactly the same as in JNC 7. The proposed algorithm for treatment does not contribute much that is new to the clinician’s ability to treat this disease effectively. Perhaps that is because specific therapy has not changed much in the past 5–8 years. We may have learned more about how to use certain therapies, but the actual medications haven’t changed much: the specific medications recommended are almost exactly the same as in JNC 7, except for the addition of chlorthalidone and indapamide.
DR. IZZO: Well, there is one difference: thiazide-type diuretics, dihydropyridines, and ACE inhibitors (or ARBs) are now referred to as “preferred drugs,” as was first suggested in our New York State Medicaid hypertension guideline in 2011.9 We defined a preferred agent as one with appropriate efficacy and safety that is also proven to lower cardiovascular event rates. I’d be interested in the opinions of this group with regard to treatment issues and also to the specific issue of whether beta blockers were unduly excluded.
DR. BASILE: I salute JNC 8 in leveling the playing field when they suggest that it is the amount of BP reduction achieved that is more important than the initial drug, but when you look at the outcome evidence from clinical trials for stroke as well as cardiac and renal disease, you can feel very comfortable using a renin-angiotensin system (RAS)-blocking drug, either an ACE inhibitor or an angiotensin receptor blocker (ARB), or a thiazide-type diuretic or a CCB.
I’m somewhat concerned that they lumped all CCBs together because I do think there’s more evidence of benefit for the dihydropyridines or the “pines” in hypertension than the other subclasses (diltiazem and verapamil). But I like the fact that 4 major classes are now looked at as being equal for initial therapy, even in diabetics, unless they have CKD. Unless they have CKD, JNC 8 very appropriately recommends that it’s BP reduction rather than the RAS blockade that translates into improvement in outcomes. However, for the diabetic with CKD, we would recommend an ACE or an ARB as a first drug. As for the beta blockers, they do not have the level of evidence that the thiazides have had, as most trials used once-a-day atenolol as their beta blocker. We just don’t know how some of the newer beta blockers would have stacked up to the other antihypertensive agents on clinical outcomes for those with hypertension without concomitant issues.
DR. IZZO: Dr. Gradman, as a card-carrying cardiologist, wouldn’t you be thrown out of your business if you failed to advocate for beta blockers?
DR. GRADMAN: To some extent that’s true, but the guidelines that we’re talking about are a broad-brush approach. JNC 8, based its opinion regarding the first-line use of beta blockers on one study: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial,10 which found a lower relative risk of stroke with losartan compared to atenolol. For cardiologists, beta blockers remain an essential component of treatment in the majority of patients with coronary disease, angina pectoris, and heart failure, with or without hypertension, and in patients with arrhythmias, such as atrial fibrillation. In the case of post myocardial infarction, though, it is unclear if the benefit persists, especially after 2 years.
Another criticism I have of the guidelines is that they lump all drugs from each class together. That’s especially problematic for CCBs and for beta blockers. There’s still some discussion about the variable effects of different beta blockers on glucose tolerance, side effect profile, vascular tone, and other properties.
Age may matter too, in the decision to use beta blockers. In a Canadian meta-analysis, patients under the age of 60 taking beta blockers did just as well as those taking other drugs, but beta blockers were not as effective in older patients in terms of endpoint reduction.11
In uncomplicated hypertension, though, I do agree with the broad-brush recommendations for primary care physicians that the other 4 classes of drugs (thiazide-type diuretics, ACE inhibitors, ARBs and dihydropyridine CCBs) still have more evidence of outcome benefit as first line therapy.
Again, I think these guidelines are an oversimplification and are not sufficient to guide individualized therapy.
DR. IZZO: Let’s close with some general discussion of whether the concept of the difficult-to-treat patient is useful and who might fill this definition.
DR. MOSER: It’s not necessarily related to having a comorbidity. You can have a diabetic hypertensive person with hyperlipidemia who responds very well to antihypertensive therapy. We’ve defined some patients as resistant, which may not be true. They may be difficult to treat. For example, just adding a thiazide-type diuretic to other drugs or increasing the dose of a thiazide-type diuretic will often convert a so-called “resistant patient” into a responsive patient.
That’s why I have supported JNC 7 and other guidelines that recommend starting with 2 drugs, either as 2 pills or in a single-pill combination when BP exceeds 160/100 mm Hg. One of the 2 drugs probably should be an RAS inhibitor, but the other most certainly should be a thiazide-type diuretic or perhaps a CCB.12
There are a lot of people with few other risk factors who are very difficult to control. One of the fallouts of the JNC 8 recommendations is that we may undertreat individuals over the age of 60, but that also means there will be less “resistant hypertension.”
DR. IZZO: When considering resistant hypertension, Dr. Moser suggested combination therapy. Dr. Gradman, you have had an interest in this area.
DR. GRADMAN: This is an important issue that has not really been addressed adequately in the guidelines. We know that combination therapy is required in upwards of 75% of patients using older BP targets.13 We also know that if you start people on combination therapy, you achieve target BP more rapidly and in a greater proportion of patients.
As to initial combination therapy versus the step-care type approach, either alternative is mentioned in JNC 8, but I don’t think any of the new guidelines have addressed the issue fully and no outcome studies have compared initial combination therapy versus initial monotherapy.
But the bottom line is that combination therapy is needed in the vast majority of patients although the percentage will be decreased if the newer, less aggressive BP targets are adopted. In my opinion, it should be started in almost everyone likely to eventually need more than 1 drug to achieve target BP. First-dose adverse effects, particularly hypotension, are very uncommon with 2- or 3-drug single-pill combinations that contain thiazide-type diuretics, ARBs, or CCBs. I would probably not use combinations as initial therapy in very elderly or frail patients.
DR. IZZO: I rarely use monotherapy anymore. Let me return to something that I touched on before: race as a decision point.
DR. BASILE: Well, I can understand why you’re against it, Dr. Izzo, because of the heterogeneity of how we define race. The white/black definition is certainly a simplistic approach given the way our genetics are so often mixed in today’s populations.
Both JNC 8 and the ASH/ISH document should, at least, be commended for pointing out to the clinician that if you’re looking for BP reduction, the CCB or the thiazide-type diuretic will give you more BP reduction in blacks in general than that achieved with an RAS blocker.
There are many African-American patients who are not prescribed a thiazide or a CCB as part of their cocktail. The big mistake is that these patients are considered resistant or refractory, depending on how many drugs they’re on. So I would at least point out, in line with JNC 8 and the ASH/ISH recommendations, that in the black patient, regardless of age, a CCB or a thiazide should be prescribed for BP reduction.