ACCEL: American College of Cardiology Extended Learning
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CardioSource WorldNews | PATHWAY for Prevention and Treatment of Hypertension

There are many options for treating hypertension and, to some extent, that’s the problem. Trying to determine the best treatment for an individual patient may require a lot of trial and error. Of the estimated 80 million American adults with high BP, 76.5% are currently being treated, but only 54.1% of hypertensives in the U.S. have it controlled.1

One of several organizations trying to make a dent in the problem is the British Hypertension Society and, specifically, their PATHWAY research project. The program consists of three complementary studies. The unifying themes are that measurement and interpretation of a patient’s renin status permit more rational and less empirical treatment decisions than have been traditional in hypertension; and that with hypertension now clearly recognized as a complex disorder, rational therapy in most patients means choosing the appropriate combinations.

The first study—monotherapy versus combination for initial treatment—tests the hypothesis that patients treated with a single drug never catch up with the BP control achieved with initial combination because of compensatory vasoconstriction or sodium retention. While only the study design has been published as of this writing,2 the results have been presented and they suggest that two drugs were significantly better than one. According to Tom MacDonald, MD, first author of the paper and the current president of the British Hypertension Society, this was true even when the best single medicine at optimal dose was chosen using the best predictors of effectiveness. (Professor Morris Brown, MD, of Cambridge spearheads the overall PATHWAY program.)

Dr. MacDonald added, “An understandable concern was that two medicines might have unacceptably more side effects such as dizziness compared with single-medicine therapy. But we did not find this; so, we are reassured that we can now recommend combined medicines for the initial treatment of patients with high blood pressure which will reduce blood pressure and result in fewer strokes, heart attacks, and sudden deaths.”

The second study—optimal therapy of resistant hypertension—evaluated the theory that spironolactone is the best overall treatment for patients with resistant hypertension.3 PATHWAY 2 was the first randomized clinical trial to directly compare spironolactone with other active BP-lowering treatments in patients with well characterized resistant hypertension. It showed that spironolactone (25–50 mg daily) is overwhelmingly the most effective drug treatment for resistant hypertension. It controlled BP in almost 60% of patients with resistant hypertension—and was three times as likely to be the patient’s best drug versus doxazosin or bisoprolol.

The result in favor of spironolactone was, according to the investigators, “unequivocal”—“Spironolactone is the most effective treatment for resistant hypertension, and these results should influence treatment guidelines globally.” The authors even went so far as to add that patients should not be defined as having resistant hypertension unless their BP remains uncontrolled on spironolactone.

Spironolactone was well tolerated with no significant excess adverse effects with the caveat that serum potassium levels and renal function should be monitored on treatment and treatment duration was too short to assess incident gynecomastia (~ 6% in longer-term studies).


The third study—single versus combination diuretic in patients with low-renin hypertension—tested the hypotheses that multiple nephron blockade is more effective than single and that the addition of potassium-sparing diuretic to or substitution for thiazide in patients with features of metabolic syndrome will prevent deterioration of glucose tolerance.

The trial was designed to use a combination of two commonly used diuretics, each at half dose.4 Professor Brown, first author of this paper, said, “The findings support first-line use of this combination in patients requiring diuretic therapy for hypertension. That matched doses of the two classes of diuretics could neutralize undesirable effects, while potentiating the desirable (effects), is an important discovery.”

Thiazide diuretics such as hydrochlorothiazide (HCTZ) have been first-line treatment for hypertension for many decades, but their usage has declined because of concerns that they increase the risk of diabetes. One hypothesis has been that the diabetes risk is due to depletion of potassium by thiazides. Potassium-sparing diuretics such as amiloride offer a potential solution, but theoretical risk of high potassium levels requires increased monitoring.

Dr. Brown and his colleagues based their study on the idea that a combination of both diuretics at lower than normal doses can “neutralize” these potassium changes while at the same enhancing sodium excretion at two different targets in the kidneys (which the researchers call “natriuretic synergism”), thus reducing blood pressure more than either diuretic can do alone.

The data have been published.5 In brief, the study enrolled 399 obese, hypertensive patients (mean age: 61-63 years) who had an indication for diuretic treatment and at least one additional component of the metabolic syndrome.

Patients were randomized to receive either amiloride 10 mg alone (n = 132), HCTZ 25 mg alone (n = 134) or a combination of both at half dose (n = 133) for 12 weeks, followed by another 12 weeks at double the dose for all groups.

For the primary endpoint, there was a significant difference between the amiloride and HCTZ groups, with glucose levels rising in the latter and dropping in the former. The average difference in blood glucose levels between the two groups was 0.55 mmol/l (9.9 mg/dl; p = 0.009) over the study period. Also, there were differences in 2-hour glucose concentrations between the hydrochlorothiazide group and the other groups that increased with time and dose. In contrast, blood glucose levels remained unchanged in patients on the combination regimen.

The secondary endpoint of blood pressure control was acceptable and similar in both single-drug arms, with a drop of 14.7 mm Hg in the amiloride group and 14.0 mm Hg in the HCTZ group. However, the antihypertensive impact was greatest in the combination group, with an additional drop of 3.4 mm Hg compared to the HCTZ group (p = 0.007).

Said Dr. Brown, “Our study shows that amiloride itself is a very good drug—at least as effective as HCTZ; and that combining a half dose of it with half dose of HCTZ is a ‘win-win’—producing better blood pressure, lower glucose, and no change in potassium.”


  1. Mozaffarian D, Benjamin EJ, Go AS, et al. Circulation. 2016;133:e38-e360.
  2. MacDonald TM, Williams B, Caulfield M, et al. BMJ Open. 2015 Aug 7;5:e007645.
  3. Williams B, MacDonald TM, Morant S, et al. Lancet. 2015;386:2059-68.
  4. Brown MJ, Williams B, MacDonald TM, et al. BMJ Open. 2015;5:e008086.
  5. Brown MJ, Williams B, Morant SV, et al. Lancet Diabetes Endocrinol. 2016;4:136-47.

The Glucose Paradox and Management of Patients with Type 2 Diabetes

Yeah, yeah: diabetes is not your department. Yet, as last month’s CSWN cover story less than subtly suggested, there are some basics about diabetes that cardiologists should familiarize themselves with in order to care for this growing population of patients.

We’ve known, since the last century, of the strong association between glycemia and the macrovascular and microvascular complications of type 2 diabetes mellitus (T2DM). Mark A. Creager, MD, a Professor of Medicine at Harvard, has published on the epidemiology, pathophysiology, and management of diabetes and atherosclerosis.1 T2DM markedly increases the risk of MI, stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce vascular dysfunction that predisposes diabetics to atherosclerosis.

Thus, tight glucose control should reduce risk. That suggests the inclusion of glycemic measures in algorithms used to predict the risk of CV disease (CVD) might improve their predictive ability. Indeed, the 2010 ACC/AHA guidelines on risk assessment concluded that measurement of HbA1c levels may be reasonable in asymptomatic adults without a diagnosis of diabetes.2 Makes sense, but it isn’t true. It turns out that HbA1c is not associated with clinically meaningful improvement in assessment of CVD risk. That was a big surprise when the results were first reported of an analysis of data from almost 300,000 people without known diabetes and CVD at baseline indicates.3

There seems to be a glucose paradox: while fasting blood sugar and HbA1c predict future macro- and microvascular events, tight glucose control definitely reduces microvascular events but does not impact macrovascular effects. That’s quite different from blood pressure control and the use of statins for lipid lowering, which both reduce macrovascular events. So, is there any place for tight glucose control? Probably.

Diabetes: Risk Multiplier

Recently, Dr. Creager and colleagues published a pair of papers on diabetes and vascular disease.4,5 Despite this paradox, diabetes is most certainly a risk multiplier in atherosclerosis. It increases the risk of developing atherosclerosis and the incidence of complications of atherosclerosis, and is associated with poorer outcomes from these events.

They noted that health care professionals have the benefit of a wide variety of clinical trial data supporting specific treatments and targets for patients with diabetes. These include:

Lipid-lowering therapy with statins, blood pressure control, and antiplatelet therapy in patients with increased cardiovascular risk scores.

Hyperglycemia should be treated to a target glycosylated hemoglobin or HbA1c of 7%, with therapy that includes an agent that improves insulin sensitivity, such as metformin.

Optimal medical treatment, including risk factor modification, antiplatelet therapy, and antianginal medications, is the preferred approach for most patients with diabetes and stable CAD.

What about glucose-lowering therapy? There is still a place for aggressive glucose lowering, because when you parse the data, there were individuals who seemed to benefit from this approach. At ACC.15, Dr. Creager said, aggressive glucose lowering is particularly warranted in younger, leaner patients, with a shorter duration of T2DM, lower baseline HbA1c levels, and without evident CAD.

In short, tight glycemic control improves microvascular events, but caution is warranted in older patients and those with established CVD or multiple comorbidities. Dr. Creager also emphasized that aggressive early treatment of T2DM may impact CV events due to a legacy, or memory, effect which may take many years to become evident.


  1. Beckman JA, Creager MA, Libby P. JAMA. 2002;287:2570-81.
  2. Greenland P, Alpert JS, Beller GA, et al. J Am Coll Cardiol. 2010;56(25):e50-e103.
  3. Di Angelantonio E, Gao P, Khan H, et al. JAMA. 2014;311:1225-33.
  4. Paneni F, Beckman JA, Creager MA, et al. Eur Heart J. 2013;34:2436-43.
  5. Beckman JA, Paneni F, Cosentino F, Creager MA. Eur Heart J. 2013;34:2444-52.

What’s Been the Impact of AUC in PCI?

The American College of Cardiology (ACC) and the American Heart Association (AHA) have an ongoing 30-year commitment to produce clinical practice guidelines to provide evidence-based recommendations across a number of clinical conditions, diagnostic tests, and therapeutic interventions.

In 2005, partly in response to concerns about the increased use of cardiovascular imaging and procedures, the two organizations partnered to create appropriate use criteria (AUC) to aid clinical decision-making using case scenarios that provide real-world specifics for applying guideline recommendations.

In 2009, the ACC and AHA, along with other professional societies (the Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, and the American Society of Nuclear Cardiology, to name a few) released AUC for coronary revascularization.1 Chaired by Manesh R. Patel, MD, FACC, an Assistant Professor and Assistant Director of the Cardiac Catheterization Laboratory at Duke University Medical Center, Durham, NC, the document critically examined the evidence in an effort to improve patient selection for PCI and address concerns about potential overuse. Specifically, studies demonstrated that one in six non-acute PCIs were classified as inappropriate—although more recent AUC documents use the term “rarely appropriate”—suggesting that the benefits of the procedure are unlikely to outweigh the risks.

It was also anticipated that AUC might reduce the tremendous variations in cardiology practice across the country that cannot be readily explained by differences in patient characteristics or by disease severity. So, what’s happened?

Impact of AUC

In late 2015, Dr. Patel and colleagues reported their analysis of almost 2.7 million PCI procedures at 766 hospitals.2 Using National Cardiovascular Data Registry (NCDR®) data, they applied the 2012 Appropriate Use Criteria for Coronary Revascularization to these procedures and noted that the volume of non-acute procedures decreased (from 89,704 in 2010 to 59,375 in 2014), whereas the number of acute procedures was similar (377,540 in 2010 vs. 374,543 in 2014).

Compared to 2010, they noted a shift in the patients undergoing non-acute procedures, with those undergoing PCI in 2014 showing more severe angina, more antianginal agents prior to PCI, and more high-risk findings on pre-PCI noninvasive testing. The classification of non-acute PCIs as inappropriate declined from 26% in 2010 to 13% in 2014, although hospital-level variation in PCIs classified as inappropriate did not change substantially, with an interquartile range of 5.9%–22.9% (median:12.6%).

The authors said the findings suggest that clinicians are doing a better job of identifying and limiting non-acute PCI procedures to those patients most likely to benefit from revascularization.

In an accompanying editorial,3 Robert A. Harrington, MD, MACC, noted that, while there has been some appropriate criticism of cardiology practices that overuse imaging technologies and even coronary revascularization procedures, “the majority of practicing U.S. cardiologists typically respond to data, evidence, and guidelines in a positive manner of adoption and change.”

Current Approach “Not OK”

There’s still one issue that needs work, as Dr. Patel himself recently noted: current risk stratification for patients with chest pain is poor. In patients with intermediate pre-test probability of CAD, the guidelines say to consider a stress test; if there is chest pain, a nondiagnostic ECG, and negative cardiac markers, stress myocardial perfusion imaging is an option as is stress echo; computed tomography (CT) angiography is another option.

He said the significant variability in PCI around the U.S. (and the world) may, in part, be driven by noninvasive tests, such as echo, radionuclide imaging, CT, and cardiac magnetic resonance. Not only are there more options, there is direct-to-consumer marketing of cardiac imaging benefits.

Dr. Patel said evidence of noninvasive imaging exists but is limited. One thing is certain: what passes today for usual imaging and care patterns (multiple tests with repeat testing) will not be OK in the near future. Both CT-fractional flow reserve (FFR) and invasive FFR co-registration are emerging opportunities.4,5


  1. Patel MR, Dehmer GJ, Hirshfeld JW, et al. J Am Coll
  2. Cardiol. 2009;53(6):530-53.
  3. Desai NR, Bradley SM, Parzynski CS, et al. JAMA. 2015;314:2045-53.
  4. Harrington RA. JAMA. 2015;314:2029-31.
  5. Douglas PS, Pontone G, Hlatky MA, et al. Eur Heart J. 2015;36:3359-67.
  6. Douglas PS, Hoffman U, Patel MR, et al. N Engl J Med. 2015;372:1291-300.
Read the full April issue of CardioSource WorldNews at

Clinical Topics: Dyslipidemia, Prevention, Lipid Metabolism, Novel Agents, Hypertension

Keywords: American Heart Association, Amputation, Atherosclerosis, Blood Glucose, Diabetes Mellitus, Type 2, Diagnostic Tests, Routine, Hypertension, Renin, Stroke, CardioSource WorldNews

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