Hypertension and End‐Organ Disease in African Americans: Case Presentations

The excess of hypertension among African Americans has been recognized since the early part of the 20th century and accounts for a substantial portion of the health disadvantage of this population. The incidence of hypertension has now reached epidemic proportions in the African‐American population. It has been well documented that African Americans have a higher prevalence of hypertension, an earlier onset, and a more rapid progression of hypertensive end organ disease, as well as an excessive hypertensive mortality compared with other racial/ethnic groups. Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal.

The following cases offer commentary on the scope of the problem of hypertension and end organ disease in this population. Moreover, several disease‐state specific rather than ethnicity‐related aspects of these cases are emphasized.

CASE 1

The patient is a 62‐year‐old African‐American woman with an 18‐year history of diabetes mellitus and a 5‐year history of poorly controlled hypertension. She has a history of smoking (40 packs/y) and very occasionally uses alcohol. She has a strong family history of diabetes mellitus, chronic kidney disease (CKD), and coronary artery disease. Her current medications include atenolol 100 mg q.d. and neutral protamine Hagedorn insulin 50 U q.d. Her insulin dose has been gradually decreased from 80 U q.d. over the past 6 months. She had previously been on a 25‐mg dose of hydrochlorothiazide (HCTZ), but it was discontinued because of persistent hypokalemia unresponsive to oral potassium supplements. Prior therapy with a sustained‐release form of nifedipine also failed because of dizziness, flushing, and peripheral edema. She experienced asthma in relation to aspirin therapy.

Physical Exam

The patient is overweight, with a body mass index of 37, blood pressure (BP) of 180/102 mm Hg, and resting heart rate of 92 bpm. Diabetic retinopathy is present on fundoscopic examination. Cardiopulmonary examination is unremarkable except for a soft, grade I/VI systolic ejection murmur along the left sternal border. Also, 2⁺ peripheral edema to the knees is present.

Laboratory

Laboratory values include serum creatinine 2.7 mg/dL, 2⁺ proteinuria on dipstick, 7.5 g protein in 24‐hour urine collection, serum potassium 5.0 mEq/L, low‐density lipoprotein (LDL) cholesterol 200 mg/dL, high‐density lipoprotein cholesterol 30 mg/dL, and hemoglobin Al_c 7.2%.

What Is the Hypertensive Profile of African Americans?

Significant racial/ethnic diversity exists in the pathophysiology of essential hypertension, supporting the notion that it is a complex, polygenetic disorder. Unique pathophysiologic and hemodynamic features of this condition in African Americans must also be considered in the context of different mixes and intensities of supposed hypertension risk factors. That being said, compared with whites, African Americans generally have a more volume‐dependent, salt‐sensitive form of hypertension in association with lower basal and/or stimulated levels of plasma renin activity. ¹ Other neurohumoral abnormalities—such as increased immunoreactive endothelin‐1 ² and transforming growth factor β ³ and decreased levels of kallikrein‐kinin, ¹ prostaglandin E₂, ⁴ and atrial natriuretic peptide ⁵ —have been observed in African‐American patients with hypertension, although the cause‐and‐effect relationship between each and the onset and/or progression of hypertension is poorly characterized. What should not be ignored in this physiologic profiling of African‐American patients is that socioeconomic factors (including access to health care), mistrust of the health care system, and delay in diagnosis are important modifiers of the course of the disease.

What Factors Most Likely Led to Hypokalemia When This Patient Was Administered HCTZ?

Hypokalemia occurs in a dose‐dependent manner when thiazide‐type diuretics are given. This patient received only a 25‐mg dose of HCTZ, which reduces the likelihood that the dose of HCTZ was a major factor in her hypokalemia. In this setting, difficult‐to‐manage hypokalemia can arise from several sources. First, high sodium intake typically exaggerates urinary potassium losses produced by diuretics. This may have been the case in this patient, who was fairly noncompliant with suggested dietary restrictions. Second, poor glucose control can promote urinary potassium loss as part of the osmotic diuresis, which arises from glucosuria. Her prior glucose control had been suboptimal so this was a likely contributor to the prior hypokalemia. Finally, unrecognized magnesium deficiency—as may occur with diuretic therapy and/or glucosuria—can give rise to renal potassium wastage. In a patient such as this one there was likely some contribution from each of these factors. Confronted with such a situation, a potassium‐sparing diuretic, such as spironolactone (usually with a small dose of a thiazide), would have provided a sensible solution if there were a continued need for diuretic therapy to control BP. ⁶

What Factors Contributed to Her Current Serum Potassium Value and Is This Value an Absolute Contraindication to the Use of an Angiotensin‐Converting Enzyme Inhibitor?

The patient's current serum potassium value relates to her CKD. As CKD worsens, renal potassium handling becomes progressively more compromised—particularly in persons with diabetes. A serum potassium value in the low 5s is not an explicit contraindication to the use of either an angiotensin‐converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). However, in anticipation of a modest increase in serum potassium values with initiation of ACE inhibitor or ARB therapy, some reduction in dietary potassium intake would be advisable. If the indications for ACE inhibitor or ARB therapy are strong enough—in this patient they are—and the on‐therapy serum potassium level rises to the 6.0–6.5 mEq/L range, the potassium binding resin sodium polystyrene sulfonate can be used. Sodium polystyrene sulfonate should usually be given with a laxative, such as sorbitol, and can prove quite effective in controlling hyperkalemia. ⁷ The concurrent use of a diuretic with the ACE inhibitor or ARB may help to lower BP and keep potassium levels from rising.

Why Does She Have a Decreasing Insulin Requirement?

An important factor in a decreasing insulin requirement can be a modest reduction in weight, which was not the case in this patient. Alternatively, insulin is a small peptide that is both filtered and degraded by the kidney. In the setting of progressive renal failure the half‐life of insulin is prolonged; thus, there is the need for gradual dose reduction to avoid hypoglycemia. ⁸ This process expresses itself as the glomerular filtration rate drops below 30 mL/min. In fact, it is not uncommon for persons with type 2 diabetes who were previously dependent on insulin for control of hyperglycemia to cease insulin therapy completely in the later stages of CKD.

What Might Be the Most Effective Way to Diminish Protein Excretion in This Patient?

Proteinuria in the setting of CKD is increasingly viewed as a specific therapeutic target. In a patient like this one, every effort should be made to reduce BP to at least 130/80 mm Hg (if not lower). In doing so, an ACE inhibitor or an ARB, each being given at a maximal dose, should be a component of the therapeutic regimen. ⁹ A diuretic has usually been necessary as part of the treatment regimen. If creatinine levels are above 2.5–3.0 mg/dL, a loop diuretic instead of a thiazide may be indicated. A calcium‐channel blocker is often needed for BP control, and verapamil or diltiazem is preferred, particularly if pulse rate reduction is indicated as a component of the treatment plan. In this regard, it is increasingly recognized that activation of the sympathetic nervous system, as is the case for the renin‐angiotensin‐aldosterone system, contributes to the level of proteinuria and/or the CKD progression rate. A combined αβ blocker, such as carvedilol, may also be considered in this patient—again with the intent of dampening the negative cardiovascular (CV) and cardiorenal consequences of sympathetic nervous system activation. ¹⁰

Is Antiplatelet Therapy Recommended and, If So, With Which Agent?

A meta‐analysis conducted by the Antithrombotic Trialists' Collaboration ¹¹ found that aspirin given as a secondary prevention strategy reduced the risk of ischemic vascular events in numerous high‐risk groups, including patients with diabetes. Based on results from placebo‐controlled randomized trials, the American Diabetes Association ¹² presently recommends low‐dose, enteric‐coated aspirin as a primary prevention strategy for diabetics at high risk for CV events. The platelet release reaction for thromboxane synthesis is exquisitely sensitive to inhibition by aspirin; thus, the utility of aspirin doses begins as low as 75 mg. When platelet turnover is rapid, as may be the case in diabetic vascular disease, enteric preparations may offer a theoretic advantage because plasma aspirin concentrations are subject to less fluctuation than immediate‐release forms of aspirin. This high‐risk patient qualifies for antiplatelet therapy. Because she is allergic to aspirin, the alternative therapy recommended by the American Diabetes Association is clopidogrel. ¹²

What Is a Reasonable Approach to the Treatment of Her Lipid Abnormalities?

The importance of bringing diabetic dyslipidemia under control cannot be overemphasized. National Cholesterol Education Program Adult Treatment Panel III Guidelines ¹³ suggest, and the Heart Protection Study ¹⁴ confirms, that CV outcomes are greatly reduced in diabetic subjects who receive statin therapy for a prolonged period of time. In the Heart Protection Study, ¹⁴ the proportional reduction in the rate of adverse cardiac events was similar and significant in each subcategory of patients studied, including those with diabetes. The initial priority in diabetic dyslipidemia is to lower LDL cholesterol to <100 mg/dL, with statin therapy being considered the primary means of accomplishing this goal. In diabetic patients with hypertriglyceridemia, the main goal is always glycemic control. Adult Treatment Panel III Guidelines ¹³ recommend using nicotinic acid or fibric acid derivatives if triglyceride levels are ≤500 mg/dL, and using statins when triglyceride levels are ≥499 mg/dL. ¹³ Nicotinic acid should be used cautiously in patients with diabetes because of the possibility of worsening glucose control. Two other points merit comment: rosuvastatin should probably be avoided because its safety in advanced proteinuric CKD (as in this patient) remains to be determined, and the ability to substantially reduce urinary protein excretion (and thereby increase serum albumin concentration) will disable a potent stimulus (hypoalbuminemia) to LDL cholesterol generation. Up to a 15% reduction in LDL cholesterol can occur based on this strategy. ¹⁵

CASE 2

The patient is a 64‐year‐old African‐American man with a long history of poorly controlled hypertension, in part due to medication noncompliance. He has a history of smoking (60 packs/y) and is a weekend drinker. He has a strong family history for CKD and coronary artery disease. He recently had a myocardial infarction (MI) and reports having been hospitalized for 5 days at that time. His medications now include lisinopril 40 mg, HCTZ 50 mg, and amlodipine 10 mg, all being taken once daily. He notes difficulty in tolerating many medications but is vague as to which medications these are and what the specific side effects have been.

Physical Exam

The patient is overweight with a body mass index of 34, BP of 160/105 mm Hg, and resting heart rate of 88 bpm. Hypertensive retinopathy is present on fundoscopic examination. Cardiopulmonary examination reveals a grade II/VI systolic ejection murmur along the left sternal border, bibasilar rales halfway up each lung, and 1⁺ peripheral edema to the knees.

Laboratory

Laboratory values include serum creatinine 2.2 mg/dL, 1⁺ proteinuria on dipstick, serum potassium 5.0 mEq/L, LDL cholesterol 240 mg/dL, and high‐density lipoprotein cholesterol 40 mg/dL. Echocardiogram revealed left ventricular hypertrophy with an ejection fraction of 0.30 and 2⁺ mitral and tricuspid regurgitation. Chest x‐ray revealed cardiomegaly and interstitial edema.

Which Antihypertensive Agents are the Most Effective in African Americans With Hypertension?

It has been well documented that, as monotherapy or in the absence of diuretic therapy, β blockers, ACE inhibitors, and ARBs do not lower BP to the same extent in African‐American patients as they do in white patients with hypertension. It has also been observed that thiazide diuretics and calcium channel blockers have greater BP‐lowering efficacy than do other drug classes in African Americans. ¹⁶ , ¹⁷ With the above observations in mind, several additional therapeutic maxims require comment. First, multi‐drug therapy is the norm in this patient population with a diuretic being a critical component of any such regimen. Moreover, additional consideration should be given in this population to the use of aldosterone‐receptor antagonists ¹⁸ and combined α and β blockers. ¹⁹ Second, although β blockers, ACE inhibitors, and ARBs do not lower BP to the same extent in African‐American patients as in white patients, they do lower BP effectively; therefore, it cannot be assumed a priori that these drug classes would not work in each and every African‐American patient. Any racial difference in response disappears if a β blocker, ACE inhibitor, or ARB is given along with a diuretic. Finally, the perception that it is uniformly more difficult to lower BP in an African‐American patient than in other patients is unjustified. If careful attention is directed toward combining antihypertensive drug classes, BP can be effectively controlled in African‐American patients with hypertension and CKD. ²⁰

What Is the Role of Diuretic Therapy in the Management of This Patient's Hypertension?

This patient clearly is both volume‐expanded and hypertensive. His current diuretic regimen, which is HCTZ 50 mg daily, is clearly of insufficient potency to control his extracellular fluid volume excess. A next step would be conversion to a loop diuretic to effect sufficient volume removal to reduce BP. Patients such as this can often experience a significant reduction in BP with a decrease in extracellular volume. ²¹ Not to be neglected is the impact of dietary sodium intake on maintaining a volume‐expanded state, even with what would otherwise seem to be an effective diuretic dose. Finally, volume removal/BP reduction is coupled with afterload reduction, which presents additional cardiac benefits; thus, this person's functional cardiac status is likely to improve in parallel with sustained BP reduction.

How Do ACE Inhibitors and/or ARBs Fit Into This Patient's Management?

ACE inhibitors reduce mortality and CV morbidity among patients with MI complicated by left ventricular systolic dysfunction, heart failure, or both. This is a consistent observation derived from studies involving more than 100,000 patients. ARBs have been studied in post‐MI patients with congestive heart failure and, at least in the case of valsartan, there seem to be comparable favorable outcomes to those observed with the ACE inhibitor captopril. ²² One or the other of these drug classes should be strongly considered in this patient's long‐term management. Moreover, ACE inhibition and/or ARB therapy will help to reduce BP, particularly when a patient is maintained in a euvolemic to slightly hypovolemic state. ²³ What is unclear with ACE inhibition and/or ARB therapy in the post‐MI patient is the degree to which dose titration is warranted. In the immediate post‐MI period, BP may fall precipitously with these compounds and they should be introduced cautiously. ²⁴ Data suggest that caution should be exercised when using an ACE inhibitor in the acute phase of an MI in patients with a history of hypertension and a low systolic BP at presentation. ²⁴ Another issue that has drawn some attention has been the issue of ethnicity and response to ACE inhibitors. Although differences in the response to medical therapy have been described based on race, ACE inhibitors and β blockers remain appropriate therapy. ²⁵

The Patient Develops Angioneurotic Edema While Taking an ACE Inhibitor. What Is the Next Therapeutic Step?

The onset of angioedema in an ACE inhibitor‐treated patient prohibits the future use of an ACE inhibitor. Angioedema with an ACE inhibitor runs the gamut from otherwise trivial symptoms of lip and slight tongue swelling to life‐threatening tongue engorgement with the potential for full airway occlusion, and is two to three times more common in African Americans. Angioedema has a significant chance of recurrence if ACE inhibitor therapy is continued. ²⁶ A logical next step in a patient with angioedema, if blockade of the renin‐angiotensin‐aldosterone axis is desired (as is the case in this patient), is a switch to ARB therapy; however, a small chance of angioedema recurrence still exists with ARB therapy. ²⁷ The slim chance of angioedema reappearing with an ARB needs to be balanced with the benefits of such therapy; therefore, an ARB can be started and the patient informed of the small chance of angioedema recurrence.

Despite Maximum Titrated Doses of ACE/ARB Plus a Diuretic, Symptoms Do Not Resolve. What Additional Management Strategies Should Be Considered?

Several additional management options exist. Both practice guidelines and physician inclination may dictate the timing of these complementary treatments, which in the case of this patient would have been considered appropriate before reaching his current stage of disease. First, β blocker or combined α‐β blocker therapy with carvedilol can be considered. Because of their initial transient negative inotropic effects, β blockers were traditionally considered contraindicated in heart failure. More recent data offer strong support for the use of these drugs in heart failure. ²⁸ For example, in the Carvedilol Post‐Infarct Survival Control in LV Dysfunction (CAPRICORN) trial, adding carvedilol (a nonselective β blocker with α‐blocking capability) to standard therapy in patients with acute MI and left ventricular systolic dysfunction (ejection fraction ≤0.40), with or without heart failure symptoms, significantly reduced mortality or nonfatal reinfarction (which was not the primary end point). ²⁹ It has been suggested that African Americans with heart failure may not respond as well to β blockers. However, in the US Carvedilol Heart Failure Trials Program, carvedilol mortality benefit was apparent and of similar magnitude in both African‐American and non‐African‐American patients with heart failure. ³⁰ Almost all of these patients were receiving a diuretic. Another option relates to blockade of aldosterone effect with eplerenone. This therapy is now indicated in the post‐MI setting with heart failure. ³¹ Practice guidelines have yet to incorporate aldosterone‐receptor blockade into treatment algorithms.

After Aggressive Diuresis, Laboratory Tests Show a Rise in Serum Creatinine to 5.0 mg/dL. What Is the Next Therapeutic Step?

A rise in serum creatinine to this degree is not typical when diuresis occurs on top of background ACE inhibitor or ARB therapy. An effect of this magnitude arises when the kidney is heavily dependent on angiotensin II for filtration function, a circumstance that can emerge because of either excessive diuresis or the presence of underlying large or small vessel renovascular disease. In either case (these are not mutually exclusive possibilities) the appropriate course of action is to discontinue or reduce the dosage of both diuretic and ACE inhibitor therapy and carefully rehydrate the patient. ³² Restarting an ACE inhibitor or an ARB in a timely manner is an important step in the continued care of this patient. The fact that he had previously tolerated high‐dose ACE inhibitor therapy offers some reassurance as to the safe continued use of this drug class.

If Progression of His Heart Failure Leads to Refractory Edema, What Options Exist to Overcome His Diuretic Resistance?

The available options to manage his diuretic resistance relate to whether this patient was hospitalized or not. Two important points merit discussion in this regard. First, what constitutes a diagnosis of diuretic resistance? Often, progressive weight gain is used as the finding of relevance for this diagnosis. Progressive weight gain can occur because of either diuretic resistance or, more commonly, excessive sodium intake in the setting of a modest tendency for sodium retention. These two possibilities can be separated by an estimation of the natriuretic response to diuretic therapy with a timed urine collection for sodium excretion. A 24‐hour urine sodium excretion >100 mmol makes significant diuretic resistance unlikely. Alternatively, to avoid the rather cumbersome nature of a 24‐hour urine collection, a spot urine sample (with an accompanying blood sample for serum creatinine and sodium) can be obtained from 2 to 4 hours after a loop diuretic dose. The computed value from these parameters represents a fractional excretion of sodium and, if in excess of 3%, all but rules out diuretic resistance. Second, loop diuretic response is highly dependent on the rate and extent of absorption; in this regard furosemide is quite unpredictably absorbed. Thus, one option available to circumvent the issue of poor diuretic absorption as a cause of diuretic resistance is to switch therapy to the loop diuretic torsemide. Torsemide has a much more predictable pattern of absorption. ³³ If the diuretic response remains abnormal, then the possibility of diuretic resistance is much more likely and combination therapy with a loop/thiazide diuretic is warranted. ³⁴