Role of Single-Pill Combination Therapy in Optimizing Blood Pressure Control in High-Risk Hypertension Patients and Management of Treatment-Related Adverse Events

Authors

  • Abdul Ali Abdellatif MD, FASN

    1. From the Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, and Kidney Hypertension Transplant Clinic, Clear Lake Specialties, Webster, TX
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Abdul Ali Abdellatif, MD, FASN, Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, and Kidney Hypertension Transplant Clinic, Clear Lake Specialties, 500 N. Kobayashi, Webster, TX 77598
E-mail:abdula@bcm.tmc.edu

Abstract

J Clin Hypertens (Greenwich). 2012;14:718–726. ©2012 Wiley Periodicals, Inc.

Renin-angiotensin-aldosterone system (RAAS) inhibitors in combination with other antihypertensive drugs (eg, calcium channel blockers [CCBs] and/or diuretics) are a preferred treatment option for managing uncontrolled hypertension in high-risk patients with chronic kidney disease (CKD), diabetes, or heart failure because RAAS inhibitors provide cardiorenal benefits in addition to lowering blood pressure (BP). However, when prescribing antihypertensive therapies to high-risk patients, physicians must be aware of the risks of treatment-related adverse events of hyperkalemia and peripheral edema associated with RAAS inhibitors and CCBs, respectively. This review discusses the use of single-pill combination antihypertensive therapy to optimize BP control in high-risk patients with CKD, diabetes, and/or heart failure and provides strategies for preventing and managing hyperkalemia and peripheral edema in this group. Single-pill combination therapy can utilize different classes of antihypertensive drugs to reduce BP while mitigating the risks of treatment-related adverse events, reducing pill burden, lowering medical cost, and improving patient compliance.

Recent analyses of National Health and Nutrition Examination Survey (NHANES) data show that 50% to 55% of adult hypertensive patients in the United States have uncontrolled blood pressure (BP).1,2 Furthermore, approximately 65% of hypertensive diabetic patients are not achieving the recommended BP target.3 Uncontrolled BP (ie, ≥140/90 mm Hg) and high levels of total cardiovascular risk are common problems for hypertensive patients who have concomitant diseases such as diabetes, chronic kidney disease (CKD), and/or cardiovascular disease (CVD).4–7 Factors that predispose patients to uncontrolled hypertension and cardiovascular and/or renal complications include heavy drinking, smoking, obesity, African American or Hispanic ethnicity, and history of stroke.5,6,8–11 In high-risk patients, intense cardiovascular risk reduction is necessary, including tight BP control.4 Indeed, guidelines and results from recent trials indicate a BP goal of <130 to 135/80 mm Hg in high-risk patients, compared with <140/90 mm Hg in the general population.4,12–14

Comorbid cardiovascular and renal conditions are associated with increased resistance to antihypertensive therapy due to multiple factors, including increased sodium retention and activation of the renin-angiotensin-aldosterone system (RAAS).4,6 Thus, to achieve the lower target BP of <130/80 mm Hg, most high-risk patients require ≥2 antihypertensive drugs. Results from large outcomes trials in high-risk patients (eg, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT], Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressue–Lowering Arm [ASCOT-BPLA], Heart Outcomes Prevention Evaluation [HOPE], International Verapamil SR and Trandolapril Study [INVEST], Losartan Intervention for Endpoint Reduction in Hypertension [LIFE], and Valsartan Antihypertensive Long-Term Use Evaluation [VALUE]) have shown that, irrespective of comparative effects on BP, regimens incorporating a RAAS inhibitor provide equal or greater cardiovascular risk reduction and target-organ protection compared with regimens lacking this component.15,16 Moreover, the specific drug classes chosen for use in combination may have clinical relevance. In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, for example, an angiotensin-converting enzyme (ACE) inhibitor/calcium channel blocker (CCB) combination reduced cardiovascular events and death to a significantly greater extent than an ACE inhibitor/diuretic combination, despite similar reductions in BP, in high-risk hypertensive patients.17 The majority of outcomes evidence to date with RAAS inhibitors stems from the use of ACE inhibitors or angiotensin II receptor blockers (ARBs). ARBs provide an effective first-line treatment in some cases or an alternative therapy in patients who are intolerant of ACE inhibitor–related cough or angioedema, which occur in 5% to 35% and 0.1% to 6% of patients, respectively, presumably due to inhibition of bradykinin catabolism by ACE inhibition.18,19

It is important to note, however, that when multiple antihypertensive drugs are used, patient and physician treatment barriers can present challenges, including poor patient compliance and adherence to therapy associated with the intake of an increased number of medications20 and the susceptibility of high-risk patients to treatment-related adverse events (AEs). For example, RAAS inhibitors impair renal potassium excretion, increasing the risk of hyperkalemia,21 and CCBs are associated with an increased risk of peripheral edema due to arteriolar dilation and fluid extravasation.22 However, withholding these drugs or using suboptimal doses in high-risk patients because of fear of treatment-related AEs can deprive patients of lifesaving cardiovascular benefits.23

The use of single-pill therapies that combine drugs with the potential to antagonize or mitigate the risks of treatment-related AEs is one strategy that can be used to overcome many patient and physician barriers. In addition, single-pill combination formulations can reduce the complexity of antihypertensive treatment regimens and improve patient compliance.20

This review discusses the use of single-pill combination antihypertensive therapy and optimizing BP control in high-risk patients with CKD, diabetes, and/or heart failure (HF). A discussion of treatment-related AEs that are particularly relevant to consider when prescribing antihypertensive therapy to high-risk patients is presented, and strategies for preventing and managing hyperkalemia and peripheral edema in this group are provided.

Importance of BP Control in High-Risk Hypertensive Patients With CKD, Diabetes, and/or HF

CKD

The kidneys play a prominent role in BP regulation, and when patients develop CKD, sodium retention and subsequent volume overload associated with impaired renal function are hallmarks of hypertension. In addition, hormonal mechanisms and reduced blood flow to the kidneys can activate the RAAS, which leads to vasoconstriction and increased peripheral vascular resistance and contributes to the development of renovascular hypertension.6,24

Proven measures that can slow the progression of CKD include controlling hypertension and diabetes and smoking cessation.12 RAAS blockade is critical for the management of hypertension in patients with CKD, and combinations of RAAS inhibitors with diuretics may be required.4,12,14 Effectively controlling BP in patients with CKD reduces the likelihood that they will progress to end-stage renal disease and require renal replacement therapy, including dialysis, and/or develop CVD.12,14

Furthermore, frequent consultation with a nephrologist before kidney failure occurs has been shown to significantly improve long-term outcomes, including reducing the risks of progression to dialysis and cardiovascular and all-cause mortality.25,26 When referral to a nephrologist is delayed, CKD may become too severe for meaningful improvements to be made.25,26 Also, CKD patients might be deprived of therapies that are known to slow CKD progression. Thus, collaboration between primary care providers (PCPs) and nephrologists is essential to provide comprehensive care to patients with kidney disease and slow disease progression in early-stage CKD before irreversible damage becomes prominent.

Diabetes

In patients with diabetes, hypertension increases the risks of microvascular and macrovascular complications and cardiovascular morbidity and mortality compared with patients without diabetes.27 Data from NHANES indicate that from 1988 to 2006, no improvements were made in controlling BP in diabetic patients, with approximately 65% being uncontrolled to the recommended BP target.3,28 Of particular concern, no BP improvements were made in patients 20 to 44 years of age, suggesting that these young adults will have a high risk of developing vascular complications and subsequent increased mortality rates.28

The UK Prospective Diabetes Study (UKPDS) was a landmark randomized multicenter trial that studied 5102 patients with newly diagnosed type 2 diabetes mellitus for up to 30 years.27 In a critical interpretation of results from the UKPDS, early and sustained tight BP control was shown to be necessary and more beneficial than glycemic control for reducing the risks of microvascular and macrovascular diabetic complications.27

Patients with both hypertension and hyperglycemia have an increased risk of microalbuminuria and, in these patients, microalbuminuria is a predictor of end-stage renal disease, CVD, and death.8 RAAS-blocker therapy may be particularly beneficial in this population because it reduces albuminuria29,30 and microvascular damage associated with RAAS activation.31

Heart Failure

Hypertension is a well-established risk factor for development of HF, particularly in African American and elderly patients, and optimal BP control can decrease the risk of developing HF by approximately 50%.32 RAAS inhibitors are appropriate initial therapy for patients with HF because they reduce morbidity, hospitalization rates, and mortality in all stages of the disease.7,32 In addition, RAAS activation has been linked to the pathophysiology of HF, contributing to cardiac remodeling, fibrosis, sympathetic activation, and dilated cardiomyopathy.33 In the Randomized Aldactone Evaluation Study (RALES), use of an aldosterone blocker (potassium-sparing diuretic) in addition to RAAS blockers reduced mortality in patients with moderate to severe HF.34

Common AEs in High-Risk Patients Treated With Combination Antihypertensive Therapy

Hyperkalemia

Patients with CKD, diabetes, and/or HF have an increased risk of hyperkalemia.21 In CKD, reduced glomerular filtration rate (GFR) and low urine flow can decrease renal potassium excretion.35 Geriatric patients are particularly vulnerable to hyperkalemia because age-related declines in renal function can impair potassium elimination; this risk is often magnified because elderly patients frequently use nonsteroidal anti-inflammatory drugs, which can exacerbate renal dysfunction and decrease potassium excretion.36,37 Further, there is a common misconception that over-the-counter potassium supplements or potassium-based salt substitutes are needed, especially when taking diuretics for hypertension, edema, or HF. In diabetes, reduced insulin levels may cause potassium accumulation in the extracellular space and, in HF, impaired renal function and treatment with drugs that interfere with renal potassium excretion, including a combination of different RAAS blockers±aldosterone blockers, can cause and/or exacerbate hyperkalemia.35

The risk of hyperkalemia is increased when agents that block RAAS activation are used in combination because these agents impair renal potassium excretion by interfering with the stimulatory effect of angiotensin II on adrenal aldosterone secretion.21 This risk is often increased because patients who are taking diuretics are counseled to increase their potassium intake to negate diuretic-induced hypokalemia; however, if patients are taking RAAS inhibitors with diuretics, potassium supplementation can shift potassium levels too high and cause hyperkalemia. Further, if diuretics are prescribed to treat hyperkalemia, the risk becomes very high if patients are instructed to increase their intake of potassium.

The combination of an ARB and ACE inhibitor is one example of how different classes of RAAS inhibitors, when combined, can result in a higher incidence of hyperkalemia.38 The observation that ARBs and ACE inhibitors increased the risk of hyperkalemia in high-risk patients led to concern among physicians about prescribing RAAS-inhibitor therapy. The RALES trial reported that increased spironolactone use was associated with an increased rate of hyperkalemia resulting in hospitalization and mortality.39Awareness of hyperkalemia also increased substantially when results of the landmark Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) evaluating telmisartan, ramipril, or both reported a significantly increased risk of hyperkalemia in high-risk patients using combination therapy.40 More recently, the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) was stopped early because the addition of a direct renin inhibitor to an ACE inhibitor or ARB did not provide clinical benefit and resulted in an increased risk of adverse events, including hyperkalemia.41 As a result of these studies, many PCPs have undertreated hypertension in high-risk patients, and if RAAS inhibitors are used, they are often prescribed at suboptimal doses.42

Management of Hyperkalemia  The Figure 1 outlines steps physicians can take to manage hyperkalemia, and Table I provides an overview of drugs used to antagonize membrane effects and alter potassium levels. The first step in the management of hyperkalemia is to determine whether it is acute or chronic. A rapid increase in serum potassium (>6.0 mmol/L), sudden decrease in renal function, electrocardiography finding changes, and/or significant acidosis are signs of acute hyperkalemia requiring emergency treatment.43 If any new electrocardiography finding changes are present, urgent efforts should be made to stabilize cardiac myocyte membrane potential using intravenous calcium. If electrocardiography results are normal, insulin or β2-adrenergic agonists can be given to shift potassium into cells and loop diuretics or ion-exchange resins can be used to remove potassium from the body; however, in patients refractory to this medical therapy, dialysis should be considered.43 Once acute hyperkalemia is under control, potassium level and volume status should be monitored to prevent recurrence and maintain euvolemia, and efforts should be made to determine the underlying etiology of hyperkalemia.

Figure 1.

 Evaluation and management of hyperkalemia. Pseudohyperkalemia is a laboratory artifact that can be caused by hemolysis, leukocytosis, thrombocytosis, repeated fist clenching during phlebotomy, or traumatic venipuncture.43 AKI indicates acute kidney injury; CKD, chronic kidney disease; ECG, electrocardiogram; IV, intravenous; K+, potassium.

Table I.   Therapies Used for the Treatment of Hyperkalemia
TherapyDosageOnset of ActionDuration of ActionMechanism of ActionPossible Side Effects/Complications
  1. Abbreviations: GI, gastrointestinal; IV, intravenous. Adapted from Hollander-Rodriguez and Calvert.43

CalciumCalcium gluconate 10% solution, 10 mL (4.65 mEq of Ca) IV (1 amp) over 5–10 min or calcium chloride 10 mL (13.6 mEq of Ca) IV (0.5 or 1 amp)1–3 min30–60 minAntagonizes membrane effects (no effect on serum potassium level)Hypercalcemia, tissue necrosis, can worsen digoxin toxicity, bradycardia
InsulinRegular insulin, 10 units IV with 50 mL of 50% dextrose if plasma glucose <250 mg/dL15–30 min2–6 hIncreases cellular potassium uptake (no effect on total body potassium)Hypoglycemia, dextrose-induced hyperosmolarity, volume overload
β2-Adrenergic agonistNebulized albuterol, 10 mg over 10 min15–30 min2–4 hIncreases cellular potassium uptake (no effect on total body potassium)May cause a brief initial rise in serum potassium and tachycardia
Loop diureticFurosemide, IV (dose based on expected response), given with saline if volume depletion is a concern15–60 min 4 hIncreases renal potassium excretionPotential ototoxicity with large IV doses, nephrotoxicity with volume depletion; only effective if there is adequate renal response to loop diuretic
Ion exchangeSodium polystyrene sulfonate, 15–60 g orally in 20–100 mL water or syrup, or 30–50 g in a retention enema1–2 h4–6 hExchanges potassium in the gut with sodiumUse with sorbitol is not recommended; may cause gastric irritation and possible bowel necrosis in patients with impaired GI motility

If chronic hyperkalemia is present and the underlying etiology is determined, it can often be controlled by eliminating potassium supplements, potassium-containing salt substitutes, or potassium-rich foods, especially in patients with CKD.35 Patients should be educated about the complexities of their disease and the importance of following a strict low-potassium diet while providing the patient with educational material. Further, medications with the potential to cause hyperkalemia (Table II) should be avoided whenever possible if hyperkalemia persists.35 In particular, alternatives to potassium-sparing diuretics should be considered, and patients with CKD or HF should be monitored closely when using aldosterone blockers with a RAAS inhibitor.21,35

Table II.   Drugs That May Exacerbate or Cause Hyperkalemia or Peripheral Edema23,35,43,46
Drugs Associated With Risk of HyperkalemiaDrugs Associated With Risk of Peripheral Edema
  1. Abbreviations: ATRA, all-trans-retinoic acid; CCB, calcium-channel blocker; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; RAAS, renin-angiotensin-aldosterone system. aDihydropyridine CCBs are more likely to cause peripheral edema than nondihydropyridine CCBs.22

Amilorideα-Adrenergic antagonists
Amino acids (IV)Antirheumatic drugs (eg, meloxicam, celecoxib)
RAAS inhibitorsβ-Blockers
Azole antifungalsCCBsa
β-BlockersChemotherapeutic agents (eg, docetaxel, gemcitabine, ATRA, As2O3)
CyclosporineClonidine
Digoxin intoxicationCorticosteroids
EplerenoneDiazoxide
Ethinyl estradiol/drospirenoneEndothelin receptor antagonists (eg, bosentan, ambrisentan)
Fluoride toxicityErythropoietic agents
Glucose infusions with insulin deficiencyEstrogens/progesterones
HeparinGuanethidine
MannitolHydralazine
NSAIDsMethyldopa
Potassium-rich nutritional and herbal supplementsMinoxidil
Packed red blood cellsMonoamine oxidase inhibitors
Penicillin G potassiumNSAIDs
PentamidinePregabalin
Potassium supplements/salt substitutesReserpine
SpironolactoneTestosterone
SuccinylcholineThiazolidinediones (eg, rosiglitazone, pioglitazone)
Tacrolimus 
Triamterene 
Trimethoprim 

Patients with CKD should be monitored for development of hyperkalemic renal tubular acidosis, which can occur when the collecting duct retains excess bicarbonate and fails to excrete protons and potassium. This type of acidosis may be a result of hypoaldosteronism, which is common in patients with diabetic nephropathy or interstitial renal disease, and may be exacerbated when patients are treated with ACE inhibitors, ARBs, or β-blockers.23,44 Hyperkalemic metabolic acidosis caused by increased serum potassium levels upon initiation of RAAS-inhibitor therapy can be managed with nonpotassium-based bicarbonate supplements.23,43

Table III outlines strategies for management of patients at risk for hyperkalemia upon treatment with RAAS inhibitors. Because of their significant cardiovascular and renoprotective benefits in high-risk patients, RAAS inhibitors should only be discontinued as a last resort, if the underlying etiology has been corrected and hyperkalemia persists.21 If patients experience worsening CKD (eg, GFR <60 mL/min/1.73 m2) or hyperkalemia, they should be referred to a nephrologist as described in the section on CKD.25,26

Table III.   Strategies for Management of Patients at High Risk for Hyperkalemia Upon Treatment With RAAS Inhibitors
  1. Abbreviations: BID, twice daily; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug; RAAS, renin-angiotensin-aldosterone system. Adapted from Palmer21 and Palmer.23

Assess kidney function to accurately define the risk of hyperkalemia
 Patients with eGFR <30 mL/min/1.73 m2 should be considered high risk
 Patients with diabetic nephropathy and eGFR <90 mL/min/1.73 m2 should be considered high risk
 All patients with CKD should be referred to a nephrologist for  evaluation
If possible, discontinue drugs that interfere with renal potassium secretion
 Confirm patients are not using herbal preparations (eg, milkweed, lily of the valley, Siberian ginseng, noni juice, alfalfa, dandelion)
 Confirm patients are not taking over-the-counter NSAIDs
Recommend a low-potassium diet and advise against use of potassium-containing salt substitutes
Prescribe thiazide or loop diuretics
 Loop diuretics are required for patients with eGFR <30 mL/min/1.73 m2
Prescribe sodium bicarbonate to correct metabolic acidosis in patients with CKD or diabetic nephropathy
 650–1300 mg BID or 0.5–1.0 tsp of baking soda per day
Monitor potassium levels and renal function closely
 Check potassium levels 2 weeks after initiation of therapy or 1 week after initiation of therapy if potassium levels were border-line high at baseline
 If patients develop worsening CKD or hyperkalemia, refer to a nephrologist as soon as possible
 If potassium increases to ≥5.5 mmol/L, decrease the dose or discontinue 1 RAAS inhibitor
 The dose of spironolactone should be ≤25 mg/d when used with a RAAS inhibitor
 Do not use spironolactone in combination with a RAAS inhibitor if eGFR is <30 mL/min/1.73 m2
If all of the above steps have been taken and potassium levels remain >5.5 mmol/L, discontinue RAAS inhibitor therapy

Peripheral Edema

Peripheral edema rates reported with CCBs are as high as 10.7%, compared with 3.2% for controls or placebo (P<.0001), and rates of peripheral edema are significantly higher with dihydropyridine CCBs (eg, amlodipine) compared with nondihydropyridine CCBs (12.3% vs 3.1%; P<.0001).22 According to prescribing information, women treated with amlodipine have a greater incidence of edema than do men (14.6% vs 5.6%).45

Individuals with diabetes, renal failure, or nephrotic syndrome have an increased risk of developing peripheral edema, which is a primary manifestation of HF.46,47 Other factors that can predispose patients to peripheral edema include elevated body mass index, female sex, advanced age, peripheral venous insufficiency, and prolonged standing or sitting.46

Management of Peripheral Edema  To decrease the risk of peripheral edema, it is important to educate patients on the importance of maintaining a low-salt diet and reading food labels.46 Medications with the potential to cause peripheral edema are listed in Table II. If peripheral edema is related to volume overload (ie, not CCB-induced), diuretics can rapidly reduce swelling, especially in patients with HF.47 When peripheral edema is induced by CCB therapy, addition of a RAAS inhibitor can mitigate symptoms by normalizing intracapillary pressure and reducing fluid extravasation.48 Many single-pill therapies are available that combine the CCB amlodipine with a RAAS inhibitor (with or without a diuretic), and these combination therapies are recommended for high-risk hypertensive patients with diabetes and/or CKD.11

Peripheral edema associated with CCBs is dose-dependent,48 and many patients can achieve good BP control with a low-dose CCB and a high-dose RAAS inhibitor with a low risk of peripheral edema.46 In a meta-analysis of 25 trials that compared CCB monotherapy vs combination CCB/RAAS inhibitor therapy (N=17,206), the incidence of peripheral edema was 38% lower with combination therapy (P<.0001; relative risk, 0.62; 95% confidence interval [CI], 0.53–0.74).48

Single-Pill Combinations

Table IV summarizes the RAAS inhibitor–based single-pill combination therapies that are available for the management of high-risk patients with hypertension. Tolerability is an important factor to consider when prescribing combination therapy. Combining drugs with complementary mechanisms of action can often times minimize adverse events and improve tolerability relative to use of high doses of monotherapy. Single-pill combination therapies can be effectively utilized to manage hyperkalemia and peripheral edema associated with RAAS inhibitors and CCBs, respectively. For example, single pills that combine a RAAS inhibitor with a diuretic may reduce the risk of RAAS inhibitor–induced hyperkalemia, and single pills that combine a RAAS inhibitor with a CCB can reduce the incidence of peripheral edema compared with CCB monotherapy. Single pills that combine 3 antihypertensive agents (ie, RAAS inhibitor+CCB+diuretic) can be used to maximize BP-lowering effects in high-risk patients with incidences of hyperkalemia and peripheral edema that are similar to incidences reported with dual therapy. Using a single-pill combination may also clarify for the pharmacist what drugs are being prescribed and that potassium supplementation is not appropriate or may decrease the efficacy and/or safety of this common recommendation. In addition, prescribers can specify on a prescription that patients should have their potassium intake restricted if they have persistent hyperkalemia.

Table IV.   RAAS Inhibitor–Based Single-Pill Combination Therapies for the Management of High-Risk Patients With Hypertensiona
Therapy/Year Approved in the United StatesIndication and DosageSafety as Reported in Prescribing Information
  1. Abbreviations: BP, blood pressure; CCB, calcium channel blocker; HCTZ, hydrochlorothiazide; RAAS, renin-angiotensin-aldosterone system; ULN, upper limit of normal. aNumerous single-pill therapies that combine a single RAAS inhibitor (ie, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or direct renin inhibitor) plus a diuretic are approved and available; these combinations are not included in this Table. Valturna, the single-pill combination of aliskiren and valsartan, is not included in this Table because, based on findings from the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), the manufacturer has elected to withdraw this combination from the market.

CCB+RAAS inhibitor
 Amlodipine+benazepril/1995Indicated for the treatment of hypertension in patients not adequately controlled on either agent as monotherapy
Dosing: 2.5/10, 5/10, 5/20, 5/40, 10/20, 10/40 mg
Any edema: 2.2% placebo, 5.1% amlodipine, 0.9% benazepril, 2.1% amlodipine/benazepril
Hyperkalemia (serum potassium ≥0.5 mEq/L above ULN): approximately 1.5% amlodipine/benazepril; generally reversible
 Amlodipine+valsartan/2007Indicated for the treatment of hypertension in patients not adequately controlled with monotherapy and as initial therapy in patients likely to need multiple agents to achieve BP goals
Dosing: 5/160, 10/160, 5/320, 10/320 mg
Peripheral edema: 3.0% placebo, 5.4% amlodipine/valsartanHyperkalemia: incidence not reported
 Amlodipine+olmesartan/2007Indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents, and as initial therapy in patients likely to need multiple agents to achieve BP goals
Dosing: 5/20, 10/20, 5/40, 10/40 mg
Any edema (placebo-subtracted incidence): 0.7–24.5% amlodipine, −2.4% to 6.2% olmesartan, 5.7%–13.3% amlodipine/olmesartan Hyperkalemia: incidence not reported
 Amlodipine+telmisartan/2009Indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents, and as initial therapy in patients likely to need multiple agents to achieve BP goals
Dosing: 5/40, 10/40, 5/80, 10/80 mg
Peripheral edema: 0% placebo, 0.7–17.8% amlodipine, 0.7–0.8% telmisartan, 1.4–11.3% amlodipine/telmisartan Hyperkalemia: incidence not reported
 Amlodipine+aliskiren/2010Indicated for the treatment of hypertension in patients not adequately controlled with monotherapy; may be substituted for titrated components; as initial therapy in patients likely to need multiple agents to achieve BP goals
Dosing: 5/150, 10/150, 5/300, 10/300 mg
Peripheral edema: 1.0% placebo, 6.2% amlodipine/aliskiren (8.9% at high dose)Hyperkalemia: incidence not reported
CCB+RAAS inhibitor+diuretic
 Amlodipine+valsartan+HCTZ/2009Indicated for the treatment of hypertension; not indicated as initial therapy
Dosing: 5/160/12.5, 10/160/12.5, 5/160/25, 10/160/25, 10/320/25 mg
Any edema: 6.5% with triple-combination therapy vs 1.4–11.5% with dual therapies Hyperkalemia (serum potassium >5.7 mEq/L): 0.4% with triple-combination therapy vs 0.2%–0.7% with dual therapies
 Amlodipine+olmesartan+HCTZ/2010Indicated for the treatment of hypertension; not indicated as initial therapy
Dosing: 5/20/12.5, 5/40/12.5, 5/40/25, 10/40/12.5, 10/40/25 mg
Peripheral edema: 7.7% with triple-combination therapy vs 1.0–8.3% with dual therapies; incidence based on highest approved doses Hyperkalemia: incidence not reported
 Amlodipine+aliskiren+HCTZ/2010Indicated for the treatment of hypertension; not indicated as initial therapy
Dosing: 5/150/12.5, 5/300/12.5, 5/300/25, 10/300/12.5, 10/300/25 mg
Peripheral edema: 7.1% with triple-combination therapy vs 2.0%–8.0% with dual therapies Hyperkalemia (serum potassium >5.5 mEq/L): 3.0% with triple-combination therapy vs 0.7–2.0% with dual therapies

Single-pill combinations may also improve antihypertensive efficacy. A meta-analysis of 9 hypertension trials (N=1671) found an additional BP reduction of 4.1/3.1 mm Hg with the use of single-pill combination therapy compared with free-drug combination regimens.49 Moreover, single-pill combination therapy increased BP normalization (systolic BP <140 mm Hg and/or diastolic BP <90 mm Hg) by 30%.49 These improvements could be the result of improved compliance with study medication. Use of single-pill combinations has been associated with improved treatment persistence and adherence, reduced pill burden, and lower medical costs compared with free-drug combination therapies.20,50–52 A meta-analysis by Bangalore and colleagues51 (N=17,175 hypertensive patients) found that single-pill combination therapy increased persistence and adherence by 24% compared with the free-drug combination regimen (P<.0001). Similar results were reported in another study in which patients taking single-pill combinations (n=2213) were more likely to adhere to antihypertensive therapy and less likely to discontinue their medication during the first year of treatment compared with patients taking free-drug combination regimens (n=2312; both P<.001).50 A 6-month study reported that initiating single-pill combinations (n=382,476 hypertensive patients) was associated with higher medication possession ratios (11.6% difference; 95% CI, 11.4%–11.7%), fewer all-cause hospitalizations (adjusted incidence rate ratio, 0.77; 95% CI, 0.75–0.79), fewer emergency department visits (adjusted incidence rate ratio, 0.87; 95% CI, 0.86–0.89), and lower all-cause medical costs (−$208; 95% CI, −$302 to −$114) compared with patients initiating free-drug combination therapies (n=197,375).20 Consistent results were obtained in a smaller meta-analysis (N=44,336 hypertensive patients) by Sherrill and colleagues who found that single-pill combinations were associated with higher 12-month medication possession ratios (13.3% difference; 95% CI, 8.3%–18.4%), lower total annual all-cause and hypertension-related costs (−$1357; 95% CI, −$1935 to −$778), and lower total annual pharmacy costs (−$335; 95% CI, −$530 to −$139) compared with patients taking free-drug combination therapies.50,52

Several disadvantages may also relate to the use of single-pill combinations, including a possible reduction in dose management flexibility.53 In addition, some single-pill combinations may not provide adequate drug amounts to manage certain comorbidities that can coexist with hypertension (eg, angina, congestive HF). Others combine drugs with differing times to peak effect and may therefore be considered “pharmacokinetically irrational.” However, this may help minimize severe drops in BP, which could be particularly beneficial in certain patient populations (eg, elderly).53 Lastly, some single-pill combinations may not be covered by insurance companies.

Conclusions

Most high-risk hypertensive patients require at least 2 different antihypertensive therapies to control BP. Despite the increased risk of hyperkalemia associated with RAAS inhibitor therapy in high-risk patients, RAAS inhibitors in combination with other classes of antihypertensive drugs remain a preferred treatment choice because they provide cardiovascular and renoprotective benefits in addition to effectively lowering BP. With proper patient education, diet and medication adjustments, careful monitoring, and input from a nephrologist, the risk of hyperkalemia associated with RAAS inhibitors can be effectively managed without depriving patients of essential therapy. Single-pill formulations that combine a RAAS inhibitor and a CCB (with or without a diuretic) have been shown to significantly improve patient outcomes by mitigating the risk of AEs (eg, RAAS inhibitor–induced hyperkalemia, CCB-induced peripheral edema), reducing pill burden, improving patient compliance, and lowering health care costs and utilization.

Disclosures:  Dr Abdellatif is a member of the speakers’ bureaus for Amgen, Genzyme, Novartis, and Takeda. Technical assistance with editing, figure preparation, and styling of the manuscript for submission was provided by Cherie Koch, PhD, and Michael S. McNamara, MS, of Oxford PharmaGenesis Inc, and was funded by Novartis Pharmaceuticals Corporation. Dr Abdellatif was fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the author, and Novartis Pharmaceuticals Corporation had no influence on the contents.

Ancillary