User login
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
MODULE 4: Enhancing Adherence with Antihypertensives: The Role of Fixed-Dose Combinations and Home Blood Pressure Monitoring
Dr Kuritzky is a paid consultant to Takeda Pharmaceuticals International, Inc.
Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.1
The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.2
Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).3 Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.4
Barriers to adherence
A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.5,6 These medications must often be taken at different times of the day, with varying frequency.6-9
Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.
A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.10
In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.11,12
One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.13 In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.14
TABLE
Currently available combination therapies
| Fixed-Dose Combination | Brand Name | Dose Range, Total, mg/da |
|---|---|---|
| Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Azilsartan/chlorthalidone | Edarbyclor | 40/12.5; 40/25 |
| Candesartan/HCTZ | Atacand HCT | 16/12.5; 32/12.5; 32/25 |
| Eprosartan/HCTZ | Teveten HCT | 600/12.5; 600/25 |
| Irbesartan/HCTZ | Avalide | 150/12.5; 300/25 |
| Losartan/HCTZ | Hyzaar | 50/12.5; 100/12.5; 100/25 |
| Olmesartan/HCTZ | Benicar HCT | 20/12.5; 30/12.5 |
| Telmisartan/HCTZ | Micardis HCT | 40/12.5; 80/12.5; 80/25 |
| Valsartan/HCTZ | Diovan HCT | 80/12.5; 160/12.5; 160/25; 320/12.5 |
| β-Blocker + Thiazide Diuretic | ||
| Atenolol/chlorthalidone | Tenoretic | 50/25; 100/25 |
| Bisoprolol/HCTZ | Ziac | 2.5/6.25; 5/6.25; 10/6.25 |
| Metoprolol tartrate/HCTZ | Lopressor HCT | 50/25; 100/25; 100/50 |
| Metoprolol succinate extended/release + HCTZ | Dutoprol | 25/12.5; 50/12.5; 100/12.5 |
| Nadolol + bendroflumethiazide | Corzide | 40/5; 80/5 |
| Propanolol + HCTZ | Inderide | 40/25; 80/25 |
| Calcium Channel Blocker + ACEI | ||
| Amlodipine/benazepril | Lotrel | 2.5/10; 5/10; 5/20; 5/40; 10/20; 10/40 |
| ACEI + Thiazide Diuretic | ||
| Benazepril/HCTZ | Lotensin HCT | 5/6.25; 10/12.5; 20/12.5; 20/25 |
| Captopril/HCTZ | Capozide | 25/15; 25/25; 50/15; 50/25 |
| Enalapril/HCTZ | Vaseretic | 10/25 (1-2) |
| Fosinopril/HCTZ | Monopril HCT | 10/12.5; 20/12.5 |
| Lisinopril/HCTZ | Prinzide Zestoretic | 10/12.5; 20/12.5 20/25 |
| Moexipril/HCTZ | Uniretic | 7.5/12.5; 15/12.5; 15/25 |
| Quinapril + HCTZ | Accuretic | 10/12.5; 20/12.5; 20/25 |
| ACEI + Calcium Channel Blocker | ||
| Trandolapril/verapamil | Tarka | 2/180; 2/240; 4/240 |
| Enalapril/felodipine | Lexxel | 5/5 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker | ||
| Telmisartan/amlodipine | Twynsta | 40/5; 40/10; 80/5; 80/10 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker + Thiazide Diuretic | ||
| Olmesartan/amlodipine/HCTZ | Tribenzor | 40/10/25 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker | ||
| Amlodipine/olmesartan | Azor | 5/20; 5/40; 10/20; 10/40 |
| Amlodipine/valsartan | Exforge | 5/160; 10/160; 5/320; 10/320 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Amlodipine/valsartan/HCTZ | Exforge HCT | 5/160/12.5; 10/160/12.5; 5/160/25; 10/160/25; 10/320/25 |
| Central α-Agonist + Thiazide Diuretic | ||
| Methyldopa/HCTZ | Aldoril Aldoril D | 250/15; 250/25 500/30; 500/50 |
| Direct Renin Inhibitor + Angiotensin II Receptor Blocker | ||
| Aliskiren/valsartan | Valturna | 150/160; 300/320 |
| Direct Renin Inhibitor + Calcium Channel Blocker | ||
| Aliskiren + amlodipine | Tekamlo | 150/5; 150/10; 300/5; 300/10 |
| Direct Renin Inhibitor + Thiazide Diuretic | ||
| Aliskiren/HCTZ | Tekturna HCT | 150/12.5; 150/25; 300/12.5; 300/25 |
| Direct Renin Inhibitor + Calcium Channel Blocker + Thiazide Diuretic | ||
| Aliskiren/amlodipine/HCTZ | Amturnide | 150/5/12.5; 300/5/12.5; 300/5/25; 300/10/12.5; 300/10/25 |
| Diuretic Combination (K+ Sparing + Thiazide) | ||
| Amiloride/HCTZ | Several generics | 5/50 (1-2) |
| Spironolactone/HCTZ | Aldactazide | 25/25 (1/2-1) |
| Triamterene/HCTZ | Dyazide Maxide | 37.5/25 (1/2-1) 37.5/25; 75/50 |
| ACEI, angiotensin-converting enzyme inhibitor; HCTZ, hydrochlorothiazide. aAll 1 dose/d unless otherwise noted. Source: Available at: http://www.RxList.com; http://www.Drugs.com; http://www.empr.com/combination-treatments-for-hypertension-chart/article/191718/. Accessed June 27-28, 2012. | ||
Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.15,16
Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.21
A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.22
One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.6
Other opportunities to improve adherence to antihypertensive medications
Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.23,24
Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.25
Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.24
Home blood pressure monitoring
Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.26 Many major medical societies recommend HBPM as part of any hypertension management strategy.27-30
Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.28 Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).31 Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.28 It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.
There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.32 This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.33,34
The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).35
A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).36
Conclusion
Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.
The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.
It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.
1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
2. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336(7653):1114-1117.
3. Nelson MR, Reid CM, Ryan P, Willson K, Yelland L. Self-reported adherence with medication and cardiovascular disease outcomes in the Second Australian National Blood Pressure Study (ANBP2). Med J Aust. 2006;185(9):487-489.
4. Muszbek N, Brixner D, Benedict A, Keskinaslan A, Khan ZM. The economic consequences of noncompliance in cardiovascular disease and related conditions: a literature review. Int J Clin Pract. 2008;62(2):338-351.
5. Jamerson K, Bakris GL, Dahlöf B, et al; . ACCOMPLISH Investigators. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press. 2007;16(2):80-86.
6. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4(2):90-98.
7. World Health Organization. Adherence to long-term therapies: evidence for action. http://apps.who.int/medicinedocs/en/d/Js4883e/. Published 2003. Accessed March 21, 2012.
8. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147-1152.
9. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
10. Fung V, Huang J, Brand R, Newhouse JP, Hsu J. Hypertension treatment in a medicare population: adherence and systolic blood pressure control. Clin Ther. 2007;29(5):972-984.
11. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344.
12. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62(3):443-462.
13. Paulis L, Steckelings UM, Unger T. Key advances in antihypertensive treatment. Nat Rev Cardiol. 2012;9(5):276-285.
14. Wood S. TIPS 2: Full-dose polypill boosts efficacy, with no increased side effects. theHeart.org Web site. http://www.theheart.org/article/1387105.do?utm_campaign=newsletter&utm_medium=email&utm_source=20120419_EN_Heartwire. Published April 19, 2012. Accessed April 20, 2012.
15. Hilleman DE, Ryschon KL, Mohiuddin SM, Wurdeman RL. Fixed-dose combination vs monotherapy in hypertension: a meta-analysis evaluation. J Hum Hyper-tens. 1999;13(7):477-483.
16. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53(4):646-653.
17. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(9 suppl):2-6.
18. Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm. 2007;64(12):1279-1283.
19. Brixner DI, Jackson KC, II, Sheng X, Nelson RE, Keskinaslan A. Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations. Curr Med Res Opin. 2008;24(9):2597-2607.
20. Baser O, Andrews LM, Wang L, Xie L. Comparison of real-world adherence, healthcare resource utilization and costs for newly initiated valsartan/amlodi-pine single-pill combination versus angiotensin receptor blocker/calcium channel blocker free-combination therapy. J Med Econ. 2011;14(5):576-583.
21. Simons LA, Ortiz M, Calcino G. Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006-2010. Med J Aust. 2011;195(3):134-137.
22. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-719.
23. Makaryus AN, Friedman EA. Patients’ understanding of their treatment plans and diagnosis at discharge. Mayo Clin Proc. 2005;80(8):991-994.
24. Harmon G, Lefante J, Krousel-Wood M. Overcoming barriers: the role of providers in improving patient adherence to antihypertensive medications. Curr Opin Cardiol. 2006;21(4):310-315.
25. Oliveria SA, Chen RS, McCarthy BD, Davis CC, Hill MN. Hypertension knowledge, awareness, and attitudes in a hypertensive population. J Gen Intern Med. 2005;20(3):219-225.
26. Abdullah A, Othman S. The influence of self-owned home blood pressure monitoring (HBPM) on primary care patients with hypertension: a qualitative study. BMC Fam Pract. 2011;12:143.-
27. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
28. Pickering TG, White WB. American Society of Hypertension Writing Group. When and how to use self (home) and ambulatory blood pressure monitoring. J Am Soc Hypertens. 2008;2(3):119-124.
29. Institute for Clinical Systems Improvement. Health Care Guideline: Hypertension Diagnosis and Treatment. 13th ed. http://icsi.org/hypertension_4/hypertension_diagnosis_and_treatment_4.html. Published November 2010. Accessed March 26, 2012.
30. National Institute for Health and Clinical Evidence. Hypertension: Clinical management of primary hypertension in adults. http://guidance.nice.org.uk/CG127. Published August 2011. Accessed March 26, 2012.
31. Mengden T, Chamontin B, Phong Chau N, Luis Palma Gamiz J, Chanudet X. User procedure for self-measurement of blood pressure. First International Consensus Conference on Self Blood Pressure Measurement. Blood Press Monit. 2000;5(2):111-129.
32. Ogedegbe G, Schoenthaler A. A systematic review of the effects of home blood pressure monitoring on medication adherence. J Clin Hypertens (Greenwich). 2006;8(3):174-180.
33. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review [published correction appears in JAMA. 2003;289(24):3242]. JAMA. 2002;288(22):2868-2879.
34. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60(7):657-665.
35. Vrijens B, Goetghebeur E. Comparing compliance patterns between randomized treatments. Control Clin Trials. 1997;18(3):187-203.
36. Souza WK, Jardim PC, Brito LP, Araújo FA, Sousa AL. Self measurement of blood pressure for control of blood pressure levels and adherence to treatment. Arq Bras Cardiol. 2012;98(2):167-174.
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
MODULE 4: Enhancing Adherence with Antihypertensives: The Role of Fixed-Dose Combinations and Home Blood Pressure Monitoring
Dr Kuritzky is a paid consultant to Takeda Pharmaceuticals International, Inc.
Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.1
The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.2
Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).3 Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.4
Barriers to adherence
A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.5,6 These medications must often be taken at different times of the day, with varying frequency.6-9
Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.
A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.10
In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.11,12
One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.13 In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.14
TABLE
Currently available combination therapies
| Fixed-Dose Combination | Brand Name | Dose Range, Total, mg/da |
|---|---|---|
| Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Azilsartan/chlorthalidone | Edarbyclor | 40/12.5; 40/25 |
| Candesartan/HCTZ | Atacand HCT | 16/12.5; 32/12.5; 32/25 |
| Eprosartan/HCTZ | Teveten HCT | 600/12.5; 600/25 |
| Irbesartan/HCTZ | Avalide | 150/12.5; 300/25 |
| Losartan/HCTZ | Hyzaar | 50/12.5; 100/12.5; 100/25 |
| Olmesartan/HCTZ | Benicar HCT | 20/12.5; 30/12.5 |
| Telmisartan/HCTZ | Micardis HCT | 40/12.5; 80/12.5; 80/25 |
| Valsartan/HCTZ | Diovan HCT | 80/12.5; 160/12.5; 160/25; 320/12.5 |
| β-Blocker + Thiazide Diuretic | ||
| Atenolol/chlorthalidone | Tenoretic | 50/25; 100/25 |
| Bisoprolol/HCTZ | Ziac | 2.5/6.25; 5/6.25; 10/6.25 |
| Metoprolol tartrate/HCTZ | Lopressor HCT | 50/25; 100/25; 100/50 |
| Metoprolol succinate extended/release + HCTZ | Dutoprol | 25/12.5; 50/12.5; 100/12.5 |
| Nadolol + bendroflumethiazide | Corzide | 40/5; 80/5 |
| Propanolol + HCTZ | Inderide | 40/25; 80/25 |
| Calcium Channel Blocker + ACEI | ||
| Amlodipine/benazepril | Lotrel | 2.5/10; 5/10; 5/20; 5/40; 10/20; 10/40 |
| ACEI + Thiazide Diuretic | ||
| Benazepril/HCTZ | Lotensin HCT | 5/6.25; 10/12.5; 20/12.5; 20/25 |
| Captopril/HCTZ | Capozide | 25/15; 25/25; 50/15; 50/25 |
| Enalapril/HCTZ | Vaseretic | 10/25 (1-2) |
| Fosinopril/HCTZ | Monopril HCT | 10/12.5; 20/12.5 |
| Lisinopril/HCTZ | Prinzide Zestoretic | 10/12.5; 20/12.5 20/25 |
| Moexipril/HCTZ | Uniretic | 7.5/12.5; 15/12.5; 15/25 |
| Quinapril + HCTZ | Accuretic | 10/12.5; 20/12.5; 20/25 |
| ACEI + Calcium Channel Blocker | ||
| Trandolapril/verapamil | Tarka | 2/180; 2/240; 4/240 |
| Enalapril/felodipine | Lexxel | 5/5 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker | ||
| Telmisartan/amlodipine | Twynsta | 40/5; 40/10; 80/5; 80/10 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker + Thiazide Diuretic | ||
| Olmesartan/amlodipine/HCTZ | Tribenzor | 40/10/25 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker | ||
| Amlodipine/olmesartan | Azor | 5/20; 5/40; 10/20; 10/40 |
| Amlodipine/valsartan | Exforge | 5/160; 10/160; 5/320; 10/320 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Amlodipine/valsartan/HCTZ | Exforge HCT | 5/160/12.5; 10/160/12.5; 5/160/25; 10/160/25; 10/320/25 |
| Central α-Agonist + Thiazide Diuretic | ||
| Methyldopa/HCTZ | Aldoril Aldoril D | 250/15; 250/25 500/30; 500/50 |
| Direct Renin Inhibitor + Angiotensin II Receptor Blocker | ||
| Aliskiren/valsartan | Valturna | 150/160; 300/320 |
| Direct Renin Inhibitor + Calcium Channel Blocker | ||
| Aliskiren + amlodipine | Tekamlo | 150/5; 150/10; 300/5; 300/10 |
| Direct Renin Inhibitor + Thiazide Diuretic | ||
| Aliskiren/HCTZ | Tekturna HCT | 150/12.5; 150/25; 300/12.5; 300/25 |
| Direct Renin Inhibitor + Calcium Channel Blocker + Thiazide Diuretic | ||
| Aliskiren/amlodipine/HCTZ | Amturnide | 150/5/12.5; 300/5/12.5; 300/5/25; 300/10/12.5; 300/10/25 |
| Diuretic Combination (K+ Sparing + Thiazide) | ||
| Amiloride/HCTZ | Several generics | 5/50 (1-2) |
| Spironolactone/HCTZ | Aldactazide | 25/25 (1/2-1) |
| Triamterene/HCTZ | Dyazide Maxide | 37.5/25 (1/2-1) 37.5/25; 75/50 |
| ACEI, angiotensin-converting enzyme inhibitor; HCTZ, hydrochlorothiazide. aAll 1 dose/d unless otherwise noted. Source: Available at: http://www.RxList.com; http://www.Drugs.com; http://www.empr.com/combination-treatments-for-hypertension-chart/article/191718/. Accessed June 27-28, 2012. | ||
Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.15,16
Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.21
A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.22
One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.6
Other opportunities to improve adherence to antihypertensive medications
Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.23,24
Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.25
Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.24
Home blood pressure monitoring
Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.26 Many major medical societies recommend HBPM as part of any hypertension management strategy.27-30
Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.28 Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).31 Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.28 It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.
There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.32 This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.33,34
The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).35
A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).36
Conclusion
Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.
The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.
It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.
MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension
MODULE 3: Using Thiazide-Type Diuretics in African Americans with Hypertension
MODULE 4: Enhancing Adherence with Antihypertensives: The Role of Fixed-Dose Combinations and Home Blood Pressure Monitoring
Dr Kuritzky is a paid consultant to Takeda Pharmaceuticals International, Inc.
Although an estimated 1 out of 3 people in the United States has been diagnosed with hypertension, data from the 2007-2008 National Health and Nutrition Examination Survey found that just 72% are currently being treated and, of those, just half have their blood pressure (BP) controlled with lifestyle changes and/or medication.1
The failure of so many people with hypertension to obtain BP control, despite the availability of numerous effective medications, is partially due to a lack of adherence to recommended treatments (eg, taking medication, following a diet, and executing lifestyle changes). Adherence is a significant problem in hypertension and evidence shows that just half of patients who initiate drug therapy are persistent with treatment after 1 year.2
Although few studies link nonadherence with long-term outcomes, 1 study found that patients who “forgot” to take their antihypertensive medication were nearly one-third more likely to experience a cardiovascular event or death (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.04-1.57).3 Adherence is important not only for the health of the patient, but also to provide overall cost savings from the reductions of hospitalizations for complications from an untreated disease.4
Barriers to adherence
A significant contributor to nonadherence is treatment complexity, which manifests in hypertension as pill burden. Up to 75% of patients will require more than 1 medication to control their BP; those with resistant hypertension will require 4 or more.5,6 These medications must often be taken at different times of the day, with varying frequency.6-9
Reducing the number of daily doses has been consistently found to enhance adherence, and should be considered routinely as a first-line strategy. Complex strategies (eg, group visits, designated office staff to assist hypertensive patients, pharmacist consultation and comanagement, exercise counseling, dietary counseling, multidisciplinary hypertension team care, specific interviewing techniques such as motivational interviewing) are promising, but individual clinicians may not have the resources to take advantage of such labor-intensive intervention. Further, when multimodal intervention is employed, it is often difficult to discern which component(s) of the intervention were most impactful, unless multifactorial study design is employed, which it rarely is. We await further randomized controlled trials in this regard.
A study of approximately 85,000 members of a large managed care organization found that the greater the number of antihypertensive medications prescribed, the lower the rate of patient adherence. Just 63% of those receiving 3-drug regimens and 55% of those receiving 4-drug regimens were completely adherent.10
In addition, many patients with hypertension, particularly older patients, have comorbid conditions (eg, dyslipidemia or diabetes) that also require treatment, leading to increased treatment complexity and pill burden.11,12
One option for reducing pill burden is the use of fixed-dose therapies ( TABLE ). Since 2000, many new fixed-dose combinations, including at least 3 triple therapies, have entered the market.13 In addition, a so-called “poly-pill” that combines aspirin, 3 antihypertensives, and a statin is under investigation and demonstrating good results in reducing BP and cholesterol levels.14
TABLE
Currently available combination therapies
| Fixed-Dose Combination | Brand Name | Dose Range, Total, mg/da |
|---|---|---|
| Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Azilsartan/chlorthalidone | Edarbyclor | 40/12.5; 40/25 |
| Candesartan/HCTZ | Atacand HCT | 16/12.5; 32/12.5; 32/25 |
| Eprosartan/HCTZ | Teveten HCT | 600/12.5; 600/25 |
| Irbesartan/HCTZ | Avalide | 150/12.5; 300/25 |
| Losartan/HCTZ | Hyzaar | 50/12.5; 100/12.5; 100/25 |
| Olmesartan/HCTZ | Benicar HCT | 20/12.5; 30/12.5 |
| Telmisartan/HCTZ | Micardis HCT | 40/12.5; 80/12.5; 80/25 |
| Valsartan/HCTZ | Diovan HCT | 80/12.5; 160/12.5; 160/25; 320/12.5 |
| β-Blocker + Thiazide Diuretic | ||
| Atenolol/chlorthalidone | Tenoretic | 50/25; 100/25 |
| Bisoprolol/HCTZ | Ziac | 2.5/6.25; 5/6.25; 10/6.25 |
| Metoprolol tartrate/HCTZ | Lopressor HCT | 50/25; 100/25; 100/50 |
| Metoprolol succinate extended/release + HCTZ | Dutoprol | 25/12.5; 50/12.5; 100/12.5 |
| Nadolol + bendroflumethiazide | Corzide | 40/5; 80/5 |
| Propanolol + HCTZ | Inderide | 40/25; 80/25 |
| Calcium Channel Blocker + ACEI | ||
| Amlodipine/benazepril | Lotrel | 2.5/10; 5/10; 5/20; 5/40; 10/20; 10/40 |
| ACEI + Thiazide Diuretic | ||
| Benazepril/HCTZ | Lotensin HCT | 5/6.25; 10/12.5; 20/12.5; 20/25 |
| Captopril/HCTZ | Capozide | 25/15; 25/25; 50/15; 50/25 |
| Enalapril/HCTZ | Vaseretic | 10/25 (1-2) |
| Fosinopril/HCTZ | Monopril HCT | 10/12.5; 20/12.5 |
| Lisinopril/HCTZ | Prinzide Zestoretic | 10/12.5; 20/12.5 20/25 |
| Moexipril/HCTZ | Uniretic | 7.5/12.5; 15/12.5; 15/25 |
| Quinapril + HCTZ | Accuretic | 10/12.5; 20/12.5; 20/25 |
| ACEI + Calcium Channel Blocker | ||
| Trandolapril/verapamil | Tarka | 2/180; 2/240; 4/240 |
| Enalapril/felodipine | Lexxel | 5/5 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker | ||
| Telmisartan/amlodipine | Twynsta | 40/5; 40/10; 80/5; 80/10 |
| Angiotensin II Receptor Blocker + Calcium Channel Blocker + Thiazide Diuretic | ||
| Olmesartan/amlodipine/HCTZ | Tribenzor | 40/10/25 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker | ||
| Amlodipine/olmesartan | Azor | 5/20; 5/40; 10/20; 10/40 |
| Amlodipine/valsartan | Exforge | 5/160; 10/160; 5/320; 10/320 |
| Calcium Channel Blocker + Angiotensin II Receptor Blocker + Thiazide Diuretic | ||
| Amlodipine/valsartan/HCTZ | Exforge HCT | 5/160/12.5; 10/160/12.5; 5/160/25; 10/160/25; 10/320/25 |
| Central α-Agonist + Thiazide Diuretic | ||
| Methyldopa/HCTZ | Aldoril Aldoril D | 250/15; 250/25 500/30; 500/50 |
| Direct Renin Inhibitor + Angiotensin II Receptor Blocker | ||
| Aliskiren/valsartan | Valturna | 150/160; 300/320 |
| Direct Renin Inhibitor + Calcium Channel Blocker | ||
| Aliskiren + amlodipine | Tekamlo | 150/5; 150/10; 300/5; 300/10 |
| Direct Renin Inhibitor + Thiazide Diuretic | ||
| Aliskiren/HCTZ | Tekturna HCT | 150/12.5; 150/25; 300/12.5; 300/25 |
| Direct Renin Inhibitor + Calcium Channel Blocker + Thiazide Diuretic | ||
| Aliskiren/amlodipine/HCTZ | Amturnide | 150/5/12.5; 300/5/12.5; 300/5/25; 300/10/12.5; 300/10/25 |
| Diuretic Combination (K+ Sparing + Thiazide) | ||
| Amiloride/HCTZ | Several generics | 5/50 (1-2) |
| Spironolactone/HCTZ | Aldactazide | 25/25 (1/2-1) |
| Triamterene/HCTZ | Dyazide Maxide | 37.5/25 (1/2-1) 37.5/25; 75/50 |
| ACEI, angiotensin-converting enzyme inhibitor; HCTZ, hydrochlorothiazide. aAll 1 dose/d unless otherwise noted. Source: Available at: http://www.RxList.com; http://www.Drugs.com; http://www.empr.com/combination-treatments-for-hypertension-chart/article/191718/. Accessed June 27-28, 2012. | ||
Studies have found that patients receiving fixed-dose combination pills are more likely to reach their target BP, physicians are more satisfied with their ability to manage hypertension, and adverse effects are either similar or less with the fixed-dose therapies compared with monotherapies.15,16
Studies of adherence patterns among patients treated with fixed-dose combinations of antihypertensive agents vs separate antihypertensive agents demonstrate increased adherence among patients treated with fixed-dose combinations.17-21 In a clinical trial involving 4146 participants who were treated with a fixed dose of amlodipine and atorvastatin or separate pills, 33% of patients in the fixed-dose cohort had ceased treatment by 12 months compared with 59% of patients who were taking the 2-pill regimen (HR, 2.17; 95% CI, 2.05–2.13; P < .0001), resulting in a 117% higher rate of nonadherence in the 2-pill regimen. The median persistence time (ie, time to discontinuation with medication) was 8 months with the 2-pill regimen, but 37 months or longer with the fixed-dose combination.21
A meta-analysis of 9 studies found that fixed-dose combinations reduced the risk of nonadherence by 26% compared with single-pill combination therapy.22
One downside to fixed-dose therapy is cost. Out-of-pocket costs are a significant barrier to medication adherence and most fixed-dose options are branded drugs that generally require higher copayments or coinsurance vs generic single-pill drugs that may have copayments as low as $4.6
Other opportunities to improve adherence to antihypertensive medications
Other evidence-based opportunities to improve adherence to antihypertensive medications include improved relationships with, and communication from, health care providers, given that patients often do not understand their disease and recommended treatments.23,24
Interviews with 826 patients with hypertension found that although 90% knew that lowering their BP would improve their health and 91% reported that a health care provider had told them that they had hypertension or high BP, 41% did not know their BP level. In addition, just 34% of patients with hypertension identified systolic BP (SBP) as the “top” number of their reading and only 32% identified diastolic BP (DBP) as the “bottom” number. Finally, only one-third of patients were able to identify both SBP and DBP, and one-quarter of them did not know the optimal level for either.25
Other provider interventions that have resulted in improved adherence include changing medication to reduce or avoid adverse effects, simplifying dosing (as described earlier), and switching to less-expensive drugs if cost is an issue. Nurses and pharmacists are also important members of the team when it comes to improving adherence and reinforcing education.24
Home blood pressure monitoring
Another reason for nonadherence is that patients may not believe they need treatment since hypertension rarely manifests with symptoms. Furthermore, patients may not perceive that the medication they take has any effect because they did not have symptoms to begin with. Home BP monitoring (HBPM), or self BP monitoring, is one tool for improving adherence, possibly by providing immediate feedback to patients on how well their BP is controlled.26 Many major medical societies recommend HBPM as part of any hypertension management strategy.27-30
Patients who use HBPM can avoid many limitations associated with office BP monitoring (OBPM), including poor measurement techniques, infrequent measurement, white coat hypertension, and masked hypertension. Patients can also avoid reverse white coat hypertension, where OBPM is normal although out-of-office BP is high.28 Patients should take 3 readings at 1-minute intervals, usually in the morning and evening. The weekly average of these readings is their home BP (normotension is defined as an average BP <135/85 mm Hg).31 Typically, the HBPM monitoring is more accurate in identifying risk than OBPM when there are discrepancies between them.28 It is good practice to instruct patients utilizing HBPM to bring their home BP device to the office for a comparison.
There is some evidence that HBPM may contribute to improved adherence. A systematic review of 11 randomized controlled trials found that in 6 trials the use of HBPM resulted in improved medication adherence, although in 5 of those studies additional interventions were used. These interventions included patient counseling about adverse effects of the medication, timepiece caps that reminded patients to take their medication, tips to enhance adherence, and reinforcement of positive behavior by nurses, pharmacists, lay health workers, or a telephonic system.32 This illustrates an important point in adherence interventions: more is better, and it usually takes a combination of approaches to improve adherence.33,34
The only trial in the review that demonstrated that HBPM alone improved adherence randomized 628 patients to either HBPM or usual care for 6 weeks. The groups had similar compliance rates at baseline, and both demonstrated less adherence at the end of the 6-week trial. However, patients who measured their BP at home still demonstrated greater compliance than those receiving usual care (P < .05).35
A more recent trial in 57 patients, 38 of whom measured their BP at home and 19 of whom received usual care, found greater medication adherence in the HBPM group than in the control group (100% vs 88%, P < .031). The HBPM group also reached their treatment goals significantly faster than the control group (P = .02).36
Conclusion
Approximately 50% of individuals with hypertension who receive antihypertensive medication still do not reach their BP goal. One reason is nonadherence to medication, which is often related to treatment complexity, or pill burden. Given that most patients with hypertension will require more than 1 drug to manage their blood pressure, it is important that clinicians identify opportunities to simplify treatment. This may include fixed-dose combination therapy, which can improve adherence, as well as additional education regarding the efficacy and adverse effects of therapy.
The use of HBPM may also improve adherence by providing frequent feedback on treatment effectiveness.
It is important, however, that clinicians understand that no single approach to adherence will work for every patient. The greatest success comes with combining several approaches based on the barriers that affect each individual patient.
1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
2. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336(7653):1114-1117.
3. Nelson MR, Reid CM, Ryan P, Willson K, Yelland L. Self-reported adherence with medication and cardiovascular disease outcomes in the Second Australian National Blood Pressure Study (ANBP2). Med J Aust. 2006;185(9):487-489.
4. Muszbek N, Brixner D, Benedict A, Keskinaslan A, Khan ZM. The economic consequences of noncompliance in cardiovascular disease and related conditions: a literature review. Int J Clin Pract. 2008;62(2):338-351.
5. Jamerson K, Bakris GL, Dahlöf B, et al; . ACCOMPLISH Investigators. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press. 2007;16(2):80-86.
6. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4(2):90-98.
7. World Health Organization. Adherence to long-term therapies: evidence for action. http://apps.who.int/medicinedocs/en/d/Js4883e/. Published 2003. Accessed March 21, 2012.
8. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147-1152.
9. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
10. Fung V, Huang J, Brand R, Newhouse JP, Hsu J. Hypertension treatment in a medicare population: adherence and systolic blood pressure control. Clin Ther. 2007;29(5):972-984.
11. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344.
12. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62(3):443-462.
13. Paulis L, Steckelings UM, Unger T. Key advances in antihypertensive treatment. Nat Rev Cardiol. 2012;9(5):276-285.
14. Wood S. TIPS 2: Full-dose polypill boosts efficacy, with no increased side effects. theHeart.org Web site. http://www.theheart.org/article/1387105.do?utm_campaign=newsletter&utm_medium=email&utm_source=20120419_EN_Heartwire. Published April 19, 2012. Accessed April 20, 2012.
15. Hilleman DE, Ryschon KL, Mohiuddin SM, Wurdeman RL. Fixed-dose combination vs monotherapy in hypertension: a meta-analysis evaluation. J Hum Hyper-tens. 1999;13(7):477-483.
16. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53(4):646-653.
17. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(9 suppl):2-6.
18. Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm. 2007;64(12):1279-1283.
19. Brixner DI, Jackson KC, II, Sheng X, Nelson RE, Keskinaslan A. Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations. Curr Med Res Opin. 2008;24(9):2597-2607.
20. Baser O, Andrews LM, Wang L, Xie L. Comparison of real-world adherence, healthcare resource utilization and costs for newly initiated valsartan/amlodi-pine single-pill combination versus angiotensin receptor blocker/calcium channel blocker free-combination therapy. J Med Econ. 2011;14(5):576-583.
21. Simons LA, Ortiz M, Calcino G. Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006-2010. Med J Aust. 2011;195(3):134-137.
22. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-719.
23. Makaryus AN, Friedman EA. Patients’ understanding of their treatment plans and diagnosis at discharge. Mayo Clin Proc. 2005;80(8):991-994.
24. Harmon G, Lefante J, Krousel-Wood M. Overcoming barriers: the role of providers in improving patient adherence to antihypertensive medications. Curr Opin Cardiol. 2006;21(4):310-315.
25. Oliveria SA, Chen RS, McCarthy BD, Davis CC, Hill MN. Hypertension knowledge, awareness, and attitudes in a hypertensive population. J Gen Intern Med. 2005;20(3):219-225.
26. Abdullah A, Othman S. The influence of self-owned home blood pressure monitoring (HBPM) on primary care patients with hypertension: a qualitative study. BMC Fam Pract. 2011;12:143.-
27. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
28. Pickering TG, White WB. American Society of Hypertension Writing Group. When and how to use self (home) and ambulatory blood pressure monitoring. J Am Soc Hypertens. 2008;2(3):119-124.
29. Institute for Clinical Systems Improvement. Health Care Guideline: Hypertension Diagnosis and Treatment. 13th ed. http://icsi.org/hypertension_4/hypertension_diagnosis_and_treatment_4.html. Published November 2010. Accessed March 26, 2012.
30. National Institute for Health and Clinical Evidence. Hypertension: Clinical management of primary hypertension in adults. http://guidance.nice.org.uk/CG127. Published August 2011. Accessed March 26, 2012.
31. Mengden T, Chamontin B, Phong Chau N, Luis Palma Gamiz J, Chanudet X. User procedure for self-measurement of blood pressure. First International Consensus Conference on Self Blood Pressure Measurement. Blood Press Monit. 2000;5(2):111-129.
32. Ogedegbe G, Schoenthaler A. A systematic review of the effects of home blood pressure monitoring on medication adherence. J Clin Hypertens (Greenwich). 2006;8(3):174-180.
33. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review [published correction appears in JAMA. 2003;289(24):3242]. JAMA. 2002;288(22):2868-2879.
34. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60(7):657-665.
35. Vrijens B, Goetghebeur E. Comparing compliance patterns between randomized treatments. Control Clin Trials. 1997;18(3):187-203.
36. Souza WK, Jardim PC, Brito LP, Araújo FA, Sousa AL. Self measurement of blood pressure for control of blood pressure levels and adherence to treatment. Arq Bras Cardiol. 2012;98(2):167-174.
1. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303(20):2043-2050.
2. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336(7653):1114-1117.
3. Nelson MR, Reid CM, Ryan P, Willson K, Yelland L. Self-reported adherence with medication and cardiovascular disease outcomes in the Second Australian National Blood Pressure Study (ANBP2). Med J Aust. 2006;185(9):487-489.
4. Muszbek N, Brixner D, Benedict A, Keskinaslan A, Khan ZM. The economic consequences of noncompliance in cardiovascular disease and related conditions: a literature review. Int J Clin Pract. 2008;62(2):338-351.
5. Jamerson K, Bakris GL, Dahlöf B, et al; . ACCOMPLISH Investigators. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press. 2007;16(2):80-86.
6. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4(2):90-98.
7. World Health Organization. Adherence to long-term therapies: evidence for action. http://apps.who.int/medicinedocs/en/d/Js4883e/. Published 2003. Accessed March 21, 2012.
8. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165(10):1147-1152.
9. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497.
10. Fung V, Huang J, Brand R, Newhouse JP, Hsu J. Hypertension treatment in a medicare population: adherence and systolic blood pressure control. Clin Ther. 2007;29(5):972-984.
11. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287(3):337-344.
12. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62(3):443-462.
13. Paulis L, Steckelings UM, Unger T. Key advances in antihypertensive treatment. Nat Rev Cardiol. 2012;9(5):276-285.
14. Wood S. TIPS 2: Full-dose polypill boosts efficacy, with no increased side effects. theHeart.org Web site. http://www.theheart.org/article/1387105.do?utm_campaign=newsletter&utm_medium=email&utm_source=20120419_EN_Heartwire. Published April 19, 2012. Accessed April 20, 2012.
15. Hilleman DE, Ryschon KL, Mohiuddin SM, Wurdeman RL. Fixed-dose combination vs monotherapy in hypertension: a meta-analysis evaluation. J Hum Hyper-tens. 1999;13(7):477-483.
16. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53(4):646-653.
17. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(9 suppl):2-6.
18. Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm. 2007;64(12):1279-1283.
19. Brixner DI, Jackson KC, II, Sheng X, Nelson RE, Keskinaslan A. Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations. Curr Med Res Opin. 2008;24(9):2597-2607.
20. Baser O, Andrews LM, Wang L, Xie L. Comparison of real-world adherence, healthcare resource utilization and costs for newly initiated valsartan/amlodi-pine single-pill combination versus angiotensin receptor blocker/calcium channel blocker free-combination therapy. J Med Econ. 2011;14(5):576-583.
21. Simons LA, Ortiz M, Calcino G. Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006-2010. Med J Aust. 2011;195(3):134-137.
22. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-719.
23. Makaryus AN, Friedman EA. Patients’ understanding of their treatment plans and diagnosis at discharge. Mayo Clin Proc. 2005;80(8):991-994.
24. Harmon G, Lefante J, Krousel-Wood M. Overcoming barriers: the role of providers in improving patient adherence to antihypertensive medications. Curr Opin Cardiol. 2006;21(4):310-315.
25. Oliveria SA, Chen RS, McCarthy BD, Davis CC, Hill MN. Hypertension knowledge, awareness, and attitudes in a hypertensive population. J Gen Intern Med. 2005;20(3):219-225.
26. Abdullah A, Othman S. The influence of self-owned home blood pressure monitoring (HBPM) on primary care patients with hypertension: a qualitative study. BMC Fam Pract. 2011;12:143.-
27. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
28. Pickering TG, White WB. American Society of Hypertension Writing Group. When and how to use self (home) and ambulatory blood pressure monitoring. J Am Soc Hypertens. 2008;2(3):119-124.
29. Institute for Clinical Systems Improvement. Health Care Guideline: Hypertension Diagnosis and Treatment. 13th ed. http://icsi.org/hypertension_4/hypertension_diagnosis_and_treatment_4.html. Published November 2010. Accessed March 26, 2012.
30. National Institute for Health and Clinical Evidence. Hypertension: Clinical management of primary hypertension in adults. http://guidance.nice.org.uk/CG127. Published August 2011. Accessed March 26, 2012.
31. Mengden T, Chamontin B, Phong Chau N, Luis Palma Gamiz J, Chanudet X. User procedure for self-measurement of blood pressure. First International Consensus Conference on Self Blood Pressure Measurement. Blood Press Monit. 2000;5(2):111-129.
32. Ogedegbe G, Schoenthaler A. A systematic review of the effects of home blood pressure monitoring on medication adherence. J Clin Hypertens (Greenwich). 2006;8(3):174-180.
33. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review [published correction appears in JAMA. 2003;289(24):3242]. JAMA. 2002;288(22):2868-2879.
34. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60(7):657-665.
35. Vrijens B, Goetghebeur E. Comparing compliance patterns between randomized treatments. Control Clin Trials. 1997;18(3):187-203.
36. Souza WK, Jardim PC, Brito LP, Araújo FA, Sousa AL. Self measurement of blood pressure for control of blood pressure levels and adherence to treatment. Arq Bras Cardiol. 2012;98(2):167-174.