Controversal question: When and in which patients would you initiate antihypertensive treatment with a fixed combination?



When and in which patients would you initiate antihypertensive treatment with a fixed combination?

1. H. R. Black, USA
2. I. E. Chazova, Russia
3. J. Dalal, India
4. H. Elghetany, Egypt
5. Z. Gaciong, Poland
6. Ö. Kozan, E. E. Özcan, Turkey
7. G. Latkovskis, Latvia
8. J. Polónia, Portugal
9. Y. Sirenko, Ukraine
10. C. Tsioufis, Greece
11. P. N. Vinh, Vietnam




1. H. R. Black, USA



Henry R. BLACK, MD, MACP, FASH
Clinical Professor of Internal Medicine
New York University School of Medicine
Center for the Prevention of
Cardiovascular Disease
New York, NY 10024, USA
(e-mail: hrbmd63@gmail.com)



In the 1960s, the most popular initial treatment for hypertension was a fixed-dose combination (FDC) of three drugs: hydrochlorothiazide, reserpine, and hydralazine (Ser-Ap- Es®).With the development of newer antihypertensives came a choice between two basic approaches when initiating therapy. One, “stepped care,” recommends starting with one drug, increasing it to the highest tolerated dose, before adding agents of a different class in a stepwise fashion, until the treatment goal is reached. The alternative, “sequential monotherapy,” recommends starting with a drug of the class expected to be most effective based on demography, pathophysiology, comorbidity, and other risk factors, and titrating that drug until the highest tolerated and appropriate dose is reached. Should the patient not achieve the goal, or if the first choice was poorly tolerated, then rather than add a drug of a different class, the recommendation would be to stop the first drug and start one of a different class—also at the lowest dose— and titrate.

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) offered both choices, but JNC 7 dropped the recommendation for sequential monotherapy, as it became clear that most hypertensives, perhaps as many as 75%, needed two or more drugs to reach goal BP, and based on results from the VALUE trial (Valsartan Antihypertensive Longterm Use Evaluation), the time duration to get to that goal was also recognized as important.1,2 Sequential monotherapy may simply take too long, but stepped care can also be a lengthy process involving multiple dose titrations before the right regimen is achieved.

JNC 7, and later, European guidelines, recommended that initial treatment for hypertensives with systolic BP ≥160 mm Hg and/or diastolic BP ≥100 mm Hg (and some with systolic BP ≥140-159 mm Hg and/or diastolic BP ≥90-99 mm Hg) begin with two drugs. The rationale was that high-risk hypertensives— determined on the basis of BP, target organ damage, diabetes mellitus, and other risk factors (lipid profile or smoking)— needed to be aggressively treated to get their BP to goal promptly.2,3

If treatment with two or more drugs would ultimately be required, why not start treatment with two drugs? In addition to the more robust BP reduction, combining agents with different mechanisms of action broadens the treatment spectrum and can reduce the metabolic and clinical adverse reactions seen with either or both drugs individually.

But what about starting treatment with an FDC if the compounds in that combination match what the clinician wants to use? Combining drugs in a pharmacokinetically and pharmacodynamically calibrated FDC assures that the doses and timing of treatment is appropriate. Using FDCsmay improve treatment adherence and reduce the pill burden for patients on multidrug regimens. FDCs are usually less expensive than each element separately, since there is a single charge rather than one for each prescription. But there are disadvantages. The desired combination may not be available. The dose titration schedule may not be possible with the FDCs available. And dose-independent adverse events such as angioedema, or cough with angiotensin-converting enzyme (ACE) inhibitors, may occur if the drugs are used in fixed combination rather than as a two-drug combination separately.

The wise clinician will start therapy with an FDC in a high-risk patient for whom they feel getting BP to goal promptly is necessary. In such patients, starting with an FDC is appropriate, if the right combination is available and affordable.

If we are to manage the worldwide cardiovascular epidemic and burden that hypertension places on our health care systems, we must improve the quality of care we give our citizens and improve the rates of getting BP to goal. The skillful use of FDCs will advance this aim.

References
1. [No authors listed] The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-2446.
2. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
3. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.




2. I. E. Chazova, Russia



Irina E. CHAZOVA, MD, PhD
Professor, Director of the Institute of
Clinical Cardiology of the Russian Cardiology
Scientific and Production Complex
3rd Cherepkovskaya str, 15a
Moscow, RUSSIA
(e-mail: chazova@hotmail.com)



The main goal in the treatment of hypertension is reduction of cardiovascular (CV) events and mortality risk. This is only achievable with tight blood pressure (BP) control. Many large studies have shown that BP reduction decreases CV events and mortality risk in hypertensive patients. Twenty-two randomized controlled trials incorporating 210 566 participants were recently analyzed,1 and the authors concluded that BP reduction per se has significant prognostic value regardless of baseline BP.

Current guidelines on diagnosis and treatment of hypertension recommend target BP 130-139/80-89 mm Hg in all patients, except those with kidney disease (<130/80 mm Hg). The lower limits (systolic BP 110-115 mm Hg and diastolic BP 70-75 mm Hg) should also be kept in mind. Achievement of such a low target BP with a single drug, even at the highest dose, is only possible in one-third of patients with uncomplicated hypertension. In patients with elevated BP and target organ lesions, metabolic syndrome, diabetes, or associated clinical conditions, the efficacy of monotherapy becomes doubtful. It is thus recommended that in patients with high/very high risk, therapy commence with two medications at low doses. Combination therapy has many advantages: (i) increased antihypertensive effect due to the different drug mechanisms of action, hence increased numbers of patients with stable BP reduction; (ii) less frequent side effects due to lower drug doses and mutual neutralization of side effects; and (iii) the most effective organ protection and reduction of risk and CV events. Furthermore, it is evident that in the choice of treatment strategy, “the lower the better” should be replaced by “the sooner the better.” The need for achievement of BP goal in the shortest time to reduce the risk of CV events and mortality was demonstrated in the VALUE trial (Valsartan Antihypertensive Long-term Use Evaluation).2 Systolic BP lowering to <140 mm Hg during the first 6 months, regardless of treatment (valsartan or amlodipine), resulted in a significant decrease in the risk of death from CV causes, risk of fatal stroke, number of hospitalizations due to heart failure, and all-cause mortality, compared with patients who retained higher systolic BP. Combination therapy reduces BP more quickly than monotherapy. The main drawbacks of monotherapy are the need for frequent changes of medication and the delay caused by the need to choose a rational effective treatment. For combination therapy, both free and fixed-dose combinations (FDC) can be used. However, preference should be given to FDCs, containing two drugs in one pill. The only case for withdrawing an FDC should be impossibility of use, because such a combination: (i) will always be rational; (ii) represents the most effective strategy for achieving and maintaining target BP; (iii) provides the best organ protection and reduction of CV risk; and (iv) reduces the number of tablets, substantially improving patient compliance. Several studies have demonstrated the advantages of FDCs over free combinations. The largest meta-analysis was published in 2010.3 This included data for 32 331 hypertensives who received either free combinations or FDCs comprising similar drug classes. FDCs were associated with significantly higher compliance levels, as well as a trend toward greater BP reduction.

The only significant argument against FDCs is limited dosage varieties. The newest FDCs avoid this, as they come with different dose ratios. For example, perindopril/amlodipine is presented in four dosages, containing 5 mg/5 mg, 5 mg/10 mg, 10 mg/5 mg, and 10 mg/10 mg. Perindopril/indapamide is available in three dosages—2.5 mg/0.625 mg, 5 mg/1.25 mg, and 10 mg/2.5 mg.

The era of monotherapy domination has finished and is being replaced by the era of FDCs intended for use in a wide range of hypertensive patients, especially those at high or very high risk, regardless of baseline BP.

References
1. Czernichow S, Zanchetti A, Turnbull F, et al. The effects of blood pressure reduction and of different blood pressure lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials. J Hypertens. 2011;29:4-16.
2. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet. 2004;363:2049-2051.
3. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents. Hypertension. 2010;55: 399-407.




3. J. Dalal, India

Jamshed DALAL, MD, DM, PhD (UK)
Flat 1101, Raheja Grande
Turner Road, Bandra
Mumbai 400050, INDIA
(e-mail: jjdalal@hotmail.com)



Evidence suggests that a combination of at least two drugs is often required to control blood pressure (BP), especially in patients with diabetes or renal insufficiency.1 In the recent ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial), 90% of patients required a combination.2

There is increasing appreciation of the benefits of initiating antihypertensive treatment with a combination of two drugs instead of the traditional single drug, sequential, stepwise titration strategy. Although this may unnecessarily expose the patient to a second drug, there are several advantages: first, ACCELERATE (Aliskiren and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension) showed that initiating treatment with a fixeddose combination (FDC) of two agents is significantly more effective and quicker in controlling BP than the same two agents in a sequential drug titration strategy.3 This reassures patients and helps them retain their motivation to comply with longterm treatment. FDC, in a single tablet, once daily, simplifies treatment and improves compliance, and early normalization of BP is beneficial in reducing long-term vascular complications. Second, drugs in combination can act synergistically to reduce BP at lower doses, with lesser side effects. In many instances, they counteract the side effects of one another, further increasing compliance.

For these reasons, recent guidelines4 recommend initiation of antihypertensive treatment with drug combinations when BP is >20 mm Hg systolic or 10 mm Hg diastolic above the hypertension threshold, or for milder hypertension associated with multiple risk factors or subclinical organ damage. Except in mild hypertensives, I introduce therapy with a single, once daily, FDC. Preferred combinations are: (i) angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) plus thiazide diuretic; (ii) calcium channel blocker (CCB) plus ACEinhibitororARB; and (iii) β_-blocker plusCCB. Recently, the ACCOMPLISH trial (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension) showed that an ACE inhibitor plus CCB FDC is more beneficial than ACE inhibitor plus diuretic. However, the low dose of hydrochlorothiazide used may not have provided as effective 24-hour BP control as the ACE inhibitor plus amlodipine.5

In my clinical practice, most patients present with stage 2 hypertension and concomitant disease: I start with an FDC or substitute monotherapy for an FDC using any of the aforementioned combinations depending on cardiac/other conditions. Since many of my patients have coronary artery disease, I often use a long-acting β-blocker along with a CCB. Although the combination of β-blocker plus thiazide diuretic was effective in earlier trials, I avoid it as my first choice in patients at high risk of diabetes.4

If adequate BP control is not achieved, the next step would be to add an ARB with a diuretic. In general, I find FDCs containing an ARB more acceptable to my patients than an ACE inhibitor, due to the prevalence of cough among Indians. If a patient has reduced ejection fraction or previous myocardial infarction, I will always add an ACE inhibitor (ARB, if not tolerated). I do not combine an ACE inhibitor with an ARB, as it increases side effects without any additional benefit.6

Triple-drug FDCs containing ARB, CCB (amlodipine), and diuretic are available in India. In patients with resistant hypertension, I prescribe this triple-drug FDC in the morning and add an FDC containing bisoprolol with amlodipine at night. The vast majority of my patients are on two tablets daily, each an FDC. This controls about 80% of my patients. With FDCs (of two or three drugs each), no individual, however severe their hypertension, need take more than three tablets a day. This allows target BP control along with long-term compliance.

References
1. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351: 1755-1762.
2. Dahlof B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendoflumethiazide as required, in the Anglo- ScandinavianCardiacOutcomesTrial—BloodPressure LoweringArm(ASCOTBPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895-906.
3. Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet. 2011;377:312-320.
4. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
5. Jamerson KA, Bakris GL, Wun CC, et al. Rationale and design of the avoiding cardiovascular events through combination therapy in patients living with systolic hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens. 2004;17:793-801.
6. Teo K, Yusuf S, Sleight P, et al; ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/ Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148: 52-61.




4. H. Elghetany, Egypt

Hossam ELGHETANY, MD
Professor of Cardiology
Ain Shams University, Cairo
Cardiology Consultant
Dr Soliman Fakeeh Hospital
Jeddah, Kingdom of Saudi Arabia
EGYPT
(e-mail: hossam_elghetany@yahoo.com)



Hypertension is prevalent as a major cardiovascular risk factor. Treating hypertension to target blood pressure (BP) would avert the risk in most individuals. In clinical practice, achieving guideline-dictated target BP is not always an easy task. Monotherapy is seldom successful in reaching target BP, and the majority of patients will need more than one medication to reach it. This has been shown in many large clinical trials such as the HOT trial (Hypertension Optimal Treatment), UKPDS (United Kingdom Prospective Diabetes Study), and ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial).

Fixed-dose combination therapy offers a good option for achieving adequate BP control. Because of the simple dose regimens, fixed-dose combinations allow for better compliance, an important consideration in the management of hypertension, where poor compliance is a major obstacle. Additionally, fixed-dose combinations may produce fewer side effects due to the lower doses of each component and the potential for one agent to nullify the side effects of the other. The most important value of the fixed-dose combination, however, remains its high efficacy compared with simply increasing the dose of one medication to reach the target BP. One meta-analysis involving 42 trials (10 968 participants) showed that the extra BP reduction produced by combining drugs from two different classes is approximately 5 times greater than that from doubling the dose of one drug.1 This also helps achieve rapid BP control, which helps avoid patient frustration resulting from a lack of ability to reach the desired BP, and it may also have prognostic implications.

The 2007 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines suggest starting treatment with combination therapy in grade 2 or 3 hypertension, or in cases where the estimated overall cardiovascular risk is high or very high. This was reconfirmed in the 2009 reappraisal of these guidelines.2 The 2010 Canadian Hypertension Education Program recommendations suggest that combination therapy should be the first option if BP is more than 20/10 mm Hg above target.

Not all drug combinations are equal; the perindopril-amlodipine combination in ASCOT was more effective in lowering BP and providing cardiovascular protection than the combination of a β-blocker and thiazide diuretic—the latter combination was particularly diabetogenic. After 5.5 years of follow- up, there was an 11% difference in all-cause mortality in favor of perindopril-amlodipine (P=0.0247), due to a significant reduction in cardiovascular mortality. The same combination also showed significant advantages regarding other secondary end points such as fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, total coronary events, and total cardiovascular events and procedures.3 Despite the significant systolic and diastolic BP difference of –2.7 and –1.9 mm Hg in favor of perindopril-amlodipine combination, subsequent multivariate analysis showed that differences in coronary and stroke events was not completely explained by the significant differences in BP, suggesting that the cardiovascular protective effects of perindopril-amlodipine may be, at least in part, related to inherent pharmacological properties of this combination.4

ASCOT and many other trials showing the effectiveness and reduced outcomes associated with use of an angiotensinconverting enzyme (ACE) inhibitor/calcium channel antagonist combination have led the ESH/ESC to recommend this combination as one of those for priority use.2

References
1. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
2. Mancia G, Laurent S, Rosei-Agabiti E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension task force document. J Hypertens. 2009;27:2121-2158.
3. ASCOT Investigators. The Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm. Lancet. 2005;366:895-906.
4. Poulter NR, Wedal H, Dahlof B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm. Lancet. 2005;366:907- 913.




5. Z. Gaciong, Poland

Zbigniew GACIONG, MD, PhD
Professor of Medicine, Chairman
Department of Internal Medicine
Hypertension and Vascular Diseases
Medical University of Warsaw
1a Banacha Street
02-097 Warsaw, POLAND
(e-mail: zgaciong@hotmail.com)



There is a simple “rule of thumb”: if you have a patient requiring blood pressure (BP) reduction of >20/10mmHg, you should initially use two drugs. Effectively, this means any patient with BP >160/100 mm Hg (stage 2 or 3 hypertension). Recent guidelines recommend the use of a combination of two antihypertensive drugs at fixed doses in a single tablet to improve compliance.1 Evidence from clinical trials also indicates that a fixed-dose combination (FDC) in such patients is simple and the most effective measure to achieve BP control. In the STRATHE trial (STRAtegies of Treatment in Hypertension: Evaluation), which included stage 2 hypertensives with BP >160/95 mm Hg, three treatment strategies were compared: (i) “low-dose combination,” starting initially with perindopril 2 mg/indapamide 0.625 mg, which could be increased to 3/0.937 mg and 4/1.25 mg of perindopril/indapamide, respectively; (ii) “sequential monotherapy,” which started with atenolol (50 mg), replaced if necessary by losartan (50 mg), and then by amlodipine (5 mg); and (iii) “stepped care” starting with valsartan 40 mg, then increased to 80 mg, and finally with addition of hydrochlorothiazide 12.5 mg as needed.2

The percentage of patients achieving target BP was significantly greater in the “low-dose combination” group (62%) than in the “sequential monotherapy” (49%; P=0.02) and “stepped care” (47%; P=0.005) groups. Moreover, the number of adverse events possibly related to therapy was lowest in the FDC group.

In the Canadian STITCH trial (Simplified Treatment Intervention To Control Hypertension), a simple treatment algorithm involving initial use of a low FDC of diuretic/angiotensin-converting enzyme (ACE) inhibitor or diuretic/angiotensin receptor blocker (ARB) was better than a complex strategy based on current guidelines.3 Family physicians enrolled patients with uncontrolled hypertension and employed either the STITCH algorithm or usual Canadian guidelines, and then assessed the proportion of patients treated to target BP after 6 months. The proportion was significantly higher in the STITCH group than in the guideline-based group (64.76% vs 52.7%; P=0.026), and multivariate analysis showed that assignment to the fixed combination arm increased the chance of reaching BP target by 20% (P=0.028).

The STRONG trial (SafeTy and efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension) included 1250 patients: 32.6% with newly diagnosed or untreated stage 2 hypertension, 40.5% with hypertension uncontrolled with monotherapy, and 26.9% with hypertension inadequately managed with another combination.4 After treatment with a fixed combination of perindopril 4 mg/amlodipine 5 mg once daily for 60 days, target BP was achieved in 66.1% of patients,with an excellent rate of treatment adherence (94%).

Thus, first-line management of hypertension based on an FDC allows BP normalization in a shorter time and greater proportion of patients, with no increased risk of intolerance. Therefore, initial therapy with a fixed combination should be used in all patients with stage 2 hypertension or BP uncontrolled with monotherapy. How about patients with stage 1 hypertension? Usually, they start with monotherapy, yet some data also suggest advantages with initiation of an FDC in this group. A recent metaanalysis examined nine randomized double-blind, fixed-dose, placebo-controlled trials (n=4278) comparing monotherapy with fixed combination.5 Among patients with uncomplicated stage 1 hypertension, after 8 weeks of treatment, 92% achieved their goal BP when started on combination, compared with 72% initially receiving monotherapy. Rates of discontinuation were similar in both groups. Thus, FDCs also allow immediate achievement of BP control in patients with stage 1 hypertension.

I fully agree with the recent statement of the American Society of Hypertension,6 and advise starting with an FDC routinely in patients requiring BP reduction of at least 20/10 mm Hg. Subjects with stage 1 hypertension can also be started on a low-dose FDC, which is effective and better tolerated.

References
1. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
2. Mourad JJ,Waeber B, Zannad F, et al. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens. 2004;22: 2379-2386.
3. Feldman RD, Zou GY, Vandervoort MK, et al. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53:646-653.
4. Bahl VK, Jadhav UM, Thacker HP. Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG prospective, observational, multicenter study. Am J Cardiovasc Drugs. 2009;9:135-142.
5. Weir MR, Levy D, Crikelair N, et al. Time to achieve blood-pressure goal: influence of dose of valsartan monotherapy and valsartan and hydrochlorothiazide combination therapy. Am J Hypertens. 2007;20:807-815.
6. Gradman AH, Basile JN, Carter BL, et al. ASH Position Paper. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4:42-50.




6. Ö. Kozan, E. E. Özcan, Turkey



Ömer KOZAN, MD
Emin Evren ÖZCAN, MD
Department of Cardiology
Medicine Faculty of Dokuz Eylül University
Izmir, TURKEY
(e-mail: omer.kozan@deu.edu.tr)



Cardiovascular diseases are the most common cause of mortality worldwide. Hypertension is a major risk factor, causing 54% of strokes and 47% of ischemic heart disease.1 Its incidence is increasing due to an aging population, sedentary lifestyles, and bad dietary habits. Unfortunately, control is inadequate, despite all developments and available drugs. Achievement of target blood pressure (BP) in most patients is only possible with the use of multiple drugs. In the ASCOT-BPLA trial (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm), 78% of patients received two or more drugs,2 and almost one-third of patients in the ACCOMPLISH trial (Avoiding Cardiovascular Events in Combination Therapy in Patients LIving with Systolic Hypertension)3 received ≥3 antihypertensives.

Monotherapy is inadequate in patients with significant BP elevation. Moreover, it unnecessarily delays BP control in highrisk hypertensives. VALUE (Valsartan Antihypertensive Longterm Use Evaluation)4 showed the vital consequences of such delay. In the first 6 months of treatment, amlodipine plus valsartan achieved additional BP reduction compared with valsartan treatment alone, and this was accompanied by a decrease in cardiovascular events. Thus, dual drug combination is recommended as initial therapy in patients with significant BP elevation (systolic BP ≥160 mm Hg, diastolic BP ≥100 mm Hg) or high/very high cardiovascular risk.5

Combined use of drugs with additive pharmacological features provides more BP reduction. Moreover, the lack of side effects from low doses is another advantage over full-dose monotherapy. Fewer side effects, fewer pills, and the possibility of reaching target values quicker enhances patient compliance.6 Comorbidities accompanying hypertension, in particular in the elderly, make treatment more complicated. Here, the physician may decrease the drug burden by using singlepill combinations. Hypertension guidelines also recommend single-pill administration for multiple-drug therapy.5 Fixed combinations prevent improper drug combination. Molecules with synergistic action are selected, thus increasing efficacy and decreasing side effects. Fixed combinations should be selected based on the individual patient. The β-blocker/diuretic combination should be approached with caution due to its metabolic effects. In ASCOT,2 amlodipine/perindopril combination significantly decreased cardiovascular events compared with atenolol/thiazide. In ACCOMPLISH,3 which included highrisk patients, benazepril/amlodipine combination was compared with the ACE inhibitor/diuretic combination, and was found to significantly decrease cardiovascular events. However, before reaching a negative conclusion regarding diuretics, one should remember the beneficial outcomes in ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial), which used a more potent and long-acting diuretic. The recently-published ACCELERATE trial (Aliskiren and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension) emphasized the benefits of starting treatment in combination. Treatment initiation with combination of two drugs (two separate pills) rather than with only amlodipine or aliskiren resulted in a 25% faster lowering of BP in the first 6 months. Although all patients received combination treatment, those having started therapy in combination recorded lower BP values. However, further studies are needed to confirm the prognostic benefits of renin inhibitors.

In conclusion, two drugs combined in low doses should be the preferred first-line treatment in patients with grade 2 or 3 hypertension (systolic BP ≥160 mm Hg, diastolic BP ≥100 mm Hg) or with high/very high risk for cardiovascular events.5 If target BP values are not reached in patients with slightly elevated BPand lowrisk, combination therapy should be considered. Starting treatment with a single fixed-combination pill improves compliance. In patients with orthostatic manifestation requiring careful dose adjustment, it would be better to start with the lowest possible dose or switch to single pill combination after identifying the individual doses of two separate drugs. Choice of combination should be based on the individual patient. It should be kept in mind that exercise and lifestyle modification with a salt-restricted diet is the only “combination” that remains unchanged in antihypertensive treatment.

References
1. Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513-1518.
2. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo- Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906.
3. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH trial investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428.
4. Julius S, Kjeldsen SE,WeberM; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031.
5. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 Guidelines for the Management of Arterial Hypertension. J Hypertens. 2007; 25:1105-1187.
6. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165:1147-1152.




7. G. Latkovskis, Latvia



Gustavs LATKOVSKIS, MD
Latvian Center of Cardiology
Pilsonu iela 13
LV1029 Riga, LATVIA
(e-mail: gustavs.latkovskis@gmail.com)



My decision to initiate antihypertensive treatment with a fixed combination depends on several considerations. In general, what I expect from a successful fixed combination is effective blood pressure (BP) lowering with relatively few side effects, and importantly, proven clinical efficacy in terms of cardiovascular event reduction.

The majority of hypertensive patients will need a combination of drugs to achieve their target BP. As pointed out in the 2007 European guidelines for the management of arterial hypertension, add-ons of a second drug are frequent even in hypertension trials of monotherapies.1 The crucial question for me, therefore, is how to predict who is going to need combination therapy anyway, so that I can start it early and avoid multiple uptitrations.

It has been advised that two drugs should usually be used from the outset when BP is >20/10 mm Hg above goal.2 According to the 2009 update of the European guidelines, the goal has been redefined to <140/90mmHg formost patients.3 Hence, I do not hesitate to initiate treatment with a fixed combination when BP exceeds 160/100 mm Hg. The exception is an elderly patient (aged 80 years or above), unless systolic BP is more than 170 mm Hg, since there is no good scientific evidence that one should pursue values below 150 mm Hg.3

Nevertheless, in many patients, I initiate treatment with a fixed combination even when their BP is lower than the aforementioned cutoff values. The working group of the latest update of the European guidelines has indicated that optimal BP is within the range of 130-139/80-85mmHg, and possibly closer to 130/80 mm Hg.3 This statement may be more important for high-risk individuals. For such patients, I prefer to achieve BP closer to (but not necessarily lower than) 130/80 mm Hg, which makes a case for initiation with a fixed combination when BP is >150/90 mm Hg. Additional (nonhypertension) indications for an antihypertensive agent would be another reason for early combination use; eg, an angiotensin-converting enzyme (ACE) inhibitor for heart failure or calcium channel blocker (CCB) for angina.

Clinically, a very important aspect frequently overlooked is whether pretreatment BP and on-treatment BP are evaluated only in the clinic or are monitored at home (or with 24-hour monitoring) as well. Home readings are typically lower (<130- 135/85 mm Hg considered normal) and better predict cardiovascular risk.4,5 Home BP, however, falls approximately 20% less than clinic BP with antihypertensive treatment.6 Thus, the stronger the data I have to indicate that I am dealing with true hypertension and higher home BP, the more likely I treat my patient with fixed combination therapy from the outset.

The initial choice may also depend on available doses of the fixed combinations. The aforementioned considerations apply to a combination of two agents in standard doses. However, I would prefer small doses of two antihypertensive agents to a standard dose of monotherapy in most cases, should such combination of small doses be available.

In addition to superior efficacy, better tolerability of combinations will contribute to risk reduction via improved adherence. Although combinations seem to have fewer side effects, this may not be true in all cases. Indeed, β-blocker plus diuretic may facilitate development of new-onset diabetes or erectile dysfunction, so it is not my favorite combination unless clearly indicated due to comorbidities. By contrast, the effectiveness of ACE inhibitor plus CCB in combination is not compromised by more frequent side effects such as cough or ankle edema. In fact, the latter is less frequent when CCB is coadministered with an ACE inhibitor.

In summary, fixed combination therapy, especially with an ACE inhibitor and CCB, has become increasingly common initial antihypertensive treatment in my daily practice.

References
1. Mancia G, De Backer G, Dominiczak A, et al; Task Force for the Management of Arterial Hypertension of the European Society of Hypertension, Task Force for the Management of Arterial Hypertension of the European Society of Cardiology. 2007 guidelines for the management of arterial hypertension. Eur Heart J. 2007;28:1462-1536.
2. Rosendorff C, Black HR, Cannon CP, et al; American Heart Association Council for High Blood Pressure Research; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115:2761-2788.
3. Mancia G, Laurent S, Agabiti-Rosei E, et al; European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
4. Asayama K, Ohkubo T, Kikuya M, et al. Use of 2003 European Society of Hypertension- European Society of Cardiology guidelines for predicting stroke using self-measured blood pressure at home: the Ohasama study. Eur Heart J. 2005;26:2026-2031.
5. Niiranen TJ, Hanninen MR, Johansson J, Reunanen A, Jula AM. Home-measured blood pressure is a stronger predictor of cardiovascular risk than office blood pressure: the Finn-Home study. Hypertension. 2010;55:1346-1351.
6. Ishikawa J, Carroll DJ, Kuruvilla S, Schwartz JE, Pickering TG. Changes in home versus clinic blood pressure with antihypertensive treatments: a meta-analysis. Hypertension. 2008;52:856-864.




8. J. Polónia, Portugal



Jorge POLÓNIA, MD
Professor Associado com Agregação
de Farmacologia Clínica
Faculdade de Medicina do Porto
Alameda Professor Hernani Monteiro
Piso 4, 4200-319 Porto
PORTUGAL
(e-mail: jjpolonia@gmail.com)



Control of blood pressure (BP) to the desirable target values (within the range of 130-139/80-89 mm Hg) represents the main mechanism by which antihypertensive treatment reduces cardiovascular (CV) risk. For a long time, monotherapy with dose uptitration and consecutive add-on therapy has been the main strategy in the treatment of hypertensive patients. However, it is recognized that less than only 40% of treated hypertensive patients worldwide really achieve good BP control.1 This may be related to low tolerability profiles, complicated regimens, or unaffordable costs, leading to inertia on the part of the physician, and in particular, patient noncompliance, which has been recognized as a major cause of therapeutic failure. Consequently, a more aggressive attitude to improving adherence to therapy is crucially needed to improve BP control in clinical practice.

Around 75% of patients with hypertension will require combination therapy of two or more drugs to achieve desirable BP targets.1 Initiation of antihypertensive treatment based on the combination of two antihypertensive drugs with complementary mechanisms of action and pharmacokinetic compatibility is now advised by the guidelines,1 particularly for highrisk patients, based on the available evidence of its advantages over monotherapy. These advantages are greater efficacy, easier achievement of BP targets, rapidity of BP control, increase in the percentage of good responders in any population of hypertensive patients, better tolerability, improvement of patient adherence, and enhanced CV protection.2

Once-daily, two-drug fixed combinations share many of the merits of rational free combinations when initiating therapy, particularly with respect to gains in efficacy, efficiency, and tolerability. However, by simplifying treatment, fixed combinations offer additional advantages such as reduction in the number of pills and administrations, improvement of compliance, reduction in health costs, a decrease in the need for repeated medication adjustments and the number of office visits, and facilitation of doctor prescription.2

Thus, in my practice, when would I initiate antihypertensive treatment with a fixed combination? First, based on scientific evidence and/or guidelines. Guidelines support the use of two-drug combinations in a single tablet as the first treatment step when high CV risk makes early BP control desirable.1 So, this could be applied to all hypertensive patients with high initial BP or who are at high/very high CV risk due to the presence of organ damage, diabetes, renal disease, or a history of CV disease, and if there is a 20/10 mm Hg elevation in BP above goal (ie, BP is >160/100 mm Hg for those with uncomplicated hypertension or >150/90mmHg for those with diabetes and other comorbid conditions). Second, based on practical needs and “common sense.” Although there is limited evidence to support starting treatment with fixed combinations in patients with mild-to-moderate added risk, evidence illustrates that BP control is achieved more rapidly with fixed combinations than with free combinations of separate drugs.

Meanwhile, the increasing availability of more favorable, effective, and well-tolerated fixed combinations may allow us to consider their use as initial therapy in certain other scenarios, such as: (i) patients for whom multidrug therapy is likely to be needed soon, while there still is a positive risk/benefit ratio estimation for starting with a fixed combination; and (ii) patients with difficulty in understanding multiple prescriptions and in attending frequent consultations, and/or for whom the increased number of medications and frequency of dosing may represent a determinant factor regarding cost constraints, mistakes, and nonadherence.

This approach may contribute to improved compliance and BP control rates, although further evidence is needed to support it.

References
1. Mancia G, Laurent S, Agabiti-Rosei E, et al; European Society of Hypertension. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
2. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2011;13:146-154.




9. Y. Sirenko, Ukraine



Yuriy SIRENKO, MD, PhD
Professor and Head of Department of
Arterial Hypertension in National Scientific
Centre “Institute of Cardiology”
5, Narodnogo Opolcheniya St
NSC Institute of Cardiology
03151, Kyiv, UKRAINE
(e-mail: sirenkoyu@gmail.com)



The answer to this question stems from the indications for combination of antihypertensive drugs. In 2003, in the Seventh Report of the Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure (JNC-VII), experts proposed that all hypertensive patients without compelling indications start on combination therapy if their blood pressure (BP) level was ≥160/100 mm Hg.1 In the 2003 European guidelines, experts offered a choice to physicians: in all patients, they could either start with monotherapy or with low-dose combination therapy, according to their understanding of the clinical condition of the patient.2

Table I
Table. Comparison of free and fixed combination drug regimens.

In 2007, the European guidelines were clarified with respect to the indications for prescription of combination therapy from the beginning: high or very high risk level, high BP level (≥160/ 100 mm Hg), or low target BP level (<130/80 mm Hg, for example). So, combination treatment should be considered as first choice, particularly when a patient is at high cardiovascular risk: ie, individuals in whom BP is markedly above the hypertension threshold (eg, more than 20 mm Hg systolic or 10 mm Hg diastolic above threshold), or milder degrees of BP elevation that are associated with multiple risk factors, subclinical organ damage, diabetes, renal disease, or associated cardiovascular disease.3 However, this recommendation was not supported with evidence from morbidity/mortality trials, because there were no studies in which the advantage of this approach had been prospectively assessed. The recommendation was based on the arguments that: (i) combination therapy can reduce BP to a greater extent than monotherapy and can achieve the BP goal more promptly; (ii) when a high-risk condition exists, an event may occur within a relatively short time period, thus protective intervention without excessive delay is needed; (iii) the protective effect of BP reduction manifests shortly after initiation of the treatment; and (iv) initial combination treatment is associated with a lower degree of treatment discontinuation.

In the 2009 reappraisal of the European guidelines, the expert position was more assertive, and the text contains the following words concerning fixed combinations: “use of fixed dose combinations of two drugs can directly follow initial monotherapy when addition of a second drug is required to control BP, or be the first treatment step when a high cardiovascular risk makes early BP control desirable.”4

Briefly, the comparison of free and fixed combination is presented in the Table. The main advantage of fixed-dose combinations of two drugs in a single tablet compared with free combination is simplification of the treatment regimen, which impacts positively on the effectiveness of BP control. Thus, all patients who have indications for starting with combination therapy may receive a fixed combination as the first step.

References
1. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. US Department of Health and Human Services. NIH Publication No. 03-5233. Available at: http://www.nhlbi. nih.gov/guidelines/hypertension/jnc7full.pdf. Accessed November 4, 2011.
2. European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;21:1011-1053.
3. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.
4. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.




10. C. Tsioufis, Greece



Costas TSIOUFIS, MD
Assistant Professor of Cardiology
University of Athens
Chief of Hypertension Unit
Hippocratio Hospital Athens
GREECE
(e-mail: ktsioufis@hippocratio.gr)



According to the European Society of Cardiology/ European Society of Hypertension (ESC/ESH) 2007 guidelines,1 dual antihypertensive therapy should be initiated on top of lifestyle interventions in all high and very high cardiovascular risk patients, in those with marked blood pressure (BP) elevation, and each time we opt for lower BP with respect to the traditional threshold. Fixed combination therapy (FCT) is preferred to giving each drug individually, both because of the increase in patient adherence and the improved cost-effectiveness ratio. In the majority of trials to date, combination therapy has been administered with two drugs given separately. However, in the BP-lowering arm of ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron MR Controlled Evaluation),2 diabetic patients received perindopril and indapamide as dual FCT, with an 18% relative risk reduction in cardiovascular death compared with placebo. The above dual FCT had enough clinical support for its implementation in the above guideline-indicated patients; however, individualization of treatment is equally important, which should be taken into account in clinical practice.

Advanced age is by definition a high cardiovascular risk condition, and there is no trial evidence to support lowering BP below 140 mm Hg in patients of advanced age. Additionally, since the majority of older patients are characterized by concomitant cardiovascular comorbidities, aggressive initial reduction of BP with dual FCT might be harmful. In advanced aged patients, it may be prudent to initiate monotherapy and to eventually add a second drug separately if BP levels continue to be elevated. In a final step, FCT (probably an angiotensin- converting enzyme [ACE] inhibitor plus diuretic based on the results of HYVET [HYpertension in the Very Elderly Trial]) could substitute for the previously-administered free regimen.

In my view, FCT is advisable for middle-aged patients with minimum stage 2 hypertension and no history of cardiovascular events. The majority of these patients possess additional risk factors such as obesity, diabetes mellitus, or metabolic syndrome, or are characterized by established target organ damage. All these latter conditions upgrade the initial suggestion to a compelling need for early BP reduction.

In patients with a history of cardiovascular disease, FCT should be used when initiating antihypertensive treatment, with the aim of lowering the BP level below the traditional BP threshold. To date, no study has provided solid evidence for BP thresholds below 130/80 mm Hg for the secondary prevention of cardiovascular diseases. In the case of patients post myocardial infarction, we should recognize that they are already being treated with a β-blocker and an angiotensin-converting enzyme (ACE) inhibitor. Whether the latter drug category should be incorporated into FCT with a diuretic or calcium channel blocker should be based on the individual (depending on the BP levels achieved).

According to a recent meta-analysis,3 patients with chronic kidney disease should be treated to a more conservative BP threshold. Given that these patients are characterized by volume overload, a thiazide-like diuretic should be administered assuming that the estimated filtration rate is higher than 35-40 mL/kg/1.73m2. Along the same lines, a renin-angiotensin system inhibitor is strongly recommended, and thus in chronic kidney disease patients with moderately preserved kidney function, FCT represents a plausible way to initiate antihypertensive therapy.

Triple FCT should be reserved for those whose BP lies outside of the traditional BP goal after dual FCT. So far, there is not enough evidence to support initiation of antihypertensive treatment with three drugs. Finally, by definition, triple FCT nullifies the concept of chronotherapy (implementation of the latter is not fully supported by current evidence, however). Nonetheless, some patients control their BP better when taking part of their medication at bedtime.

References
1. Mancia G, De Backer G, Dominiczak A, et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens. 2007;25:1751-1762.
2. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007;370:829-840.
3. Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med. 2011;154:541-548.




11. P. N. Vinh, Vietnam



Pham Nguyen VINH, MD, PhD, FACC
Professor, Tam Duc Heart Hospital-4
Nguyen Luong Bang Street
Tan Phu Ward, District 7
Ho Chi Minh City
VIETNAM
(e-mail: phamnguyenvinh@yahoo.com)



Hypertension is the leading risk factor for premature death, and according to a 2009 report fromtheWorld Health Organization, it is responsible for 7.5 million deaths worldwide. However, despite therapeutic advances, more than two-thirds of hypertensive adults in the United States, Canada, and Europe fail to reach blood pressure (BP) target (<140/90 mm Hg).1

The current guidelines recommend initiating two hypertensive drugs in hypertensive patients when BP is ≥20/10 mm Hg above goal.2,3 The fixed-dose combination (FDC) approach is also recommended by many guidelines, either as a first-line treatment, or early in the treatment of patients with risk factors that necessitate rapid BP reduction.2,4,5

There are many reasons to initiate antihypertensive treatment with two synergistic drugs, or better, with an FDC. In high- or very high-risk individuals, treatment with a combination of two or more antihypertensive drugs is almost always necessary. In many clinical trials such as UKPDS (United Kingdom Prospective Diabetes Study), RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan), ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial), and ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm), an average of more than two antihypertensive drugs was needed to achieve the target BP.

In the Mahmoud study, a single-pill mixture of four drugs at a one-quarter dose each provided a significantly superior BPlowering effect than that of any of the individual drugs used at a full dose.

Starting antihypertensive treatment with two drugs will achieve more rapid and effective BP reduction; this has been shown in the ACCOMPLISH trial (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension). A delay in achieving BP control, even for a few months, may lead to an event.

The initial use of two antihypertensive drugs may also have the theoretical advantage of avoiding the compensatory physiological mechanisms induced by initiation of a single drug class. This compensatory physiological mechanism may reduce the BP-lowering efficacy of a single agent.

In comparison with separate pills, FDC therapy achieves better compliance. This was shown in a recent meta-analysis of relevant clinical trials.6 Improved compliance is associated with
increased BP control.

Finally, FDCs also reduce the cost of treatment. The second drug in a combination pill is usually free. For example, in a renin-angiotensin-system blocker and diuretic combination pill, the diuretic is “free.” Indirect costs may also be reduced by the use of FDCs because of improved compliance.

References
1. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertensive treatment and control in five European countries, Canada and the United States. Hypertension. 2004;43:10-17.
2. Mancia G, Laurents S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
3. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2011;57:2037-2114.
4. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC7 report. JAMA. 2003;289:2560-2572.
5. Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007;28:1462-1536.
6. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55:399-407.