Controversal question: Multiple-drug combinations in hypertension and cardiovascular prevention: should they be used in primary or secondary prevention?

Multiple-drug combinations in hypertension and cardiovascular prevention: should they be used in primary or secondary prevention?

1. M. Alami, Morocco
2. C. Amodeo, Brazil
3. I. Attia, Egypt
4. M. Bastos, Portugal
5. A. Bhagwat, India
6. K. J. Filipiak, Poland
7. R. O’Hanlon, Ireland
8. E. J. Ramos, Philippines
9. H. A. Remah Mohammed, Saudi Arabia
10. M. Rizzo, Italy
11. R. S. Tan, Singapore
12. S. L. Tokgozoglu, Turkey
13. M. Vrablik, Czech Republic

1. M. Alami, Morocco

Mohamed ALAMI, MD
Professor of Cardiology
Ghandi Cardiology Center
264 Boulevard Ghandi
Residence Jawhara, Apartment 9
Casablanca, BP 20200

Cardiovascular prevention is “sick” and the prognosis is bad in developing countries: by 2020, 80% of cardiovascular mortality will occur in low- and middle-income countries. One optimistic solution is the multiple-drug combination or polypill. Combining two or three blood pressure– lowering drugs and a statin and aspirin in the same pill should improve adherence and reduce cost. In terms of primary prevention, the initial concept was “a polypill for all, starting at age 55,” with no screening and no monitoring. In theory, this strategy would reduce heart attacks and strokes by more than 80%.1 In practice, putting apparently healthy people on a polypill with the risk of adverse events (from four to five drugs) and no proven benefit on mortality is not at all convincing at this time. In addition, it seems wiser to advise people to improve their diet and exercise than to rely on pills. Several trials have used a polypill in people without cardiovascular disease but with moderate to high risk. The TIPS study (The Indian Polycap Study) evaluated the use of a polypill in people with one risk factor.2 The effect of simvastatin was lower than expected, but the polypill formulation reduced multiple risk factors and the global cardiovascular risk. A feasibility study by the World Health Organization showed a reduction in systolic blood pressure, total cholesterol, and 10-year risk of cardiovascular disease with use of a multiple-drug combination, which was highly accepted by physicians and study individuals.3 The PILL pilot trial (Program to Improve Life and Longevity) used a polypill with aspirin (75 mg), lisinopril (10 mg), hydrochlorothiazide (12.5 mg), and simvastatin (20 mg) in individuals with a Framingham score of more than 7.5% at 5 years. There was a significant reduction in blood pressure and cholesterol, but side effects were present in about 1 in 6 people. TIPS-3 is evaluating the polypill without aspirin versus placebo in 5000 individuals without cardiovascular disease over 5 years.

In secondary prevention, proven therapies are under used(80% of patients in developing countries do not receive any preventive drug),4 and long-term adherence to treatment is low (often less than 50% in developed countries). A combination of four drugs—aspirin, -blocker, statin, and angiotensin-converting enzyme (ACE) inhibitor—should, in theory, reduce vascular events by 75% in those with prior vascular disease. This approach has been established as being cost-effective in developing countries. However, in practice, is there any level of evidence of a reduction in events in patients with vascular disease with the use of such a polypill? TIPS-2 compared the use of high doses with low doses (used in TIPS) of the polypill components in patients with previous vascular disease. The study showed a more effective reduction in blood pressure and cholesterol with the high doses. The ongoing FOCUS trial (Fixed-dOse Combination drUg for Secondary cardiovascular prevention) is assessing adherence and access to the polypill (aspirin, ACE inhibitor, statin) in 4000 post–myocardial infarction patients. SPACE (Single Pill to Avert Cardiovascular Events) is a collaboration of ongoing trials assessing the role of multiple-drug combinations mainly in patients with vascular disease: UMPIRE (Use of a Multidrug Pill In Reducing cardiovascular Events), IMPACT (IMProving Adherence using Combination Therapy), KANYINI-GAP (Kanyini Guidelines Adherence with the Polypill) and similar studies will collectively enroll around 7000 people. Data on safety and adherence, blood pressure– and cholesterol-lowering efficacy, and mortality, will be decisive.

In conclusion, multiple-drug combination will probably get its “approval” soon in secondary prevention. For primary prevention, the debate will last longer and has already raised a crucial question for the medical community. “Firefighting” cardiovascular diseases: should we add more water (pills) or stop the fuel (risk factors)? Please, answer…and act! ■

1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419-1424.
2. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:1341- 1351.
3. Soliman EZ, Mendis S, Dissanayake WP, et al. A polypill for primary prevention of cardiovascular disease: a feasibility study of the World Health Organization. Trials. 2011;12:3.
4. Yusuf S, Islam S, Chow CK, et al; Prospective Urban Rural Epidemiology (PURE) Study Investigators. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey. Lancet. 2011; 378:1231-1243.

2. C. Amodeo, Brazil

Head of Hypertension and
Nephrology Division
Institute Dante Pazzanese of Cardiology
São Paulo, BRAZIL

Hypertension is a major independent risk factor for the development of coronary artery disease, stroke, and renal failure. Systolic blood pressure (BP) above 115 mm Hg explains 60% of the population-attributable stroke risk.1 Cardiovascular risk in hypertension can be diminished with multidrug antihypertensive therapy. The major reductions in cardiovascular morbidity and mortality over the past 50 years have been attributed mainly to increased availability and combined utilization of various antihypertensive drugs. Randomized trials have shown that BP lowering produces rapid reductions in cardiovascular risk.2 Moreover, it appears that some drug classes may have additional cardiovascular protective effects beyond BP reduction. Studies such as HOPE (Heart Outcomes Prevention Evaluation)3 and EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease)4 have shown a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on cardiovascular risk in hypertensives and nonhypertensives, indicating that the protective effect of ACE inhibition could be, in part, independent of BP reduction. Antihypertensive medications should thus be selected not only for their potential to reduce BP, but also for potential effects on concomitant diseases and other cardiovascular risk factors.

Hypertension treatment aims to prevent associated morbidity and mortality through reduction of BP and cardiovascular risk status. Multiple-drug therapy implies the use of lower doses of several antihypertensive classes. This not only offers the possibility of greater therapeutic efficacy, but also a reduced incidence of side effects.

Stroke is the most serious complication of hypertension and better BP control is the only way to avoid stroke. A reduction of 5 to 6 mm Hg in diastolic BP maintained over 5 years was shown to reduce the incidence of stroke by 40%.5 In the Chinese PATS study (Post-stroke Antihypertensive Treatment Study), patients with previous stroke history were treated with 2.5 mg/day of indapamide or placebo. After 2 years, indapamide decreased BP by 5 mm Hg systolic and 2 mm Hg diastolic and reduced stroke recurrence by 29% (P=0.0009).6 In the PROGRESS study (Perindopril pROtection aGainst REcurrent Stroke Study), patients in the active treatment group received perindopril (4 mg/day) alone or together with indapamide (2.5 mg/day). Combination therapy lowered systolic and diastolic BP by 12.3 mm Hg and 5.0 mm Hg, respectively, and reduced stroke recurrence by 43% (P<0.001). Perindopril monotherapy lowered BP by 5.0 mm Hg systolic and 2.0 mm Hg diastolic, but the relative risk reduction was only 4% (95% confidence interval, 19% to 23%). Because hypertension control generally requires more than one medication, particularly in patients with comorbid conditions, choosing a “first-line” agent may be less important than identifying beneficial combinations for an individual patient. The presence of “compelling indications” may necessitate treatment with antihypertensive agents that have demonstrated a particular benefit in primary or secondary prevention. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends diuretics and ACE inhibitors for secondary stroke prevention. In a study evaluating angiotensin receptor blockers (ARBs) versus calcium channel blockers for secondary stroke prevention, two-thirds of patients in both treatment arms required at least one additional agent to achieve adequate BP lowering. Despite equivalent BP lowering in both groups, patients in the ARB-based treatment group had lower stroke incidence (absolute risk reduction, 8%; number needed to treat, 12.5). Multiple-drug combination has the added advantage of less need to switch medications. Initial management with combination therapy should be considered in patients whose BP is >20 mm Hg above systolic goal or >10 mm Hg above diastolic goal. The optimal choice of multiple antihypertensives remains controversial as doubts remain regarding the mechanisms of beneficial treatment effects: are they simply a function of BP-lowering, or do certain drug classes exert protective effects in addition to lowering BP? ■

1. Lawes CM, Vander HS, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden. J Hypertens. 2006;24:423-430.
2. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other bloodpressure- lowering drugs: results of prospectively designed overviews of randomized trials. Lancet. 2000;356:1955-1964.
3. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in highrisk patients: the Heart Outcomes Prevention Evaluation Study. N Engl J Med. 2000;342:145-153. [Published correction in N Engl J Med. 2000;342:1376].
4. Fox KM; European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
5. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull. 1994;50:272-298.
6. PATS Collaborative Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J. 1995;108:710-717.

3. I. Attia, Egypt

92 El Tahrir Street
Dokki, Giza

Although primary prevention measures are a key component of any public health strategy to reduce the burden of cardiovascular disease, a large proportion of potential candidates do not receive adequate treatment. Defective prescription of medication, noncompliance with treatment, side effects, and unaffordable costs are some of the causes of this treatment gap. Fixed-dose combination therapy can overcome most of these issues. Poor compliance with drug treatment is related to social, psychological, economic, and clinical factors. Advanced age, psychiatric disorders, and complexity of treatment have been repeatedly identified as predictors of poor compliance, and there is a clear correlation with the number of pills a patient needs to take daily.1

These factors led to the concept of a multidrug combination with the potential to improve the management of cardiovascular risk factors. However, arguments against multidrug combinations have been that the estimated risk reduction could be too optimistic, that many patients will remain undertreated, and that patient and doctor acceptability will be less than expected. An additional source of concern is the potential adverse effects related to some of the components of cardiovascular multidrug combinations such as aspirin (gastrointestinal complications). Adverse effects from one or more of the drugs could lead to discontinuation of treatment and, therefore, loss of the benefit of all the other drugs included in the formulation. Furthermore, the need for the efficacy of a multidrug combination in primary prevention remains to be proven in large, randomized trials before it can be accepted in clinical practice.

In addition, the pharmaceutical development of a cardiovascular multidrug combination presents several unique challenges, including the selection of components and doses, the type of pharmaceutical formulation, and regulatory problems. From a formulation development standpoint, an almost linear relationship exists between the number of active components in a multidrug combination and the technical problems of formulation development. The association of different drugs in a single pharmaceutical dosage form may have an effect on the physicochemical properties of each and every individual component. In fact, increasing the number of active components in a multidrug combination also increases the likelihood of interactions between them.2

On the other hand, when it comes to secondary prevention in hypertension, a meta-analysis of four hypertension trials published in 2007 by Bangalore et al showed that fixed-dose combination therapy decreased the risk of medication noncompliance by 24% compared with conventional treatment.3 Pan et al have also shown a 29% improvement in treatment adherence with a fixed-dose combination treatment in patients with hypertension.4

Thus, it appears that combination therapy for primary cardiovascular prevention is not yet ready for widespread use; but for secondary prevention in hypertension, combination therapy with two or more agents in a fixed-dose combination pill will help most patients with hypertension to reach their target blood pressure and reduce morbidity. In many cases, combination therapy improves rates of blood pressure control and requires less time to achieve target blood pressure, with equivalent or better tolerability than higher-dose monotherapy. Additional benefits may include cost savings and better compliance. ■

1. Bosworth HB. Medication treatment adherence. In: Bosworth HB, Oddone EZ, Weinberger M, eds. Patient Treatment Adherence. New York, NY: Routledge; 2006:147-194.
2. Sleight P, Pouleur H, Zannad F.Benefits, challenges, and registerability of the polypill. Eur Heart J. 2006;27:1651-1656.
3. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120: 713-719.
4. Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on adherence to prescription medications. J Gen Intern Med. 2008;23:611-614.

4. M. Bastos, Portugal

Mesquita BASTOS, MD
Department of Cardiology
Escola Superior de Saúde da
Universidade de Aveiro

Arterial hypertension is the most prevalent risk factor for cardiovascular (CV) disease in developed countries.1 With the exception of the USA and Canada, arterial hypertension is characterized by a low percentage of controlled patients. A recent observational study carried out by the Portuguese Society of Hypertension, the PHYSA study (Portuguese HYpertension and SAlt), concluded that 42.2% of the adult Portuguese population has arterial hypertension and that 55.7% of these patients have uncontrolled hypertension.2 When the Portuguese population was analyzed for CV risk, 43.9% had moderate-to-high risk. Polonia et al analyzed the CV risk of Portuguese hypertensive patients using the criteria of the European Society of Hypertension (ESH)/European Society of Cardiology (ESC),1 and found that 73.4% of hypertensive patients attending primary care centers and 83.9% of hypertensive patients attending hospitals had moderate- to-very-high CV risk.3 According to the 2007 ESH/ESC hypertension guidelines,1 those who are at least at moderate CV risk should commence antihypertensive treatment, possibly with a low fixed-dose combined medication. In PHYSA, 56.4% of controlled patients were treated with two or more antihypertensive medications. Of these, 65% were fixed combinations.2

Fixed combinations enhance treatment compliance, as shown by a meta-analysis of nine studies using fixed combinations, which demonstrated a 24% reduction in noncompliance compared with the use of free drug combinations.4 Another advantage of fixed combinations is better blood pressure control, as shown in the open-label AVANT’AGE study (Age VAsculaire et risque résiduel chez l’hyperteNdu TrAité vu en médicine GénéralE), which analyzed 7032 patients with hypertension whose blood pressure was not at goal and for whom general practitioners had the intention of modifying their treatment.5 A fixed combination of perindopril plus amlodipine was added for 6256 patients, which resulted in the majority of patients meeting the criteria for controlled hypertension (74.4% for systolic or diastolic values, 63.3% for both). Since the sooner blood pressure control is reached, the better in terms of CV prognosis,6 fixed combinations can have added value. A posthoc analysis of the VALUE study (Valsartan Antihypertensive Long-term Use Evaluation) suggested that the earlier blood pressure control was achieved, the lower the incidence of CV events.6 If drugs that act through different pathways are used simultaneously, the probability of achieving hypertension control is higher. With fixed combinations, classes of drugs with complementary mechanisms of action can be used (eg, reninangiotensin system inhibitors and calcium antagonists).

Multiple-drug combinations are indicated in primary prevention, as shown by the trials ACCOMPLISH (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension), ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), and HYVET (HYpertension in the Very Elderly Trial) (reviewed in reference 6). HYVET showed that a combination of an angiotensin-converting enzyme (ACE) inhibitor with indapamide decreased stroke and heart failure incidence and overall mortality in the elderly.

Also, in secondary prevention, ADVANCE (Action in Diabetes and cardioVAscular disease: Preterax and DiamicroN MR Controlled Evaluation) and PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study) showed clear benefits for CV outcomes with use of the same combination (reviewed in reference 6). Overall mortality and CV mortality, and stroke incidence and major vascular events, respectively, were decreased in these two studies.

In conclusion, according to the present state of the art, multiple- drug combinations appear to be superior to monotherapy for both primary and secondary prevention of CV events. ■

1. 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. Polo ´ nia J, Martins M, Pinto F, Nazare J. Salt intake, and prevalence awareness, treatment and control of hypertension in Portugal. Changes over a 10-year period. J Hypertens. 2013;31:e-suppl A:e140.
3. Polo ´ nia J, Mesquita-Bastos J, Pessanha P, et al. Estratificação do risco cardiovascular global de doentes hipertensos seguidos em Portugal nos Cuidados de Saúde Primários ou Hospitalar e segundo as orientações ESH/ESC [in Portuguese]. Rev Port Cardiol. 2010;29:1685-1696.
4. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55:399-407.
5. Zhang Y, Ly C, Yannoutsos A, et al. Effect of a fixed combination of perindopril and amlodipine on blood pressure control in 6256 patients with not-at-goal hypertension: the AVANT’AGE study. J Am Soc Hypertens. 2013;7:163-169.
6. Cowart JB, Taylor AA. Should two-drug initial therapy for hypertension be recommended for all patients? Curr Hypertens Rep. 2012;14:324-332.

5. A. Bhagwat, India

Head of Cardiology Department
Kamalnayan Bajaj Hospital

The World Health Organization estimates that 70% of patients do not take their prescribed antihypertensive medication. One reason for this poor compliance is the occurrence of side effects. In antihypertensive drug trials, compliance is at best 78%. In a meta-analysis of 38 antihypertensive drug trials, of all the strategies examined, use of once daily instead of twice-daily therapy improved adherence by 8% to 20%.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends initiation of antihypertensive treatment with a two-drug combination in patients with systolic blood pressure (BP) ≥160 mm Hg and/or diastolic BP ≥100 mm Hg, and in patients who are 20/10 mm Hg above their BP goal. In fact, most patients require more than one medication to achieve target BP. One method to simplify treatment is to use fixed-dose combinations.

Combination treatment allows synergistic use of drugs with complementary actions. In a meta-analysis of 42 trials, combination antihypertensive treatment was fivefold more effective in lowering BP than doubling the dose of single agents. Moreover, the lower dose of each individual agent reduces the risk of side effects, thereby improving compliance. Multiple dosing decreases compliance. Use of a fixed-dose combination (FDC) overcomes this. In a meta-analysis of four hypertension studies, FDC treatment improved compliance by 24% compared with individual agents given separately. A more recent meta-analysis confirmed this finding, and also reported a 50% increase in persistence with treatment with the use of FDCs. However, FDCs have some limitations: loss of flexibility in adjusting the dose of each agent, ineligibility for medical insurance plans, as well as some formulations possibly not being safe or practical for first-line treatment. Another benefit of combination treatment—particularly with calcium channel blockers (CCBs), diuretics, and angiotensin-converting enzyme inhibitors—may be a reduction in BP variability, a risk factor associated with myocardial infarction and stroke. The key issue then is selecting the best combination for most patients.

Renin-angiotensin-aldosterone system inhibitors plus calcium channel blockers
The ACCOMPLISH trial (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension) showed that a FDC of benazepril and amlodipine was superior to benazepril and hydrochlorothiazide in reducing cardiovascular events and death in patients with hypertension. In the ACCELERATE trial (Aliskiren and the Calcium ChannEL BlockER Amlodipine combination as an initial Treatment Strategy for HyperTEnsion), patients who took aliskiren and amlodipine achieved greater reduction in systolic BP than patients taking either drug as monotherapy. It should be noted that there are no outcome studies with angiotensin receptor blocker/ CCB or direct renin inhibitor/CCB combinations. However, the combination of a renin-angiotensin-aldosterone system (RAAS) inhibitor with a CCB is a rational and effective choice. In this regard, the only randomized trial evidence comparing separate drug regimens comes from the ASCOT trial (Anglo- Scandinavian Cardiac Outcomes Trial), which found that the combination of the newer agents, perindopril plus amlodipine, was significantly better in reducing cardiovascular risk than the older combination of -blocker plus diuretic.

Renin-angiotensin-aldosterone system inhibitors plus diuretics
Diuretics decrease volume, which in turn activates RAAS. This activation leads to vasoconstriction, salt and water retention, and increased BP. When added to a thiazide-like diuretic, an inhibitor of RAAS overcomes these untoward effects and provides additional BP lowering. Furthermore, hypokalemia and glucose intolerance—both commonly associated with diuretic use—are alleviated with the addition of a RAAS inhibitor, making this a rational combination for hypertensive patients. In the HYVET trial (HYpertension in the Very Elderly Trial), the combination of perindopril and indapamide significantly reduced stroke and heart failure in an elderly population, compared with placebo.

In conclusion, use of a fixed-dose combination or selection of complementary drug classes in the management of hypertension allows patients to achieve their BP goal quickly, reduces adverse drug reactions, and improves compliance. ■

6. K. J. Filipiak, Poland

Krzysztof J. FILIPIAK, MD, PhD, FESC
Department of Cardiology
Medical University of Warsaw

Adherence to medical treatment is universally poor, with estimates indicating that less than half of patients prescribed an antihypertensive, lipid-lowering, or antidiabetic drug continue treatment beyond 1 year.1 Smith et al postulated that including key medications necessary to reduce cardiovascular risk in a single pill could increase the use of effective and inexpensive medications, improving treatment adherence.2 What more can be done to speed up incorporation of multiple- drug combinations (MDCs) into everyday practice andclinical guidelines? We have still not defined proper target groups for the different MDCs in “primary” and “secondary” prevention. Thus, I would like to propose at least four stages of prevention: (i) zero-order prevention; (ii) primary prevention; (iii) secondary prevention; and (iv) tertiary prevention (Figure). “Zero-order prevention” would be for those without hypertension but with high normal arterial blood pressure, and/or without hypercholesterolemia, but with slightly elevated serum C-reactive protein concentrations. Such patients benefited from receiving renin-angiotensin blockers (reducing the probability of hypertension) in TROPHY (TRial Of Preventing HYpertension) and PHARAO (Prevention of Hypertension with the Angiotensin- converting enzyme inhibitor RAmipril in patients with high nOrmal Blood Pressure) or statins (reducing the number of deaths, myocardial infarctions, and strokes) in JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin). We could thus here propose polypill A, comprising an angiotensin-converting enzyme (ACE) inhibitor and a statin. Pill B, with two antihypertensives, a statin, and aspirin, could be proposed for those with established hypertension as the newly-defined “primary prevention.” Pill C would be for “secondary prevention” in those diagnosed with coronary artery disease or equivalent, and should also contain a β-blocker. Pill D could be used as “tertiary prevention” after a stroke, myocardial infarction, or revascularization, and might consist of two antiplatelets and more potent antihypertensives, with indapamide. I believe this is the right time for such a new classification of prevention and polypills.3 There is also an emerging need for polypills in heart failure (HF). New guidelines advocating at least four or five drugs in patients with systolic HF with reduced ejection fraction should speed up the commercialization of polypills in this field. If a patient must take a diuretic, βblocker, ACE inhibitor, eplerenone, and ivabradine, one may wonder what level of adherence is forecasted. The question is why we still do not have: (i) a polypill with once-daily ACE inhibitor and eplerenone, the aldosterone antagonist of choice; and (ii) a polypill with ivabradine and a β-blocker. Although a combination of two drugs affecting the renin-angiotensin system is not recommended in hypertension, use of such a combination in HF is routine in patients with NYHA classes II-IV and an ejection fraction of ≤35% without hypertension, hyperkalemia, or severe renal failure. A polypill with ivabradine and a β-blocker should probably include carvedilol (given twice daily like ivabradine), which has been well evaluated in patients at all NYHA stages. Vasodilatory third-generation β-blockers like carvedilol reduce the heart rate in a self-restricting manner because of a simultaneous decrease in peripheral resistance. Therefore, additional rate reduction with ivabradine might be crucial.

Figure. The four stages of cardiovascular risk prevention.

Pill A: aspirin + ACE inhibitor + statin; Pill B: aspirin + ACE inhibitor + second antihypertensive
drug (amlodipine?) + statin; Pill C: aspirin + ACE inhibitor + β-blocker
+ statin; Pill D: aspirin 75 mg or aspirin/clopidogrel 75/75 mg + ACE inhibitor
(full dose) + β-blocker (full dose) + statin (full dose) + diuretic (indapamide).
Abbreviations: ACE, angiotensin-converting enzyme; JUPITER, Justification for
the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin;
PHARAO, Prevention of Hypertension with the Angiotensin-converting
enzyme inhibitor RAmipril in patients with high nOrmal Blood Pressure;
TROPHY, TRial Of Preventing Hypertension.

In conclusion, many different MDCs will emerge in the coming years, both in hypertension and cardiovascular prevention, and in HF. We look forward to using them to improve patient adherence in zero-order, primary, secondary, and tertiary prevention, as well as to reduce the number of pills taken in diseases like HF. ■

1. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med. 2005;165:1147-1152.
2. Smith R, MacCready T, Yusuf S. Combination therapy to prevent cardiovascular disease. JAMA. 2013;309:1595-1596.
3. Siewaszewicz E, Filipiak KJ. Perspektywy pigułki typu polypill/polycap w chorobach serca i naczyń [in Polish]. Choroby Serca i Naczyń. 2010;7:131-140.

7. R. O’Hanlon, Ireland

St Vincent’s University Hospital Clinical
Director, Centre for Cardiovascular
Magnetic Resonance
Blackrock Clinic, Dublin

Fixed-dose or flexible-dose combination antihypertensives have been studied in the medical literature for over 20 years, with publications dating back to 1990 demonstrating the beneficial effects of combining three antihypertensives in a single tablet.1 Indeed in 2003, the Joint National Council–VII hypertension guidelines stated that fixed-dose combination (FDC) therapies are more convenient as they simplify blood pressure (BP) treatment regimens, with more patients achieving target BP reduction with combination agents than through uptitration of single agents to maximum doses.2 It is also widely recognized that the majority of hypertensive patients require two or more different agents to achieve adequate BP control.3-5 This need for multiple agents to control BP is reflected in the recent European guidelines published in 2009.6 Initial treatment with combination antihypertensives leads to a number of beneficial effects, and the majority of studies demonstrate more effective BP control at introductory doses of combination agents. Furthermore, side effects associated with higher doses of single agents are reduced with combination therapies, which use smaller doses of the individual agents. Compliance is also improved for a number of reasons. Typically, there is less need for frequent physician visits for drug uptitration; single-tablet regimens are always more preferable to patients than multiple tablet regimens; and as mentioned, the smaller doses of individual agents used in combination pills are associated with fewer side effects. As recently as 2003, Law et al demonstrated in a meta-analysis of over 350 randomized controlled trials of antihypertensive therapies that the side effects of all antihypertensive agents— apart from renin-angiotensin-aldosterone system (RAAS) inhibitors— are dose-responsive. Furthermore, in certain situations, the effects of a second agent taken in combination reduced the side effects of the first agent. The prime example is ankle edema caused by calcium antagonists, an effect that is reduced by combination of the calcium antagonist with a RAAS inhibitor.

It is reassuring to note that combination agents incur significant cost savings to health economies. There are a number of reasons for this, including improved patient compliance and more appropriate BP reduction, leading to significant improvements in cardiovascular and stroke incidence and mortality. Furthermore, combination agents are frequently less expensive to prescribe than the individual drug components. Bangalore et al published a nice paper in 2007 in which they analyzed 68 studies investigating FDCs, identified through a Medline search. This totaled just under 12 000 patients on FDCs versus just under 8500 patients on free drug component regimens. While the study was not restricted to FDCs for hypertension, the authors did demonstrate a reduction in noncompliance of 24% to 26% with the use of an FDC versus single medication regimens. The question of compliance was also studied by Gupta et al, who published a meta-analysis in 2009 that included 15 studies, with just under 18 000 patients included from trials reporting on drug compliance. The use of FDCs (two antihypertensive agents in a single tablet) was associated with significantly better compliance than the corresponding free drug combinations, with beneficial improvements in BP and a reduction in adverse events.

This wealth of data in favor of FDCs should therefore encourage primary care physicians to use combination agents with confidence and in the knowledge that, compared with single drug regimens, adverse events are less common, costs are reduced, compliance is improved, and more patients will achieve target BP reductions, thereby requiring fewer clinic visits. These recommendations were incorporated into the updated British Hypertension Society guidelines published in September 2012, and have been endorsed by the National Institute for Health and Clinical Excellence. These guidelines are also not secondary care–driven, but are instead primary care–focused. ■

1. Materson BJ, Cushman WC, Goldstein G, et al. Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study. Hypertension.1990;15:348-360.
2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
3. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36:646-661.
4. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin- receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
5. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393-404.
6. 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.

8. E. J. Ramos, Philippines

Eugenio Jose F. RAMOS,MD,
Director, The Medical City Cardiovascular
Center, The Medical City
Ortigas Avenue, Pasig City, 1605

Addressing the issue of hypertension is a challenge not only because it is in many instances an asymptomatic condition, but also because reaching and maintaining BP targets is not easy and eventually requires the use of multiple drugs, with the need to take into account respective efficacy profiles and adverse effects.1,2 The impact of antihypertensive drugs on clinical outcomes along the continuum of cardiac and vascular diseases has been well documented, with many landmark trials. All of these drugs reduce BP, but do not all show positive effects on clinical outcomes. These trials have provided us with sufficient documented evidence to significantly influence medical decision-making, but this remains suboptimally utilized in clinical practice. The tendency to extrapolate data and attribute positive outcomes to “class effects” contributes to the wide gap between progress in our knowledge of hypertension per se and the effectiveness of antihypertensive treatment in primary and secondary prevention settings.

Uncontrolled hypertension eventually leads to end-organ damage, not only because of the adverse effects of increased pressure on the vasculature, but also because of the neurohormonal abnormalities that occur. It stands to reason, therefore, that whatever it takes to control BP—by monotherapy at the start, or by combination therapy eventually—must be started early and chosen well, not only on the basis of BP reduction efficacy, but also of the drugs’ impact on the metabolic changes in hypertension, which—ironically—may be aggravated by some drugs themselves. Right from the start, therefore, drug choices must be based on what the evidence demonstrates, particularly on whether or not the drugs actually improve clinical outcomes.

While a significant reduction in BP by any antihypertensive may positively impact a clinical outcome—for example, reduce the risk of stroke—the metabolic changes that some classes of antihypertensives cause, such as the increased risk of diabetes posed by β-blockers or thiazide diuretics,3 should compel astute clinicians to nuance their choices and look beyond simple BP reduction. This is particularly the case as even if populations at risk start with monotherapy, effective BP control will eventually require the use of combination therapy involving two, three, or even four drugs. Moreover, there are significant differences among drugs belonging to the same class, which should warn clinicians against assuming a “class effect” and extrapolating clinical benefits. For example, angiotensin- converting enzyme (ACE) inhibitors, which have been shown to have positive outcomes in primary and secondary prevention settings, cannot just be substituted with angiotensin receptor blockers, even if the latter also affect the reninangiotensin- aldosterone system. Then again, not all ACE inhibitors are the same. This is where the treatment challenge is compounded, particularly when multiple drugs are used in combination.

The landmark trials in hypertension are there to guide the clinician, yet the clinician’s choice of which multiple-drug combination to use can be flawed by erroneous or inconsistent interpretation of data. One such landmark trial is the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial),4 which has provided the clinician with evidence that can be used to decide which drug combination works in preventing cardiovascular events, and which just lowers BP. In evidence-based medicine, it behooves the clinician to choose drugs that: (i) have synergistic or complementary benefits when used together, none of which should cause or aggravate the metabolic abnormalities in hypertension; (ii) have protective effects on the endothelium and target organs affected by hypertension; (iii) can retard or reverse the structural changes brought about by remodeling after organ injury; and (iv) most importantly, have documented evidence of a positive impact on clinical outcomes based on controlled randomized trials, when taken singly or in combination, in both primary and secondary prevention settings. ■

1. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:1461-1464.
2. 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 and the European Society of Cardiology. J Hypertens. 2007;25:1105-1187.
3. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24:3-10.
4. Dahlof B, Sever PS, Poulter NR, et al. 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 (ASCOT-BPLA): a multicenter randomized controlled trial. Lancet. 2005;366:895-906.

9. H. A. Remah Mohammed, Saudi Arabia

Cardiology Department
Al-Hammadi Hospital, P.O. Box 55004
Riyadh 11534

Evidence from the Blood Pressure–Lowering Treatment Trialists Collaboration (BPLTTC) showed that the cardiovascular benefits associated with blood pressure (BP) lowering are directly related to the degree of BP control, irrespective of the agents used. However, the question of whether certain agents—alone or in combination—exert a benefit beyond BP reduction is the source of longstanding controversy. A meta-analysis of several major randomized clinical trials suggested that the use of angiotensin-converting enzyme (ACE) inhibitors in patients with coronary heart disease provides a benefit beyond BP lowering. Similarly, it has been suggested that calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) have beneficial effects for stroke prevention beyond their BP-lowering effects, suggesting differential effects on other determinants of cardiovascular outcomes not related to BP. It is therefore not too difficult to believe that for the same level of BP control, different agents may generate different effects in terms of primary and secondary cardiovascular protection.

The relative benefits of ACE inhibitors and ARBs have been controversial. Meta-analyses have suggested that ACE inhibitors may be superior to ARBs in terms of preventing coronary heart disease events. On the other hand, other analyses have suggested that ARBs have superior benefits for stroke prevention that go beyond BP lowering. With great anticipation, the ONTARGET trial (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) studied the effect of ACE inhibitors, ARBs, and their combination in a large-scale trial of high-risk individuals. Overall, it was shown that neither agent was superior to the other or to the combination. Moreover, in stark contrast to the expected results, the combination induced a significant increase in hard renal end points, although proteinuria was significantly improved. By contrast, the HYVET trial (HYpertension in the Very Elderly Trial) was stopped early due to the observation of large benefits for all cardiovascular events in the active intervention group (ACE inhibitors and thiazide-like diuretics). The VALUE trial (Valsartan Antihypertensive Long-term Use Evaluation) studied cardiac morbidity and mortality among hypertensive patients with high cardiovascular risk, and reported no differences in the primary composite end point; however, myocardial infarction and stroke occurred less commonly in patients receiving CCBs than ARBs. The ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) evaluated two combination antihypertensive regimens in patients with three or more common cardiovascular risk factors but without established coronary heart disease: a standard regimen ( -blocker/thiazide) versus a newer regimen (CCB/ACE inhibitor). The newer regimen was clearly superior in terms of preventing cardiovascular events overall, and significantly so for most of the primary, secondary, tertiary, and post hoc end points studied. CAFÉ (Conduit Artery Function Evaluation) and other substudies of the BPlowering arm of ASCOT found that lower central BP and nocturnal systolic BP control—strong predictors of cardiovascular outcomes—were in part responsible for the differential effects on cardiovascular outcomes in favor of the new regimen.

Interestingly, a recent meta-analysis of clinical trials in hypertension looked at 20 randomized controlled morbidity-mortality trials with 158 998 patients using either ACE inhibitors or ARBs in the active treatment arm.1 Only 3 out of 20 trials— ASCOT, ADVANCE (Action in Diabetes and cardioVAscular disease: Preterax and DiamicroN MR Controlled Evaluation), and HYVET (34 242 patients)—demonstrated significant reductions in all-cause mortality (13% when pooled; 95% confidence interval, 0.81-0.93; P<0.0001). All three trials had treatment strategies that included perindopril, while indapamide was used in two of the trials and amlodipine in one. Neither the level of patient risk nor the trial duration could explain the results. This indicates that fixed-combination perindopril/ amlodipine may provide physicians with the opportunity to replicate the cardiovascular risk reduction seen in ASCOT in daily clinical practice. ■

1. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33:2088-2097.

10. M. Rizzo, Italy

Manfredi RIZZO,MD, PhD
Biomedical Department of Internal
Medicine and Medical Specialties
University of Palermo
Via del Vespro, 141
90127, Palermo, ITALY

Combining multiple drugs in a single pill offers a convenience that can significantly improve poor adherence to therapy, as well as therapeutic inertia. Additional benefits of combining agents from different classes include improved efficacy and safety and a reduction in cardiovascular events. In patients for whom dual therapy is inadequate, multiple-drug therapy in a single pill offers a simplified and effective treatment strategy.1 The burden of hypertension is increasing in Europe and North America, and it has been estimated that hypertension affects about 80 million adults in the USA; yet, although antihypertensive agents are able to significantly improve blood pressure levels, only 50% of hypertensive patients achieve blood pressure control.1

In recent years, a large number of randomized clinical trials and meta-analyses have demonstrated that blood pressure reduction is the main determinant of primary and secondary cardiovascular prevention.2 Indeed, the goal of antihypertensive therapy is to reduce the cardiovascular risk associated with the elevation in blood pressure levels. Many patients require at least two antihypertensive agents, and current international guidelines emphasize the need for combination regimens for initial antihypertensive therapy.

Furthermore, for those patients requiring three drugs, it has been shown that an effective approach is to use a combination of agents with complementary mechanisms of action, such as a renin-angiotensin-aldosterone system blocker, a calcium channel blocker, and a diuretic.1 Recently, it has been suggested that novel approaches to multiple-drug combinations for cardiovascular prevention should be considered, including tablets manufactured with the drugs placed at opposite ends with a drug-free layer placed between them, or tablets divided into discrete, separate segments, which may provide additional benefits for initial close titration and dosage adjustments.2

Bangalore and Ley published a comprehensive review of all the available clinical evidence and scientific guidelines proposing multiple-drug combinations in hypertension, including combinations of an angiotensin II receptor blocker or angiotensin- converting enzyme inhibitor plus a calcium channel blocker or diuretic.3 Once-daily treatment with a single pill was effective and well-tolerated, reducing the pill burden, simplifying the treatment regimens, and improving adherence to therapy. These significant beneficial effects helped patients to reach and maintain their blood pressure targets, and ultimately, to achieve their short-term and long-term treatment goals for comprehensive cardiovascular risk reduction in both primary and secondary prevention.

It should also be highlighted that triple-combination regimens resulted in a greater proportion of patients achieving control of blood pressure compared with patients receiving dual-combination regimens, with significantly lower levels of blood pressure reported after only 2 weeks at maximum doses.1 In summary, multiple-drug combinations in hypertension and cardiovascular prevention offer a convenience that can address the barriers to reaching therapeutic targets, both for primary and secondary prevention. Physician acceptance of a singlepill combination of drugs for reducing cardiovascular risk is moderate to high, at least when considering the clinical approach to its use.4 The perspectives of physicians may, however, evolve towards a still greater acceptance with more availability of such multiple-drug combinations for use in both primary and secondary cardiovascular prevention. ■

1. Chrysant SG. Single-pill triple-combination therapy: an alternative to multipledrug treatment of hypertension. Postgrad Med. 2011;123:21-31.
2. Angeli F, Reboldi G, Mazzotta G, et al. Fixed-dose combination therapy in hypertension: cons. High Blood Press Cardiovasc Prev. 2012;19:51-54.
3. Bangalore S, Ley L. Improving treatment adherence to antihypertensive therapy: the role of single-pill combinations. Expert Opin Pharmacother. 2012;13:345- 355.
4. Viera AJ. The polypill to prevent cardiovascular disease: physicians’ perspectives. Curr Opin Cardiol. 2011;26:438-442.

11. R. S. Tan, Singapore

Senior Consultant & Director, Clinical Trials
National Heart Centre Singapore
17 Third Hospital Avenue, Mistri Wing

Contemporary hypertension guidelines advocate targeted intensive pharmacological intervention in high risk patients identified by global cardiovascular risk quantitation. In uncomplicated mild hypertension, blood pressure lowering with drugs averts target organ damage, but in randomized controlled trials, it does not appear to significantly influence hard cardiovascular outcomes.1 The latter is not unexpected given the necessary short trial durations relative to the time required to develop outcomes in this inherently low-risk population. In high-risk patients, the presence of either clinical disease (diabetes or cardiovascular or renal disease) or subclinical target organ damage portends an adverse prognosis. However, a critical review of prospective randomized controlled trials found scant evidence that more intensive blood pressure lowering can improve cardiovascular outcomes in these high-risk patients or improve the risk level to a low-risk category.2 Hence, the recommended thresholds for initiation of drug therapy, as well as target blood pressure goals, are similar for both high- and low-risk patients.2 This begs the fundamental question of whether differentiation of primary and secondary preventive approaches to hypertension management is practical or necessary, especially when viewed against the larger management challenge of endemic suboptimal attainment of blood pressure goals that cuts across all risk categories. As the majority of hypertensive patients will require two or more drugs for optimal blood pressure control, a unified approach focused on maximizing individual blood pressure goal attainment using initial combination therapy is both pragmatic and rational.

Combination therapy, even at low doses of component drugs, acts synergistically on multiple pathways to lower blood pressure more efficaciously than sequential high-dose monotherapy.3 Not only are patients more likely to achieve blood pressure goals with combination therapy, the time to blood pressure goal attainment is shortened considerably.4 The latter has an important impact on the reduction of cardiovascular outcomes, independent of drug treatment,5 which should garner support for the use of combination therapy in high-risk patients. With combination therapy, adverse event rates are not additive; this is either because of fewer dose-dependent side effects or neutralization of adverse events by complementary drug interactions.3 Even in mild hypertension, where attainment of blood pressure goals is deemed less urgent, a persuasive case should be made for initiating combination therapy on the grounds of improved tolerability with no compromise on efficacy.

Single-pill combinations, preferably comprising long-acting drugs taken once daily, should be used where possible.2 In a meta-analysis comparing two-drug single-pill combinations with equivalent free doses of component drugs, treatment adherence was significantly enhanced by more than 20% with single-pill combinations. Moreover, there were nonsignificant trends toward lower adverse events (20% reduction), larger absolute blood pressure reduction, and improved goal attainment (30% increase), the latter possibly driven by higher compliance.6 Currently, various two-drug and three-drug single-pill combinations with various dose permutations are commercially available for hypertension treatment. By simplifying hypertension management, they improve treatment adherence and persistence, as well as the success rate and speed of blood pressure goal attainment. They constitute a feasible and promising strategy for combating treatment barriers to achieving and maintaining blood pressure goals in all risk categories of hypertensive patients. ■

1. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev. 2012;8:CD006742.
2. 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.
3. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326:1427-1431.
4. Weir M, Levy D, Crikelair N, Rocha R, Meng X, Glazer R. Time to achieve bloodpressure goal: influence of dose of valsartan monotherapy and valsartan and hydrochlorothiazide combination therapy. Am J Hypertens. 2007;20:807-815.
5. 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.
6. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive. Hypertension. 2010;55:399-407.

12. S. L. Tokgozoglu, Turkey

Professor of Cardiology
Hacettepe University Faculty of Medicine
Department of Cardiology
Hacettepe, Ankara

The border between primary and secondary prevention is not clearly defined in the continuum of cardiovascular disease. Since the introduction of methods to determine subclinical atherosclerosis, we see more and more patients one would initially categorize as being candidates for primary prevention, but who are found to have atherosclerotic vascular disease on imaging. A more clinically-relevant approach would be to categorize the patients according to their risk level. As the risk increases, more aggressive therapies for prevention and treatment should be used. There are several risk prediction scores, and in Europe, the one that should be used to determine the risk of an individual patient is the SCORE system (Systematic COronary Risk Evaluation).1 Moreover, it has been shown that adding markers of organ damage to the SCORE risk estimation improves risk prediction in the hypertensive patient.2 According to the 2012 prevention guidelines of the European Society of Cardiology, individuals having any of the following are categorized as having very high risk: documented cardiovascular disease by invasive or noninvasive testing; diabetes mellitus (type 1 or type 2) with one or more cardiovascular risk factors and/or target organ damage; severe chronic kidney disease and a calculated SCORE of ≥10%.3 High-risk individuals are defined as those having any of the following: markedly elevated single risk factors, such as familial dyslipidemia and severe hypertension; diabetes mellitus (type 1 or type 2) but without cardiovascular risk factors or target organ damage; moderate chronic kidney disease or a calculated SCORE of ≥5%, and 10% for 10-year risk of fatal cardiovascular disease.

Our main aim in treating the hypertensive patient is to decrease cardiovascular mortality and morbidity and prevent end organ damage. To achieve this aim, optimal control of blood pressure and other risk factors is necessary. The relationship between blood pressure and cardiovascular risk is strong and graded, and reaching target blood pressure is important to achieve maximum benefit. Most hypertensive patients will need at least two agents to reach the targets that have been defined in the guidelines.4 Patients also need to be compliant in order to maintain the target levels throughout their lifetime. A meta-analysis of 42 studies showed that combining two agents from any two classes of antihypertensive drugs increases the blood pressure reduction much more than doubling the dose of one agent.5 For a combination to be more effective, synergistic combinations should be chosen. The guideline-recommended initial preferred combinations are a renin-angiotensin-aldosterone system antagonist with either a calcium channel blocker or a diuretic, according to current evidence. Large-scale trials such as ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) and ACCOMPLISH (Avoiding Cardiovascular events in COMbination therapy in Patients LIving with Systolic Hypertension) have shown a decrease in cardiovascular events with the use of these combinations in high-risk patients.6

The 2007 European Society of Hypertension/European Society of Cardiology guidelines recommend that combination of two drugs be considered as initial treatment whenever hypertensive patients have high initial blood pressure or are classified as being at high/very high cardiovascular risk because of the presence of organ damage, diabetes, renal disease, or a history of cardiovascular disease. This is both because of higher effectiveness and lower discontinuation rates, both of which are extremely important for high-risk patients or those with high initial blood pressure.

In conclusion, we should start thinking about the risk of the patient rather than whether he or she is a primary or secondary prevention case, and regardless of whether the patient has known cardiovascular disease or not, high-risk hypertensive patients should be considered for combination therapy. ■

1. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24:987- 1003.
2. Sehestedt T, Jeppesen T, Hansen TW, et al. Risk prediction is improved by adding markers of subclinical organ damage to SCORE. Eur Heart J. 2010;31:883-891.
3. The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2012;33: 1635-1701.
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. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
6. 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.

13. M. Vrablik, Czech Republic

Centre for Preventive Cardiology
3rd Department of Internal Medicine
1st Medical Faculty
Charles University

There is overwhelming documentation from clinical trials and epidemiological studies providing evidence of measures that improve outcomes in cardiovascular patients. Every year, we learn about novel effective therapies in the cardiovascular field and gain new information on combinations of pharmacological therapies for use in specific patient groups. As cardiovascular disease has multiple origins, the approach to its prevention and treatment must be multifaceted and rely on the use of combination therapy. The first and essential component of successful cardioprotective combination therapy is, of course, a lifestyle change.1 However, such an approach does not lead to satisfactory control of risk factors in most patients. Thus, drug therapies represent a necessary adjunct in most clinical situations.

The decision to start a patient on medication is based on several factors, the most important of which is careful risk stratification. Assessment of a patient’s risk status determines their treatment goals as well as the modes of achieving these goals. Initiation of pharmacotherapy, and any further approach to management of individual cardiovascular risk factors, depends on the patient’s risk. As there is a very thin line between so called primary and secondary prevention (usually a few seconds when atherothrombosis occludes an artery and myocardial infarction or ischemic stroke develop), it seems more feasible to categorize patients according to their risk. High-risk or very-high-risk patients deserve the same attention and aggressive risk factor management regardless of whether they have had a vascular event or not.2 There is ample evidence supporting this approach as a number of clinical trials both in primary and secondary prevention have yielded similar results, and preventing the first event seems to be even more important than averting a recurrence.3

Having said this, we have almost answered our controversial question and it does not seem to be controversial anymore. Those with increased cardiovascular risk require intensive management of their risk factors, and we must offer these patients pharmacotherapy to bring them to guideline-recommended targets. Only well-proven medications should be used to avoid unnecessary polypragmasia, and in most cases, risk factor control requires use of drug combinations. Hypertension can be controlled with monotherapy in less than 20% of patients.4 Increasingly stringent goals for low-density lipoprotein cholesterol levels can be achieved with statins, but in some patients, statin-fibrate or statin-ezetimibe combinations might be needed. All type 2 diabetics should be treated with metformin, but this medication alone does not usually lead to satisfactory control of hyperglycemia. Moreover, patients with advanced atherosclerosis should receive antiplatelet therapy. Therefore, a high-risk individual with diabetes may require at least five different medications. Nevertheless, every now and then, voices calling for “a conservative approach” avoiding the use of multiple medications can be heard.

However, there is no documentation supporting such an approach. Experience from clinical trials conducted over the last decade, together with positive trends in cardiovascular morbidity and mortality in developed countries, provide a clear answer. There are combinations of drugs that have been proven unambiguously to bring benefit to a variety of clinical situations. Just one example: the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial). The combination of an angiotensin converting enzyme inhibitor, calcium channel blocker, and statin reduced the risk of myocardial infarction by more than 50% in a high-risk population with no history of atherothrombotic events, thus showing a synergistic effect among the therapies used.5

In conclusion, the use of drug combinations in the treatment and prevention of cardiovascular disease is not only recommended by current guidelines and evidenced by the results of well-conducted clinical trials, but most importantly, it is justified by the decline in cardiovascular disease mortality that has accompanied wider implementation of this approach to all individuals at increased risk. ■

1. Perk J, Backer GD, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur J Prev Cardiol. 2012;19:585-667.
2. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias. Atherosclerosis. 2011;217:3-46.
3. Tonelli M, Lloyd A, Clement F, et al. Efficacy of statins in primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ. 2011;183:e1190-e1202.
4. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
5. Sever P, Dahlof B, Poulter N, et al. Potential synergy between lipid-lowering and blood-pressure lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006;27:2982-2988.