INTERVIEW: Combinations in hypertension and cardiovascular prevention: are they additive or synergistic?

Stefano TADDEI, MD
Professor of Internal Medicine
Department of Clinical and Experimental Medicine
University of Pisa

Combinations in hypertension and cardiovascular prevention: are they additive or synergistic?

Interview with S. Taddei, Italy

The correct use of combination therapy is crucial both to improve blood pressure control and to reduce cardiovascular events. Antihypertensive drugs can be effectively combined if they have different and complementary mechanisms of action. Thus, a typical combination contains drugs blocking (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker) and stimulating (calcium antagonist or diuretic) the renin angiotensin system. An effective combination therapy is a combination with additive or synergistic effects. The effect of a combination is additive when the blood pressure reduction it induces is the sum of the single effects of each of its components, while it is synergistic when its clinical efficacy is greater than the sum of the effects of the single components. A synergistic effect is clearly demonstrated when, despite similar blood pressure control, one drug combination leads to a better outcome than another drug combination. This was the case in ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm) and ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension), two trials that demonstrated that ACE inhibitor/calcium antagonist combination results in significant better protection than β-blocker/diuretic or ACE inhibitor/diuretic combination, respectively. It is worth noting that there is currently no evidence showing that angiotensin receptor blocker/calcium antagonist combination is as effective as ACE inhibitor/calcium antagonist combination. In conclusion, in hypertensive patients, optimal treatment should be based on combination therapy, and the combination of an ACE inhibitor with a calcium antagonist should be the first choice. This strategy should lead to improved blood pressure control and better protection from cardiovascular events.

Medicographia. 2013;35:464-467 (see French abstract on page 467)

What are the advantages of combining multiple-action drugs from the pharmacological and clinical perspectives?

Usually, in the treatment of essential hypertension, a great emphasis is placed on choosing the right drug for treatment initiation, despite the demonstration that monotherapy can normalize blood pressure values in no more than 30% to 40% of patients with grade 1 and 2 hypertension, and that it is absolutely not effective in patients with grade 3 hypertension. Thus, for the majority of patients, combination therapy should not be an option, but the cornerstone of antihypertensive treatment.

However, merely combining antihypertensive drugs together is not enough to obtain an effective combination treatment, and expert selection of specific compounds with definite characteristics leading to a positive interaction is required. This is a crucial issue since the combination of antihypertensive drugs can lead to different results. In terms of blood pressure reduction, combining antihypertensive drugs can theoretically produce the following effects. (i) A combination that is not rational may have negative effects, which means that it produces the same (or lower!) blood pressure reduction as each of its single components. Combinations with a positive interaction can either have (ii) additive or (iii) synergistic effects. The effect of a combination is additive when its blood pressure– lowering effect is the sum of the effects of each single component. In contrast, a combination has a synergistic effect when it produces an effect that is greater than the sum of the effects of its single components. However, while negative or additive effects are defined according to the extent of blood pressure reduction, synergistic effects are related to blood pressure–independent cardiovascular protection.

Basically, when used rationally, combination therapy should overcome the several limitations of antihypertensive drugs used as monotherapy. The mechanisms determining the superiority of combination therapy over single-drug administration involve the pharmacological and clinical characteristics of drug classes. Concerning antihypertensive efficacy, one major problem of monotherapy is the activation of reflex mechanisms that counterbalance, and therefore limit, the degree of blood pressure reduction. For example, diuretics and calcium antagonists may cause reflex activation of the renin angiotensin system (RAS), while angiotensin receptor blockers (ARBs) increase plasma concentrations of angiotensin II (whose beneficial effect on AT2 receptors has never been demonstrated in clinical conditions), and reductions in angiotensin II and aldosterone plasma concentrations with ACE inhibitors can be counterbalanced by angiotensin escape. This explains why the antihypertensive potency of drugs used as monotherapy is relatively modest: a single drug can easily lower blood pressure values, but only in rare cases will it be able to normalize this clinical parameter.

In contrast, combination therapy can overcome these limitations, but only if the drugs to be combined are selected on account of their different and complementary mechanisms of action. Thus, it is wise to combine a drug blocking the RAS (ACE inhibitors, ARBs, β-blockers) with drugs that stimulate this system (calcium antagonists, diuretics, vasodilators). In the same way, drugs activating the sympathetic nervous system should be combined with drugs blocking sympathetic activity. This is a fundamental aspect, which should be considered when choosing combinations of antihypertensive drugs. Unfortunately, this is not always the case in clinical practice. A typical example is the combination of an ACE inhibitor with a β-blocker. This combination is used in the treatment of hypertensive patients because of its effective cardiovascular protection in specific clinical conditions such as post–myocardial infarction or heart failure. However, it has no additive effect on blood pressure reduction since both drugs block the RAS, as clearly demonstrated in the ALLHAT study (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial),1 where the blood pressure reduction obtained with the combination of lisinopril and atenolol was significantly inferior to that obtained with the combination of chlorthalidone or amlodipine with atenolol.

Other limitations of monotherapy are related to adverse metabolic effects or the incidence of side effects. It is well established that diuretics can significantly alter carbohydrate and lipid profiles, and that patients very often have to stop treatment with calcium antagonists, despite effective blood pressure reduction, because of ankle edema. Most of these limitations can be significantly reduced by combination therapy and it has been demonstrated that RAS blockers can limit both metabolic alterations induced by diuretics and ankle edema caused by calcium antagonists.

Finally, combination therapy can also offer adjunctive advantages from a clinical point of view. Rapid normalization of blood pressure is an important target of antihypertensive treatment, especially in patients at high or very high risk. In line with this recommendation, recent evidence, although obtained by retrospective analysis, indicates that antihypertensive treatment initiated with combination therapy can induce a more rapid blood pressure reduction and/or normalization than monotherapy, and that this more rapid blood pressure control is associated with a better outcome.2 In addition, combination therapy results in a significantly greater reduction in global cardiovascular, coronary, and cerebrovascular events than monotherapy, independent of drug classes or blood pressure control.3

Thus, there is solid evidence that combination therapy offers great advantages over monotherapy, not only in terms of blood pressure reduction, but also because it provides specific cardiovascular protection. However, there are differences in efficacy among the different possible combinations of antihypertensive drugs, and, therefore, it is crucial to choose certain combinations over others.

Which properties/effects of combination therapy are considered to be additive?

As previously mentioned, the effects of combination therapy that are considered to be additive are related to blood pressure reduction. Usually, the combination of drugs with complementary mechanisms of action makes it possible to obtain a reduction in blood pressure that is the sum of the effects of its single components. Thus, from a clinical point of view, it is important to avoid those combinations that do not produce an additive effect or those that have been clearly demonstrated to be inferior to other options. In addition to the already mentioned ACE inhibitor (or ARB)/ β-blocker combination, other drug classes that should never be combined are ACE inhibitors and ARBs, since both block the RAS. Finally, another combination that should be absolutely avoided because of its negative effect is that of doxazosin— an α1-blocker—with clonidine—an α2-agonist. In this case, considering that the specificity for a receptor subtype is always relative, especially in clinical conditions, one drug reduces the blood pressure–lowering effect of the other, and the outcome is, therefore, negative.

Apart from these specific examples, all other combinations of antihypertensive drugs have additive effects and are, therefore, useful to obtain better blood pressure control. This is highlighted by the availability of fixed combinations that increase the compliance of hypertensive patients considerably. In addition to classical fixed combinations of RAS blockers or β-blockers with diuretics, new fixed combinations of RAS blockers with calcium antagonists are now available and increase the chance of choosing the best therapeutic strategy for hypertensive patients.

Is there any clinical difference between the use of a RAS blocker/ diuretic combination and a RAS blocker/calcium antagonist combination? Concerning blood pressure lowering, both regimens seem to be similarly effective. Their tolerability is also similar, especially considering that RAS blockers reduce the metabolic alterations induced by diuretics and ankle edema induced by calcium antagonists.

However, blood pressure reduction is not the only mechanism for cardiovascular protection and since scientific evidence clearly indicates that some drug classes are better than others, as a consequence, some drug combinations are also better than others.

What does pharmacological and/or clinical synergy mean?

A combination has a clearly demonstrated synergistic effect when, despite similar blood pressure control, it leads to a better outcome than another drug combination. This kind of evidence indicates that the beneficial effect of treatment is determined by specific mechanisms that amplify the outcome related to blood pressure reduction.

In line with this are the results of ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm)4 and ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension),5 which demonstrated that the combination of an ACE inhibitor with a calcium antagonist results in significantly greater cardiovascular protection than β-blocker/diuretic or ACE inhibitor/diuretic combinations, respectively.

It is clear from this line of evidence that (i) different combinations of antihypertensive drugs, while producing a similar blood pressure reduction, have a different impact on clinical outcomes, and that (ii) the combination of an ACE inhibitor with a calcium antagonist offers the best cardiovascular protection in hypertensive patients. In addition to the previously mentioned ASCOT and ACCOMPLISH trials, an interesting analysis of the results of EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) demonstrated a significant synergy between perindopril and calcium antagonists, with a significant supplementary impact on cardiac outcomes and mortality.6

Whether the beneficial effect of ACE inhibitor/calcium antagonist combination might be extrapolated to ARB/calcium antagonist combination is an interesting question. It should be stated that it is scientifically incorrect to credit ARBs with the same efficacy as ACE inhibitors. A meta-analysis evaluating studies performed in hypertensive patients has demonstrated that ACE inhibitors, but not ARBs, can significantly reduce total mortality further than comparators, the most important clinical end point.7 It is worth noting that this beneficial effect was essentially driven by the results of ASCOT, ADVANCE (Action in Diabetes and Vascular Disease),8 and HYVET (Hypertension in the Very Elderly Trial),9 which are all perindopril based clinical trials. This evidence was further reinforced by another meta-analysis comparing the effect of ACE inhibitors or ARBs versus placebo in high-risk patients.10 The results of this study confirmed that ACE inhibitors significantly reduce several hard end points such as myocardial infarction, heart failure, and total mortality, but that ARBs, as a class, do not.

Another fundamental argument against the equivalence of ARB/calcium antagonist combination and ACE inhibitor/calcium antagonist combination is the lack of specific trials, such as ASCOT-BPLA or ACCOMPLISH, evaluating the effective- ness of ARB/calcium antagonist combination versus any other combination of antihypertensive drugs, a lack of evidence which was clearly highlighted in the European Hypertension Guidelines.

In conclusion, combination therapy should be the first option for effective hypertension management. This therapeutic strategy can lead to a more rapid reduction, and possibly normalization, of blood pressure values and to a consequent decrease in cardiovascular risk. In addition, available scientific evidence clearly indicates that combining ACE inhibitors and calcium antagonists can specifically provide adjunctive protection from clinical events.

Although ACE inhibitors are considered to be first-choice drugs, especially on the basis of the results of recent meta-analyses,7,10 maybe it is time for us to change our attitude in clinical practice and start considering ACE inhibitor/calcium antagonist combination as the first-choice treatment for the best protection from cardiovascular events.

1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997.
2. Gradman AH, Parisé H, Lefebvre P, et al. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension. 2013;61:309-318.
3. Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension. 2011;58:566-572.
4. 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.
5. 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.
6. Bertrand ME, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM; EUROPA Investigators. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;159: 795-802.
7. 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
8. Patel A; ADVANCE Collaborative Group, MacMahon S, Chalmers J, et al. 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 randomised controlled trial. Lancet. 2007;370:829-840.
9. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898.
10. Savarese G, Costanzo P, Cleland JG, et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol. 2013;61:131-142.

Keywords: ACE inhibitors; angiotensin receptor blockers; calcium antagonists; essential hypertension; cardiovascular risk; perindopril