Fixed‐dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications

Despite significant advances in health care over the last 50 years, the global cardiovascular disease burden continues to increase with dire implications. It is well known that cardiovascular disease is now the leading cause of mortality, resulting in approximately one third of all deaths globally.1 This chilling statistic is projected to worsen in years to come and therefore needs to be urgently addressed. Importantly, a large proportion of these cardiovascular disease-related deaths is being driven by hypertension, a risk factor that is widely present, affecting approximately 30% of all adults worldwide and is poorly controlled.2-5 In order to address the role that hypertension plays in cardiovascular disease morbidity and mortality, there is an urgent need for a paradigm shift in the management and treatment of hypertension on a global scale. While lifestyle modification (non-pharmacologic therapy) is important, it has been very difficult to apply on an individual and population level to date. Hence, effective pharmacologic management is central to hypertension control. However, with the increasing number and diversity of pharmacologic agents available, spanning several key and complementary drug classes, treatment options are now complex and need to be simplified.6, 7 One potential untapped means of simplifying the pharmacologic management of hypertension is through the use of fixed-dose combination (FDC) agents, in which two or more drugs are present in a single pill or capsule. This approach, which is not novel, has been widely underutilized. Increasing the use of FDC therapy could significantly and rapidly improve hypertension control rates and clinical outcomes in hypertension in both high- and low- to middle-income countries (LMICs). It is important to note that two or more antihypertensive agents could also simultaneously be administered in the management of hypertension, as separate pills or capsules, where FDC agents are not available, do not come in optimal doses, or are too costly. To discuss the role of FDC therapy in hypertension, this manuscript will first highlight the importance of incorporating the strategic use of FDC pharmacologic therapy to improve control rates and outcomes in hypertension. Second, it will outline in detail the key processes in the selection of preferred and acceptable FDC medications for the inclusion in institutional, national, regional, and global formularies. While this manuscript will focus on two-drug antihypertensive FDCs in the treatment of hypertension, it is important to note that other forms of FDC therapy may also be considered in the treatment of hypertension, such as three or more drug antihypertensive FDCs or FDCs with agents such as statins to address other concomitant cardiovascular risk factors. One of the major challenges currently fueling the high burden of cardiovascular disease is the poor pharmacologic treatment rates of hypertension, which on a global scale are as low as 47% among people who know their condition.8, 9 This astonishingly low use of pharmacologic agents in the management of hypertension is the product of several factors on multiple fronts. For instance, patients frequently lack education regarding hypertension and the importance of treatment. This lack of education results in poor medication adherence and a lack of engagement in their care. On the health care provider front, factors include a lack of a full understanding of the appropriate use of pharmacologic classes and individual agents, reluctance to use standardized treatment algorithms, and the presence of “clinical or therapeutic inertia” (the phenomena of not initiating therapy promptly, delaying dose up-titration, or adding other pharmacologic agents when indicated). At the health care system level, factors such as a lack of clinic and provider access, poor availability of quality, affordable and reliable medications, the inability to sustain recognition and treatment programs once initiated, and budgetary constraints all prevent the widespread use of antihypertensive medications which contributes to poor treatment rates. While all or some of these factors are present in high-income countries, their role as barriers to the treatment of hypertension is even more dramatic in LMICs.10 For most persons with hypertension, multiple pharmacologic agents are often required to achieve blood pressure control.11 This need for multiple agents has been demonstrated in many large-scale landmark hypertension clinical trials across different geographic regions and patient populations. Such landmark studies include the following: The United Kingdom's Prospective Diabetes Study (UKPDS), the Hypertension Optimal Trial (HOT), the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the Action to Control Cardiovascular Risk in Patients with Diabetes—Blood pressure trial (ACCORD), Heart Outcomes Prevention Evaluation (HOPE)-3 Trial, and the Systolic Blood Pressure Intervention Trial (SPRINT).12-17 In these well-designed trials, participants required on average two or more drugs, with some individuals requiring as many as four drugs, to reach the goal blood pressure. The use of more than one drug in the initial management of hypertension under certain instances has been recognized as paramount and is featured in several clinical guidelines for hypertension, including those in the United States, Canada, Latin America, the United Kingdom, and Europe.4, 5, 18-20 In general, these guidelines recommend starting two-drug therapy, either with two single separate agents in a separate pill or with a FDC (two different agents combined into a single pill), in patients with a blood pressure equal to or>160/100 mm Hg, or in patients with a baseline blood pressure >20/10 mm Hg above the treatment blood pressure target goal.4, 5, 20, 21 In addition to these guideline recommendations, there has been increased interest in initiating combination drug therapy earlier in the treatment process, including the initial treatment of hypertension. For example, Kaiser Permanente in their large-scale hypertension treatment program uses FDCs as initial therapy.5 Additionally, current Canadian guidelines recommend replacing multiple-pill antihypertensive combinations with FDCs.18 Given the need for a multi-drug approach to the management and control of hypertension, the inclusion of multiple drugs in one pill (FDC) is logical. These combinations should include drug classes and individual agents within each class, which have been shown to be safe and effective in the treatment of hypertension. Beyond this principle, FDCs should include classes of agents, which, when used together, possess either additive or synergistic effects in lowering the blood pressure.22 Presently, most hypertension guidelines recommend the use of three major classes of antihypertensive agents, either alone or together: (a) renin-angiotensin-aldosterone system (RAAS) inhibitors, which includes two sub-classes: angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACE-Is); (b) calcium channel blockers (CCB); (c) thiazide and thiazide-like diuretics (DIU). Thus, two-drug combination therapy could theoretically include the use of a two-class combination of any of the three major classes, including the two sub-classes of RAAS inhibitors. The steps to choosing the two-class combinations (including agents within each class) will be discussed in detail below. The clinical use of FDCs offers several advantages and the potential to solve some of the challenges and barriers in the effective management of hypertension. One significant advantage is the potential for FDCs to reduce clinical or therapeutic inertia in the control of hypertension, since two drugs would be introduced or up-titrated simultaneously.23 Additional key advantages and benefits include increased efficacy, decreased pill burden, improved medication adherence, and reduction (mitigation) in side effects and adverse events of a given single agent when it is used as monotherapy.24, 25 In practical terms, clinical data have shown that the use of FDCs in the form of a single pill or capsule, when compared to combination therapy involving separate single agents, in the long term can be cost-effective.27 Indeed, this results in decreased expenditure to the health care system due to increased adherence and persistence to therapy. It must be acknowledged that the initial cost of using FDCs may be higher particularly in settings where FDCs are not commonly used or widely available. The ability of FDCs to offer greater adherence resulting in enhanced blood pressure–lowering efficacy, reduced rates of adverse effects, and improved rates of hypertension control was demonstrated in the ACCOMPLISH trial.28 In this large randomized control trial, over 70% of participants were able to achieve a blood pressure target of <140/90 mm Hg through the use of FDC therapy. Thus, the use of FDC therapy to reduce hypertension-related cardiovascular complications is a worthwhile strategy. Another key benefit of the use of complementary classes of antihypertensive medications in the form of FDCs is the removal of age, race, and ethnicity in treatment algorithms. Currently, several guidelines, in their recommendations on the initiation of monotherapy, stress the importance of ethnicity, taking advantage of differences in salt sensitivity across races. However, with the use of complementary drug classes, the summative blood pressure–lowering effects of antihypertensive classes allows for reaching target blood pressure. For example, a RAAS inhibitor and CCB, when used collectively, result in successful reduction in blood pressure, even though the constituent agents, when used alone, might not have been effective. This is supported by the findings of large hypertension programs, such as that implemented by Kaiser Permanente in California, which utilized FDCs and demonstrated equal and significantly increased blood pressure control rates (to approximately 85%) across a wide range of demographics, including sex, race, and ethnicities.6 Given these benefits, why have FDCs not been more commonly used to date? In addition to the limited recommendations in current hypertension guidelines, a major reason for the delayed acceptance of FDCs stems from cost and availability. As with single-drug therapy, FDCs have initially come on the market as expensive branded formulations. Their use has thus been restricted, especially in resource-limited settings. When these branded formulations are used, they come with significant individual and health care system costs.29, 30 Not surprisingly, the cost factor is a major barrier to patient adherence and acceptance onto formularies. However, with time, more FDCs are becoming generic and therefore more affordable, which should help ameliorate the cost factor. Also, as the volume of FDC use increases, it is anticipated that the cost would significantly decrease. An additional concern that has been a factor in the delayed acceptance of FDCs is the difficulty of titrating the individual components within the combination therapy with relative ease. This may pose a challenge particularly in elderly patients with significant co-morbidities, who may require options not available in the FDC, or who may have to discontinue one of the medications due to side effects.31 However, as drug patents begin to expire, and affordable and reliable generic formulations become available, access to a wide range of FDC antihypertensive medications with increased dosing combinations is likely to improve. Beyond this, greater availability of scored tablets, which would allow ½ and even ¼ tablet dosing, could occur. As outlined above, most patients with hypertension are likely to require multiple pharmacologic agents to achieve hypertension control. Given the potential advantages and benefits of FDCs in the treatment of hypertension, it is logical to consider use of FDCs in the initial therapy of hypertension management, in addition to the current recommendations for the use of FDC (ie, baseline blood pressures at or >160/100 or 20/10 mm Hg above goal). However, using FDCs in the initial treatment of hypertension irrespective of starting blood pressure goes against present prescribing practice and until recently is not discussed or recommended in most hypertension guidelines. Of note, recently the 2018 ESC/ESH Hypertension Guideline recommended the use of FDCs for most patients with hypertension.5 As newer guidelines place emphasis on strategies to increase the treatment and control rates of hypertension, recommendations in support of the earlier use of FDC therapy are very likely to occur. Presently, the strategy in the initial treatment of hypertension includes starting with one antihypertensive agent or “monotherapy.” Initial treatment would start with a lower dose of the agent and then gradually increase or titrate the dose of the agent until a target dose is reached. Only when a target dose of the single initial agent is reached, and blood pressure is still not at goal is a second agent added. However, most antihypertensive agents have a rather flat dose-response curve for blood pressure reduction, while having a steeper if not exponential dose-response curve for side effects or adverse effects. Thus, titrating the dose of the first or initial agent to a target dose may offer a small further reduction in blood pressure but at the expense of a greater increase in side effects. Furthermore, meta-analysis has demonstrated adding a drug vs titrating a drug to full dose is five times more effective at lowering blood pressure.32 Thus, the use of FDCs as initial therapy, which is usually accompanied by lower doses of each agent, would likely achieve a greater blood pressure reduction with fewer side effects, as well as in a more timely manner. A reduced side-effect profile with FDC therapy would be even more likely, if the two agents used were complementary in that each agent the side-effect profile of the other agent under In years, there has been a to include the use of FDC therapy in the initial management of hypertension, irrespective of the starting blood pressure. 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