Single Pill Combinations as Initial Therapy in the Management of Hypertension: What is Taking you so Long?

In 2017, 2 respected hypertension guidelines, those of Hypertension Canada and those of the Latin American Society of Hypertension added another treatment to their listing of first line (initial) pharmacological therapy for hypertension.1,2 This event, unlikely to be reported by CNN or Fox was still newsworthy for 2 reasons. First, it is the only new therapy added to that list in almost 2 decades (at least in Canada). Second, the therapy was one that had been used in hypertension for more than 50 years. The treatment? Single pill combinations (SPCs) of 2 antihypertensive drugs. The examination of the duration of time it took from the initial introduction of SPCs in therapy to their recognition as first line in an increasing number of countries (but not in the United States) is illustrative of the limitations of our current approach in the identification and implementation of best practices. Notably, combination therapy either as a single pill or as “free combinations” has been the norm for first-line treatment in many segments of medical therapeutics ranging from antibacterial therapy (co-trimoxazole for urinary tract infections), to anti-asthma therapy to pain relief. However, the acceptance of the use of combinations as initial therapy in hypertension and specifically the use of SPCs has been reluctant—at best. In this brief commentary, I will try to summarize what I see as the key factors as to why combination therapy and more specifically SPC therapy should have been accepted as first line (and perhaps even “preferred” first line) long ago, and some of the roadblocks that have impeded its acceptance. The supremacy of monotherapies in the therapeutics of hypertension is ingrained in most practitioners, despite the evidence to the contrary. Specifically, it has been well-established that monotherapy is seldom effective, most patients requiring 2 or more antihypertensive drugs for control. As well, combining drugs is almost always more effective in blood pressure (BP) lowering than drug doubling and is associated with no greater (and usually lesser) rates of adverse events.3 Further, in support of the use of SPC therapies, we have long known that patient adherence is higher with these formulations as compared with the use of “free” combinations. The superiority of initiating antihypertensive therapy with an SPC in regards to faster and more effective BP control has been reported in a number of rigorously controlled randomized clinical trials (RCTs). However, several of these studies have been criticized based on the imbalances in effectiveness of the trial arms (i.e., differing number of standard doses in parallel treatment arms, favoring the arm with initial SPCs). However, as demonstrated in the STITCH study,4 utilizing a more pragmatic study design, practices instructed in the advantages of initiating antihypertensive therapy with low-dose SPCs starting at doses simulating the antihypertensive effects of monotherapy had better rates of BP control. Further, health care systems like Kaiser Permanente Northern California which utilizes a STITCH-like treatment algorithm and where most patients with hypertension regardless of the extent of their BP elevations are initiated with low-dose SPCs, have control rates of more than 90%—the highest in the world.5 Perhaps the greatest impediment to the acceptance of SPCs as first-line therapy reflects the standard that most guidelines makers (exemplified by those involved in the recent ACC/AHA guidelines) utilize to judge candidate first-line drugs—i.e., a therapy must be effective at both reducing BP and at reducing hypertension-related cardiovascular risk—based on primary outcomes of RCTs. The advantage of initial combination therapy vs. initial monotherapy has been previously addressed in 2 cohort studies-admittedly a lesser level of evidence (reviewed in 1). First, a population-based case–control study from the Lombardy cohort reported an 11% reduction in cardiovascular (CV) risk in those started on combination therapy compared to those initiated with monotherapy. In a second US cohort using a case–control approach, patients on initial combination therapy had a 34% lower CV event rate (fatal and nonfatal) event rate. Of greater importance for guidelines makers, 2 RCT studies have now established that use of a SPC therapy as lead treatment (or initial treatment) leads to better CV outcomes (reviewed in 1). In a prespecified subgroup of the HOPE-3 study, those patients in the highest BP tertile (systolic BP >143.5 mm Hg) demonstrated a significant reduction in CV event rates when started on a SPC of an angiotensin receptor blocker-diuretic vs. placebo. Additionally, the ACCOMPLISH study (although admittedly a comparison of an SPC vs. an active control specifically an ACE-I/diuretic combination) did demonstrate the relative effectiveness of initial treatment with an ACE-I/calcium channel blocker (CCB) combination in reducing CV risk. Thus, from a guidelines perspective, SPCs as first line should now be viewed as having been met a reasonable minimum standard, i.e., demonstration of both reduction in BP and reduction in CV risk. Beyond the guidelines barriers, there are significant “psychological” barriers that impede the adoption of SPC in first-line antihypertensive therapy. When asked, health care providers often raise concerns regarding the difficulties in identifying which component of the single pill drug formulation may be contributing to adverse effects and second, concerns regarding excess antihypertensive effects. I would suggest that neither concern is substantive. In regards to the recognition of adverse effects, other than anaphylaxis, the patterns of adverse effects of each component of a SPC are typically unique to a singular drug, i.e., the peripheral edema of a CCB or the cough associated with an angiotensin converting enzyme inhibitor-I (ACE-I). The concern regarding potentially excess antihypertensive effects with the initiation of a SPC does reflect the well-established role of combination therapy as add-ons and does require a re-set in our practice regarding the prescription of these entities. Most of the older SPC were formulated as 1–2 standard doses of antihypertensive therapy (a standard dose generally being twice the starting dose). However, utilizing SPC in initial management of hypertension especially in Stage 1 hypertension calls for use of the prescription of a dual quarter dose SPC—shown to simulate the antihypertensive effect of a starting dose of monotherapy with less adverse effects.6 This combination is available only for some of the newer formulations but is almost universally achievable with the use of older SPC formulations and a pill-splitter. Thus, despite their availability for more than half a century, prescribers have been slow in embracing initial SPC therapy in the management of hypertension. However, with the appreciation of the greater effectiveness, lesser rates of adverse effects, greater adherence, improved BP control rates, and lower risks of hypertension-related cardiovascular complications, the HOPE (pun intended) is that there will ultimately be greater realization both by guidelines formulators in the United States and health care providers that initial SPCs is an established if not preferred form of therapy in hypertension. Dr Feldman serves as a member of the Guidelines Committee of Hypertension Canada and is a past president of that organization. He has been a consultant for GSK and has received CME support from Servier Canada. Any views or opinions are those of the author(s) only and not of the AJH or its Editors.