Overview
Hypertension is a common public health burden worldwide. Data on hypertension prevalence demonstrate a sharp increase, from 972 million in 2000 to 1.39 billion in 2010, with 73.4% residing in low to moderate income countries [1]. With hypertension predicted to be the leading cause of preventable morbidity and mortality in 2040, proper treatment is expected to reduce the mortality rate by 30.4% in males and 38% in females [2]. Despite its high prevalence and catastrophic outcomes, improvement of control is seen mainly in developed countries, further widening global disparity.
In the United States, the prevalence decreased slightly from 48.4% in 1999-2000 to 45.4% in 2015-2016, accompanied by a remarkable rise in the control rate from 25.6% to 43.5% [2]. In contrast, China saw a doubling of prevalence from 29.6% to 44.7% in 2017, disproportionate to a decrease in the control rate from 9.3% to 7.2% [3,4].
Many measures have been taken, including doctor-, patient- and environment-related strategies; yet few are of clinical significance. A look back at the history of hypertension may provide key insights into proper solutions.
At the dawn of evidence-based medicine, first-line treatment included any of the five medications: diuretics, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs). Subsequent well-designed randomised controlled trials targeted specific populations with particular risk factors and hypertension-mediated organ damage. However, the latest trend shifts the focus to precision medicine, with a single-pill combination (SPC) being at the forefront of the treatment algorithm.
The European Society of Cardiology and the American College of Cardiology, two of the most renowned associations in the cardiovascular field, have reached a consensus on initial two-drug therapy for most patients with persistent blood pressure ≥140/90 mmHg [5]. The choice of specific components is individualised for the best interests of the patient.
This article will elaborate the pros and cons of a two-drug regime at the start of treatment in newly diagnosed hypertensive patients, and whether the benefits outweigh the potential risks.
Pros
Being one part of the cardiovascular disease continuum, hypertension should not be viewed as a discrete number, but rather in relation to cardiovascular risks and hypertension-mediated organ damage. Risk stratification and cardiovascular protection, therefore, are compulsory in management for all hypertensive patients. Yielding both antihypertensive and non-hypertensive mediated protection, combination therapy is recommended in the first instance for most patients.
Rapid and sustained blood pressure lowering
Since hypertension is multifactorial in genesis, combining drug classes augments the antihypertensive effect by approximately five times, thereby increasing the control rate. Real-world data on 1,762 adults show an 18.5% earlier target blood pressure achievement in the initial combination group, corresponding to a 23% risk reduction in cardiovascular events and death [6]. Shortening time to control is of the utmost priority to provide timely protection in high-risk patients, whose events can happen at any time in the foreseeable future. This protection is not short-lived, as fewer cardiovascular events were observed after one year in hypertensive patients started with combination treatment compared to those with monotherapy [7]. In another study, sustainable control over a two-year duration translated into a significant reduction in heart failure (36%) and stroke (21%) risks. Time in the therapeutic range is also inversely related to all-cause mortality [8].
Non-antihypertensive effects
Apart from antihypertensive effects, cardiovascular protection also comes from other mechanisms [9]. In the PETRA study, initial combination therapy was associated with lower levels of total cholesterol, low-density lipoprotein cholesterol (LDL-c), triglycerides, and fasting plasma glucose. Similar reductions in HbA1c, creatinine and uric acid have been observed in other studies, highlighting the potential protective effects on people with multiple health conditions. Several studies including CAFE, J-CORE, ADVANCE, and OLAS also provide evidence on haemodynamic, renal, vascular, and inflammation-induced cardiovascular protection, which are independent from the antihypertensive effect.
Therapeutic inertia and patient adherence
Despite the wealth of evidence, many clinicians are reluctant to prescribe a two-drug combination as first-line therapy. While two thirds of patients require at least two drugs for control in clinical studies, real-word research reveals data inconsistency. Of 125,635 hypertensive patients, 80.4% were prescribed monotherapy, 36% of whom were switched to combination therapy after three years, compared to 78% of those initially treated with combination drugs [10]. Once patients were initiated on monotherapy, rarely did they receive an additional drug, despite inadequate control, inferring that the initial strategy decided the final management plan. The study illustrates the failure of stepped care treatment in clinical practice, despite being so common and seemingly radical.
According to Mancia et al, this guideline-practice gap stems from the difference between well-designed randomised controlled trials (RCTs) and the real-world setting. In trials, physicians follow a study protocol strictly and patients must adhere to treatment, whereas, in reality, the compliance of multimorbid patients rarely exceeds 80% and physicians are more concerned with the severe consequences of over-lowering blood pressure [11].
A better strategy to overcome doctor inertia and enhance patient adherence is combination therapy in the form of a single-pill combination. Due to a flat dose-response and sharp dose-adverse effect curve, combination pills, especially those at less than standard doses, provide more rapid control with limited adverse effects. A single-pill combination alleviates both psychological and financial distress on high pill burden, leading to better rapport and adherence. In an analysis of over 12,000 patients with atherosclerosis, strict adherence was associated with lower rates of major adverse cardiac events (MACE) and higher cost-effectiveness at two-year follow-up.
Homologous blood pressure lowering and good safety profile
The extent to which each mechanism affects overall blood pressure response varies widely among individuals. Factors to be considered include prior treatment, age, baseline blood pressure, comorbidities and concurrent medications. Combination therapy with appropriate dosing leads to simultaneous effects on multiple mechanisms, thus achieving therapeutic levels regardless of baseline blood pressure, cardiovascular risks and comorbidities.
Previously fixed in dose, the two-drug single pill now offers more flexible dosing of individual components, easing drug titration and enhancing therapeutic target achievement.
While two-drug combinations are extremely common, researchers are moving towards three-drug therapy at a lower dose. In a 2018 study in Sri Lanka, treatment with a three-drug single-pill combination (SPC) was initiated in mild hypertensive patients who had never been treated before or were on monotherapy. After six months, better control was achieved in the combination group (70% compared to 55%). There was no statistically significant difference in adverse effects, except for higher dizziness, pre-syncope, syncope and lower unproductive cough in the combination group. Given that 29% were diabetics, this trial provides proof of an assuring efficacy and safety profile of initial combination treatment in mild hypertensives with average to high risk [12].
Not only does SPC provide a better antihypertensive effect compared to free forms, but this benefit also comes at no cost in terms of reduced tolerability. Even for triple therapy, ankle oedema was only observed in 0.2% of patients in the PIANIST study, and 0.07% in the PETRA study. Noticeably, >50% of these patients were at maximal or submaximal doses. Most life-threatening events are not found to be associated with antihypertensive medication.
Cons
In reality, prescription patterns vary due to patient diversity. Arguments often arise in vulnerable populations - those with more risks but not-so-high blood pressure, or those who are prone to severe hypotensive episodes.
Stage 1 hypertension with low cardiovascular risk
For stage 1 hypertensives with high cardiovascular risk, the ESC guidelines recommend a two-drug regimen at the outset for timely and prolonged protection. One concern is that too much of a hypotensive effect over-reduces blood flow to vital organs as, even in high-risk patients, the lowest possible blood pressure is not necessarily the optimal target. A post hoc analysis of the ONTARGET study proved a J-curve response in blood pressure level. Specifically, mean systolic blood pressure (SBP) less than 120 mmHg during treatment is associated with increased adverse cardiovascular outcomes, except myocardial infarction and stroke.
However, there is evidence of a tolerability profile of combination therapy in stage 1 hypertensives. The HOPE-3 study consisted of patients mostly treatment naïve, with only 22% already on medications. In the upper third of the baseline blood pressure (>143 mmHg), the combination of candesartan/hydrochlorothiazide and statin is associated with a 40% relative risk reduction, accompanied by a slight increase in mild hypotensive episodes that does not require hospital visits.
While the benefits certainly outweigh the risks in high-risk (ONTARGET) and low-to-moderate-risk (HOPE-3) patients, a less sufficient body of literature is available for low-risk individuals, thus necessitating a more prudent attitude. In high-risk patients, especially in the young with expected mounting accumulative risks, the net clinical benefit of cardiovascular protection favours the use of a two-drug therapy from the beginning.
Patients 80 years and above
The age group cut-offs for blood pressure targets differ between the guidelines of the ESC (80 years) and those from the ACC (65 years), suggesting that the focal point of the treatment algorithm is functional rather than chronological age. This ever-increasing population often presents a medical dilemma due to its heterogeneous background and high cardiovascular risk, given that increasing age is already a risk factor in itself.
The elderly often suffer from impairment in haemodynamic autoregulation, leading to a higher risk of hypotensive episodes and subsequent falls. Regardless of the cause, patients are prone to devastating consequences including pulmonary embolism and decubitus ulcers from immobilisation, depression from physical dependence, and exacerbations of other comorbidities. Femoral neck fracture is common and associated with higher mortality compared to the general population of the same age [13].
The SPRINT trial included 2,600 patients aged 75 or above, allowing sufficient statistical power to detect differences between age groups. Although the elderly are associated with a higher absolute risk for serious adverse events (SAEs) relating to hypotension, syncope and fall, the relative risk does not differ significantly between people <75 and >75 years of age, with the exception of people >85 years old due to limited data. The overall SAE for hypotension, syncope and fall is 2%, but detailed informed consent and 30% more as-needed visits may lead to overreporting of SAEs [14].
Reported falls are more frequent in real-life studies, partially derived from diverse clinical backgrounds. In the SPRINT trial, intensive blood pressure control was associated with greater SAEs involving hypotension and possibly syncope, but not falls, which contradicts another real-life finding, in which more hospitalisations for femoral neck fracture were observed 30 days after treatment initiation [14,15].
Frailty is another attention-drawing aspect, especially with regard to brief consultation times in overburdened hospitals. Both the SPRINT and HYVET trials showed no evidence of modification of an antihypertensive positive impact on cardiovascular outcome. Yet, the visiting patients may have completely different characteristics from these studies’ populations. Furthermore, few validated clinical tools are readily available for rapid assessment of the heterologous population. These facts indicate the need for further research, especially in those with functional decline and loss of autonomy.
Although hypertension-induced brain lesions are improved with antihypertensive treatment, physiological ageing can interfere with this process. Similar to haemodynamic changes, cerebral autoregulation is impaired with ageing, leading to cognitive decline, which may be further exacerbated by overtreatment of hypertension. While mild and combined cognitive impairment were shown to improve with intensive blood pressure treatment in an RCT of 9,361 people (mean age 67.9), none was observed in the HYVET, SHEP and PROGRESS trials. Discontinuation of antihypertensive treatment does not significantly improve cognitive, psychological and daily functioning in ≥75-year-old individuals with mild cognitive impairment [16].
While data are still conflicting, the heterogeneous profile and catastrophic consequences of overtreatment tilt physicians towards a more cautious approach. The preferred algorithm for most cases is “start slow, go slow” with careful monitoring of patient response, taking into account comorbidities, polypharmacy, frailty, fall risk, cognitive status and life expectancy. Other components to bear in mind are patient preference, the supporting system and the financial burden. Importantly, lifestyle modification can be of great value to enhance functional capacity in the geriatric population.
Pseudo-resistance
Pseudo-resistance is a typical scenario in which a patient claims to have no response without fully adhering to the prescription. Some refuse life-long treatment and choose an as-needed approach, others take smaller or interval dosing in fear of hypotensive episodes. As a result, pills are increasing, adherence remains low, and patients are mistakenly labelled “resistant”. This phenomenon can be prevented by a thorough approach, checking (1) white-coat hypertension, (2) maximal tolerated dose, (3) patient adherence, (4) precipitating factors (sodium intake, acute conditions), (5) secondary hypertension. Resistant hypertension is reported to be <15% of treated patients, implying that treatment failure does not lie in inadequate medications but in barriers to achieving and maintaining optimal treatment.
Dose confusion and polypharmacy
Two contradicting and potentially lethal scenarios are double and missed dosing due to high pill burdens for comorbidities. The former exposes patients to a higher threat of severe hypotension, whereas the latter leads to rebound hypertension, particularly in those with pre-existing blood pressure dysregulation. Even in minor cases, both can lead to prolonged hospitalisation, reintroduction of therapy and arduous dose titration.
Polypharmacy is an increasingly pervasive phenomenon in patients with multiple chronic diseases. With the ageing baby boomers and global economic crisis, pill burden is still on the rise. A single-pill combination with two or three drugs helps to mitigate the high-priced prescription, thereby improving patient adherence. Whereas SPC is slightly more economical than free forms, it is less affordable than monotherapy. Physicians should be encouraged to educate patients on the cost-effectiveness of combination therapy, since the debilitating cost of long-term care is much higher than the relatively small increase in the medication bill. In the USA, healthcare expenditure is approximately 2,000 USD higher annually per hypertensive individual, with a trend towards an outpatient setting. Yet, lifetime treatment provides an average saving of over 7,000 USD per Caucasian patient [2]. Specifically, in the SPRINT trial, intensive blood pressure management cost roughly 23,000 USD per QALY (quality-adjusted-life year) gained [17].
Conclusion
In conclusion, a two-drug regimen is the preferred therapy at the start of treatment, with only a few exceptions requiring a stepwise approach. Specifically, a single-pill combination enhances therapeutic inertia and patient adherence by creating a more homologous response in the heterologous population. In recognition of a vulnerable patient, a more cautious and individualised approach with a higher emphasis on safety should be implemented. Even though guideline-directed medical therapy is the principle of treatment, individualised treatment and expert advice are still needed in areas of uncertainty. The subject of treatment after all is a specific patient with a unique cardiovascular profile, not a statistically derived number in clinical trials.
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