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4th October 2021
According to the American Heart Association, resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of three anti-hypertensive drug classes. The prevalence of RH has been estimated at 10.3% in the general population of anti-hypertensive treated patients, but rises among those with cardiovascular risk factors such as chronic kidney disease (22.9%) and the elderly (12.5%). Management of RH is important, especially given how one study identified how the condition was associated with a 47% increased risk of adverse cardiovascular events compared to controlled patients.
Both exercise and diet appear to play an important role in RH, although the evidence is limited. For example, an aerobic exercise programme in patients with RH reduced both systolic and diastolic pressure but the study included only 50 patients. Similarly, adoption of a low salt diet also reduced overall blood pressure in those with RH, but again, the study included only 12 patients.
This led a team from the Department of Psychiatry and Behavioural Sciences, Duke University, North Carolina, US, to set up the Treating Resistant Hypertension Using Lifestyle Modification to Promote Health (TRIUMPH) trial to examine the effect of diet and exercise on blood pressure control in those with resistant hypertension. The TRIUMPH study randomised patients to one of two arms: a Center-Based Lifestyle intervention (C-LIFE) or Standardised Education and Physician Advice (SEPA) for a 4-month period. The C-LIFE intervention included advice from a nutritionist, weekly group counselling together with behavioural weight management and a three-times weekly exercise session. Participants in the SEPA arm received a 1-hour educational session and blood pressure management diet programme and the same exercise prescription. In other words, both arms were the same except for the higher intensity of the intervention in the C-LIFE arm. Included participants had RH for at least 6 weeks with a clinic systolic blood pressure (SBP) > 130mmHg or diastolic blood pressure (DBP) > 80mmHg, or the need for four or more drugs with a SBP > 120mmHg. The primary outcome measure was the clinic SBP with secondary outcomes including ambulatory SBP and DBP. Other measures included baroreflex sensitivity (which is a measurement to quantify how much control the baroreflex has on the heart rate), high-frequency heart rate variability and flow-mediated dilation.
A total of 140 RH patients with a mean age of 63 years (48% female) were randomised to C-LIFE (90) or SEPA (50). The mean baseline SBP was 139mmHg and the diastolic 79mmHg. C-LIFE participants experienced a lower clinic SBP compared with those assigned to SEPA (126mmHg vs 132.8mmHg, p = 0.005). Similarly, mean DBP levels were significantly lower (73.2mmHg vs 75.6mmHg, p = 0.034). Ambulatory blood pressure measurements were also significantly reduced for C-LIFE but did not change among SEPA patients. In addition, C-LIFE participants had greater improvements in resting baroreflex sensitivity, high-frequency heart rate variability and flow-mediated dilation.
In their conclusion, the authors suggested that the results provided support for the value of an intensive, structured intervention to improve blood pressure in those with treatment resistant hypertension. They added that policymakers should consider RH as a new indication for cardiac rehabilitation that should be covered by government and private insurers.
Blumenthal JA et al. Effects of Lifestyle Modification on Patients With Resistant Hypertension: Results of the TRIUMPH Randomized Clinical Trial. Circulation 2021
According to the World Health Organization (WHO), the number of adults aged 30–79 years with hypertension is estimated to be 1.28 billion. However, perhaps more concerning are the WHO statistics suggesting that approximately 46% of adults are unaware that they have hypertension and that only 21% of patients have their condition under control. Various hypertension guidelines recognise that adequate blood pressure control is often only achieved with several medicines, yet guidance from NICE, for example, still recommends initiating mono-therapy. The potential value of using combination therapy as an initial approach to the management of hypertension, was explored in a small trial with 55 patients in 2017. A research team from the George Institute for Global Health, Camperdown, Australia, examined the value of using a single quad-pill with four anti-hypertensives, at a quarter of the normal treatment dose, as an initial therapy for patients with high blood pressure compared with placebo. After only 4 weeks, all patients given the quad-pill achieved a satisfactory blood pressure control (<140/90mmHg). However, these results were not surprising given the findings of a 2009 meta-analysis, which concluded that the additional blood pressure reduction from combining drugs from two different classes was approximately five-times greater than doubling the dose of one drug.
Now, the same Australian team has published the results of a randomised trial which they termed Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET). This randomised, double-blind study in adults with hypertension, allocated individuals, on a 1:1 basis, to either the quad-pill, which contained irbesartan (37.5mg), amlodipine (1.25mg), indapamide (0.625mg) and bisoprolol (2.5mg), or an indistinguishable, mono-therapy with irbesartan 150mg. The primary outcome was the difference in unattended office systolic blood pressure at 12 weeks. Moreover, a sub-cohort of patients from the trial continued with treatment for up to 52 weeks.
A total of 591 patients with a mean age of 59 years (60% male) and a mean baseline unattended blood pressure of 141mm/85mmHg, were randomised to quad-pill (300) or mon-therapy with irbesartan . By week 12 only 15% of those receiving the quad-pill compared to 40% on mono-therapy, required additional blood pressure medication. Furthermore, at week 12, a higher proportion of patients given the quad-pill (76% vs 58%) achieved a blood pressure < 140/90mmHg (relative risk, RR = 1.30, 95% CI 1.20–1.50, p < 0.0001). In addition, a blood pressure of less than 120/80mmHg, was also achieved by more patients in the quad-pill group (46% vs 26%, RR = 1.75, 95% CI 1.38–2.22, p < 0.0001). After 52 weeks, mean unattended systolic blood pressure remained 7.7mmHg lower in the intervention group. At 12 months, blood pressure control rates were also higher for the intervention group (81% vs 62%, RR 1.32, 95% CI 1.16–1.50) as were the proportion achieving a blood pressure < 120/80mmHg (53% vs 25%, intervention vs control, RR = 2.1 95% CI 1.60–2.8, p < 0.0001).
The authors concluded that “a strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting mono-therapy.”
Chow CK et al. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose mono-therapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet 2021
3rd September 2021
High blood pressure is an important risk factor for both cardiovascular and chronic kidney disease. As a result, blood pressure treatment guidelines have made recommendations, particularly for target systolic blood pressure values, as there is evidence that lowering this component reduces the risk of cardiovascular disease and all-cause mortality and the current systolic blood pressure target set by the European Society of Cardiology is 130 to 139 mmHg. While lowering systolic pressure further to under 120 mmHg in those aged 75 years and older, reduced the incidence of fatal and non-fatal major cardiovascular events, other data has found an increased mortality risk among the elderly.
Given these ambiguities, a Chinese team from the Hypertension Centre, FuWai Hospital, Peking, China, performed a randomised, controlled trial, in hypertensive patients aged 60 to 80 years of age. They included patients with a baseline systolic pressure of between 140 and 190 mmHg for at least three months prior to the study. The study examined the outcomes associated with reducing systolic blood pressure to a target of 110 to less than 130 mmHg (the intensive treatment) or a target of between 130 and less than 150 mmHg (standard treatment). All patients were provided with a home blood pressure monitoring device and were required to provide readings at least weekly during the follow-up period. The primary outcome of interest was a composite of several adverse cardiovascular events including stroke, acute coronary syndrome and hospitalisation for unstable angina, atrial fibrillation and death from cardiovascular causes.
A total of 8511 patients were randomised to either arm with a mean age of 66.2 years (46.9% male) and a mean systolic blood pressure of 146.1 and a diastolic of 82.7 mmHg. During a median follow-up of 3.34 years, the primary outcome occurred in 3.5% of those in the intensive blood pressure arm and 4.6% in the standard arm (hazard ratio, HR = 0.74, 95% CI 0.60 – 0.92, p = 0.007). Furthermore, the individual components of the primary outcome were also significantly improved in the intensive arm. For example, the hazard ratio for stroke was 0.67 (95% CI 0.47 – 0.97), acute coronary syndrome (HR = 0.67) and although death from any cardiovascular cause was reduced, this was not significant (HR = 0.72, 95% CI 0.39 – 1.32). There were also no differences in safety outcomes such as hypotension, dizziness, syncope or fracture and for renal outcomes.
The authors concluded that intensive blood pressure lowering among elderly patients was associated with a reduced risk of adverse cardiovascular outcomes. However, a recognised limitation was that it was undertaken in a Chinese population which could reduce the generalisability of their findings and that the study excluded patients with a history of stroke.
Zhang W et al. Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension. New Eng J Med 2021