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Single pill combination therapy for hypertension comes of age

Pank Jit Sin
01 Feb 2019

Single pill combination (SPC) therapy is increasingly accepted and helps to overcome some of the problems associated with multipharmacy and compliance, says an expert.

Dr Chua Seng Keong, consultant cardiologist and physician, said SPC has a role to play in bringing patients to target.  Speaking at the MSH 16th Annual Congress 2019, Chua said there is more evidence supporting the use of SPC in bringing patients to target.

One of the major problems contributing to treatment failure is patient adherence. SPCs, Chua said, reduce the risk of patient nonadherence by reducing and minimizing the amount of medication (in terms of pills) and frequency.

It took some time to arrive at the current treatment guidelines for hypertension regarding the use of SPCs. Combination therapy saw recommendation in the 2003 European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines which stated untreated blood pressure (BP) levels in the absence or presence of target organ damage and risk factors could be treated with a single agent at low dose or a two-drug combination at low dose. A decade later in 2013, the ESH-ESC guidelines then recommended that initiation of antihypertensive therapy with a two-drug combination may be considered in patients with markedly high baseline BP or at high cardiovascular risk.  

A year later, in 2014, the first mention of a fixed-dose combination appeared in the US 8th Joint National Committee, where it was recommended that fixed dose combination of antihypertensives be given to patients where the probability of achieving the recommended treatment target is low. [Drugs Context 2018;7:212531]

Similarly the 2017 US Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, which was a multi-society guideline, suggests starting with two agents (either as separate or in SPC form) if a person is diagnosed with stage 2 hypertension ie, BP >20/10 mmHg above target. 

Most recently, the 2018 ESC/ESH joint guidelines recommended initiating treatment using a two-drug combination in a SPC. This is contrary to previous stepwise guidelines which called for monotherapy before the addition of other agents, either individually or in SPC, as well.

The newest Malaysian Guidelines (2018) is in line with the combination therapy development, where it states that physicians should choose combination therapy in patients with medium, high or very high-risk stage 1 hypertension and stage 2 hypertension. Additionally, it is recommended that combination therapy, in the form of multiple monotherapy or single pill combinations, should be prescribed for most patients to achieve BP control.

Rationale for use of SPC  

SPCs refer to drug combinations involving two or more components in a fixed dose in one pill and the concept has been around for a while, noted Chua. Although relatively new in the treatment of hypertension, it has seen common use in the treatment of HIV, type 2 diabetes, heart failure and TB. The rationale for use of SPC comes from the fact that the use of more than one drug is necessary to achieve target BP in the majority of patients. This was observed in the ALLHAT* trial, where an average of two drugs were required to achieve BP control in two-thirds of the participants.

Chua also alluded to the SPRINT@ trial, which looked at cardiovascular outcomes in patients with intensively controlled BP (<120 mmHg systolic) compared to those with routinely controlled BP (<140 mmHg systolic). The trial arrived at the conclusion that those with strictly controlled BP had significantly lower cardiovascular outcomes. The mean number of antihypertensive agents used in the standard arm was 1.8 versus 2.8 in the intensive arm, which again proves multiple compounds achieve better results. 

Multiple agents used in combination therapy also allow for lower doses of each component drug to achieve better BP outcomes. The synergistic effects of multiple drug therapy were demonstrated by Mahmud in 2007 where it was revealed that quarter-dose quadruple antihypertensive combination therapy was more efficacious than individual agent. [Hypertension 2007;49(2):272-275]

The most recent evidence for the use of low-dose SPC comes from the TRIUMPH# trial, which revealed that patients on three BP lowering medications are more likely to reach target BP than those receiving usual care. 

*ALLHAT – Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
@SPRINT – Systolic Blood Pressure Intervention Trial
#TRIUMPH - Triple pill vs Usual care Management for Patients with mild-to-moderate Hypertension
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Most Read Articles
3 days ago
New drug applications approved by US FDA as of 01 - 15 July 2019 which includes New Molecular Entities (NMEs) and new biologics. It does not include Tentative Approvals. Supplemental approvals may have occurred since the original approval date.