Sequential drug decision problems in long-term medical conditions: a case Study of Primary Hypertension Eunju Kim ba, ma, msc

4.2.3Pharmacologic treatment recommendations

Antihypertensive treatment generally starts with lifestyle modification such as smoking cessation, moderation of alcohol consumption, regular physical activity, sodium restriction, weight management and healthy eating. If blood pressure is not controlled by lifestyle modification, current guidelines recommend that pharmacologic treatment can start with a single drug at low dose. The decision to start pharmacologic treatment varies depending on the level of blood pressure, age, target organ damage (e.g., left ventricular hypertrophy or CKD) and overall cardiovascular risk. National Institute for Health and Clinical Excellence (NICE) guidance recommends initializing antihypertensive drug treatment to people with stage 2 hypertension or with stage 1 hypertension who have either target organ damage, established CVD, renal disease (RD), DM or a 10-year cardiovascular risk equivalent to 20% or greater^[63].

Most guidelines aim for a target clinic blood pressure below 140/90 mmHg in people aged under 80 years, whereas lower targets (below 130/80 mmHg) are set for people with established cardiovascular or RD or DM^{[8, 10][8, 10]} and higher targets (150/90mmHg) are set for people aged over 80 years (see Table ‎4.)^{[253, 254]}. The ultimate goal of antihypertensive treatment is to reduce cardiovascular and renal morbidity and mortality.

The initial drug should be selected on the basis of the patient’s clinical characteristics, risk factors of CVDs, medical history, possible drug interactions, side effects and cost considerations^[8]. NICE guidance recommends A(B)/CD rule initializing treatment to the patients under 55 years with an ACEI or an ARB, and to the patients aged over 55 years with a CCB or a D^[63]. This age grouping is based on the capacity of drugs to inhibit (i.e., ACEIs or BBs) or not inhibit (i.e., CCBs or Ds) the components of the renin-angiotensin system (RAS). In general, the RAS is known to be more active in younger patients and less active in older patients. However, it is generally accepted that Thiazide-type Ds (as well as chlorthalidone and indapamide), BBs, CCBs, ACEIs, and ARBs are suitable for the initiation and maintenance of antihypertensive treatment either as monotherapy or in some combinations with each other^{[8-10, 223, 237]}. Nevertheless, the use of BBs for the initial treatment of primary hypertension is controversial because of the outcomes of meta-analyses and other studies that showed poor performance of atenolol based treatment in clinical outcomes^{[230, 231]}. The partial update of the NICE guidelines in 2004 indicated that BBs are no longer preferred as a routine initial therapy for hypertension^[238].

If blood pressure is not controlled with a single initial drug low dose, traditionally recommended treatment algorithm for primary hypertension is a stepped-care approach, which titrates to a maximum dose as needed or adds an additional drug as the second step^{[9, 239]}. Currently, a tailored treatment algorithm to individual patient, which allows more treatment options depending on the patient’s risk factors, is also recommended in some clinical guidelines^[8]. The variation in the recommendations from major clinical guidelines implies that there is no established standard of evidence-based optimal treatment sequence.

Combination therapy often offers greater blood pressure reduction at lower doses with fewer side effects over monotherapy because of the multiple mechanisms involved in blood pressure^{[240, 241]}. Thus, European Society of Hypertension and European Society of Cardiology (ESH/ESC) considers two-drug treatment as an alternative to monotherapy as a first choice therapeutic approach, not a necessary step after attempting monotherapy^[8]. Antihypertensive drugs of different classes can be combined if 1) they have different and complementary mechanisms of action, 2) there is evidence that the antihypertensive effect of the combination is greater than that of either combination component, 3) the combination may have a favourable tolerance profile, the complementary mechanisms of action of the components minimising their individual side effects^[8].
Table ‎4.. Recommendations from major clinical guidelines of primary hypertension

Guideline (Country)	Publication year	Treatment threshold	Treatment goals	First-line treatment
NICE (UK)^[63]	2011	SBP ≥160/100 mmHg regardless of 10-year CVD risk. SBP ≥140/90 who have 10-year CVD risk >20%.	Age<80 years, SBP 140/90 mmHg. Age≥80 years, SBP 150/90 mmHg.	Age<55 years, ACEIs/ARBs. Age ≥ 55 years or black, Ds or CCBs.
ESH/ESC (Europe) ^[8]	2013	Age<80 years, SBP ≥140/90 mmHg. Age≥80 years, SBP ≥160/100 mmHg.	SBP ≤140/90 mmHg in all patients with hypertension. SBP ≤130/80 mmHg in patients with DM and in high-risk.	Ds, BBs, CCBs, ACEIs/ARBs either as monotherapy or in some combinations.
JNC8 (US)^[9]	2014	Age<60 years, SBP ≥140/90 mmHg. Age≥60 years, SBP ≥150/90 mmHg.	Age<60 years, SBP <140/90 mmHg (same for the hypertensive population with DM or non-diabetic CKD). Age≥60 years, SBP <150/90 mmHg.	Ds, CCBs, ACEIs/ARBs either alone or in combination.
CHEP (Canada) ^[10]	2014	Age<80 years, SBP ≥160/100 mmHg or ≥140/90 mmHg with a macrovascular target organ damage. Age≥80 years, SBP ≥160/100 mmHg.	Age<80 years, SBP 140/90 mmHg. Age≥80 years, SBP 150/90 mmHg.	Ds, BBs (only age <60 years), CCBs, ACEIs/ARBs either as monotherapy or in some combinations.

1) NICE stands for the National Institute for Health and Care Excellence; ESH/ESC stands for the European Society of Hypertension (ESH)-European Society of Cardiology (ESC); JNC8 stands for the Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure published by National Heart and Blood Institute in the US; and CHEP stands for the Canadian Hypertension Education Program.

Possible combinations of different classes of antihypertensive drugs are illustrated in Figure ‎4.. Combining ACEIs and ARBs is not recommended because it does not reduce the risk in the CVD-related outcomes, but increases the risk of hypotension, renal dysfunction and hyperkalaemia^{[242, 243]}. If triple therapy is required, the combination of ACEIs, CCBs and Ds is generally recommended.

1) Solid lines stand for the rational combinations considering efficacy, complementarity of action mechanism and tolerance profile. Dash lines stand for the less favourable combinations, which should be used carefully for some patients groups or whose effectiveness is not proved yet.

Figure ‎4.. Possible combinations of antihypertensive drug classes^[8]
For particular patient subgroups having CVD, DM, kidney disease or other high risk factors specific drugs are recommended based on clinical trials demonstrating the benefits of such therapy on the natural disease history of the associated condition. Table ‎4. shows the recommendations for the patients having CVD or DM based on the major clinical guidelines; most of them are suitable for patients with CVDs and DM apart from CCBs for HF. Amlodipine is the only CCB with established safety in patients with severe HF^[244].
Table ‎4.. Recommended drugs for cardiovascular diseases and diabetes^{[8-10, 245]}

	Ds	BBs	CCBs (dihydropyridine)	CCBs (Non- dihydropyridine)	ACEIs	ARBs
Angina pectoris	∆	o	o	o	∆	∆
Past MI	∆	o	∆	o	o	o
Past stroke	o	o	o	∆	o	o
HF	o	o	∆ (only Amlodipine)	x	o	o
DM	o	∆	o	∆	o	o

1) Circle stands for the recommended drug for the relevant health state, agreed in the clinical guidelines reviewed. Triangle stands for the recommended drug for the relevant health state in some guidelines. Cross stands for the contraindicated drug for the relevant health state.