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Combination Therapy Achieves BP Goal, Reduces CV Risk

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Dr k k AggarwalAdequate BP control is the most important factor in the fight against hypertension. Guidelines recommend target BP goals to maximize protection, yet a majority of the patients do not achieve the target goal. Rather than the lack of suitable antihypertensives (AHTs), poor BP control in real life originates more from factors that prevent the AHTs from expressing their therapeutic potential.

Monotherapy: Advocated in the late seventies and the eighties, monotherapy at increasing doses was later discontinued due to increased drug-related side effects that resulted in drug discontinuation and subsequently increased CV risk. Subsequently sequential monotherapy, i.e., switching from one monotherapy to another was adopted. This approach had some therapeutic rationale since the magnitude of BP reduction tends to vary between different drug classes in the same patient. It was beneficial only in select patient groups like those with isolated systolic hypertension (ISH). Being a time consuming  strategy, it often leads to treatment discontinuation, resulting in poor BP control. Over the past 2 to 3 decades, step care treatment has been recommended by guidelines. It involves initial monotherapy followed by the addition of 2nd, 3rd or 4th drug. This strategy was supported by evidence suggesting that adding a 2nd drug can increase the chances of BP control by 5 fold vs. increasing the dose of the initial AHT. However, in real life situation, the advantage of this strategy would depend on adherence. Studies have shown adherence to be as low as only 1 in every 4 patients.

Combination therapy, till recently recommended as first-line therapy in select patient population in the guidelines, has now emerged as the treatment of choice in almost all hypertensive patients according to the recent ACC/ESC guidelines. Single pill combinations (SPCs) exhibit prompt and better BP control with lower discontinuation subsequently resulting in lower risk of hospitalization for IHD, cerebrovascular disease, and heart failure. SPC, as a treatment strategy, has been found to be associated with a 53% greater chance of achieving BP control than monotherapy. The HOPE-3 trial showed that combination reduced the risk of CV outcomes by 24% vs placebo. Many studies directly or indirectly conclude that combination treatment may be associated with a lower incidence and risk of CV morbid and fatal events. Trials like the VALUE, ALLHAT and ASCOT-BPLA show that early BP control (achievable with 2 drug combination) was more protective than late BP control. Combination therapy resulted in better BP control with lower risk of CV events (↓38%), HF (↓36%) and stroke (↓21%). Real life medical practice of 2 million patients reinforced the fact that starting and continuing treatment with drug combinations exhibited the lowest risk of CV events. Also, the risk of hospitalization for CV outcomes was 56% significantly lower when patients were on combination therapy than when they were on monotherapy. Combination with two drugs is also associated with better tolerability.

Evidence suggests that compared to monotherapy,  combination with two drugs provides an earlier and long-lasting greater protection. Currently the most widely used combinations are those that contain CCB with ACEI/ARB. Thus, while monotherapy could be a treatment of choice in frail and the old/very old, where the guidelines recommend starting with monotherapy to prevent excessive BP fall, in all other patients, combination therapy not only helps achieve goal but also lowers the risk of CV events.

Mancia G, Rea F, Corrao G, Grassi G. Two-Drug Combinations as First-Step Antihypertensive Treatment. Circ Res. 2019 Mar 29;124(7):1113-1123. 

BP: Blood Pressure, CV: Cardiovascular, ISH: Isolated Systolic Hypertension, ACC : American College of Cardiology, ESC: European society of Cardiology, IHD: Ischemic Heart Disease, HOPE-3: Heart Outcome Prevention Evaluation 3, VALUE: Valsartan Antihypertensive Long-term Use Evaluation, ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, HF: Heart Failure, ACEI: Angiotensin Converting Enzyme Inhibitor, ARB: Angiotensin Receptor Blocker, CCB: Calcium Channel Blocker

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