What is the role of the Renin-Angiotensin-Aldosterone System (RAAS) in managing hypertension?

Role of RAAS in Managing Hypertension

RAAS inhibitors—specifically ACE inhibitors and ARBs—are cornerstone antihypertensive agents that should be prioritized as first-line therapy in hypertensive patients with diabetes, chronic kidney disease, left ventricular hypertrophy, heart failure, or post-myocardial infarction, with ACE inhibitors generally preferred over ARBs for cardiovascular protection. 1, 2

Pathophysiologic Foundation

The renin-angiotensin-aldosterone system is the primary hormonal cascade controlling blood pressure through angiotensin II-mediated vasoconstriction and aldosterone-stimulated sodium retention. 3, 4 Angiotensin II acts as a potent vasoconstrictor by binding to AT1 receptors in vascular smooth muscle and stimulates aldosterone secretion from the adrenal cortex. 3 Dysregulation of this system drives the pathogenesis of hypertension and associated target organ damage. 5, 4

First-Line RAAS Inhibitor Selection

ACE Inhibitors as Preferred Initial Therapy

ACE inhibitors should be the first choice for RAAS blockade in most hypertensive patients, particularly those with diabetes, as they provide superior cardiovascular protection compared to ARBs. 6 ACE inhibitors prevent conversion of angiotensin I to angiotensin II and reduce bradykinin degradation, providing additional vasodilatory effects. 3, 4

• In diabetic hypertensive patients, ACE inhibitors (or ARBs if ACE inhibitors not tolerated) should be a regular component of combination therapy and preferred when monotherapy is sufficient. 1
• Blood pressure targets in diabetes should be <130/80 mmHg, with antihypertensive treatment potentially initiated even when BP is in the high normal range. 1
• ACE inhibitors reduce the risk of myocardial infarction more effectively than ARBs and are preferred for primary prevention of heart failure. 6

ARBs as Alternative Therapy

ARBs selectively block the AT1 receptor, preventing angiotensin II from exerting vasoconstrictor and aldosterone-secreting effects without affecting bradykinin metabolism. 3 ARBs are indicated as alternatives in patients who cannot tolerate ACE inhibitors, typically due to cough (though this risk is often overestimated). 6

• In elderly hypertensive patients with left ventricular hypertrophy, the ARB losartan reduced cardiovascular events, particularly stroke, more effectively than beta-blockers. 1
• ARBs demonstrated significant renal protective effects in type 2 diabetic patients with nephropathy, superior to calcium channel blockers for reducing heart failure. 1

Specific Clinical Scenarios Requiring RAAS Blockade

Hypertension with Diabetes

In diabetic hypertensive patients, RAAS inhibitors provide pronounced antiproteinuric effects and should be initiated even when BP is in the high normal range if microalbuminuria is present. 1 The combination of perindopril (ACE inhibitor) and indapamide (diuretic) significantly reduced both microvascular and macrovascular outcomes in diabetic patients. 1

Hypertension with Chronic Kidney Disease

• Strict blood pressure control (<130/80 mmHg, even lower if proteinuria >1 g/day) is required to protect against progression of renal dysfunction. 1
• To reduce proteinuria, an ARB, ACE inhibitor, or combination of both are required, though dual RAAS blockade increases hyperkalemia risk. 1, 2
• When eGFR is <30 mL/min/m², loop diuretics rather than thiazides should be prescribed alongside RAAS inhibitors. 1

Hypertension with Left Ventricular Dysfunction

ACE inhibitors (or ARBs if intolerant) are recommended for patients with LVEF ≤40%, diabetes, or chronic kidney disease unless contraindicated. 1 In patients with LVEF ≤35%, sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor) proved superior to ACE inhibitors for reducing heart failure hospitalization and cardiovascular death. 1

Post-Stroke Hypertension

Blood pressure reduction with ACE inhibitor-based regimens (perindopril with indapamide) reduced recurrent stroke by approximately 30% in both hypertensive and normotensive patients with stroke history. 1

Metabolic Syndrome

In patients with metabolic syndrome, RAAS blockers should be used as first-line therapy followed by calcium antagonists or low-dose thiazide diuretics, avoiding beta-blockers due to adverse metabolic effects. 1 RAAS inhibitors are associated with lower incidence of new-onset diabetes compared to other antihypertensive classes. 1

Combination Therapy Strategies

Most hypertensive patients require two or more drugs to achieve blood pressure targets, particularly elderly patients with isolated systolic hypertension. 1

• When monotherapy with a RAAS inhibitor is insufficient, add a calcium channel blocker (dihydropyridine preferred) or low-dose thiazide diuretic. 1
• The combination of RAAS inhibitor plus calcium antagonist is associated with lower incidence of diabetes than beta-blocker-based regimens. 1
• If blood pressure remains uncontrolled on three agents (including a diuretic), evaluate for secondary hypertension. 1

Critical Safety Considerations

Renal Artery Stenosis

Exercise extreme caution when using ACE inhibitors or ARBs in patients with bilateral renal artery stenosis or stenosis to a solitary kidney due to risk of acute renal failure. 1, 2 Monitor for >50% rise in serum creatinine after initiating RAAS inhibitors. 2

Hyperkalemia Management

• Monitor potassium levels closely, particularly in patients with chronic kidney disease or heart failure. 2, 7
• For K+ 4.5-5.0 mEq/L: Continue up-titration of RAAS inhibitors with close monitoring. 2
• For K+ >5.0 mEq/L: Initiate potassium-lowering therapy (dietary restriction, loop diuretics, potassium binders) rather than discontinuing RAAS inhibitors. 2, 7
• For K+ >6.0 mEq/L: Temporarily discontinue RAAS inhibitors and implement acute hyperkalemia management (insulin/glucose, beta-agonists, dialysis if necessary). 2

Pregnancy

RAAS inhibitors are absolutely contraindicated during pregnancy due to fetal risks. 1, 2 In pregnant patients with chronic hypertension, target BP 110-129/65-79 mmHg using alternative agents. 1

Common Pitfalls to Avoid

• Do not discontinue RAAS inhibitors prematurely for mild asymptomatic hyperkalemia (K+ 5.0-5.5 mEq/L), as discontinuation increases cardiovascular events and mortality. 2
• Do not assume cough incidence with ACE inhibitors is prohibitive—the risk is often overestimated and can be reduced by using lipophilic ACE inhibitors or combining with calcium channel blockers. 6
• Do not use beta-blockers as first-line therapy in metabolic syndrome or diabetes due to adverse effects on glucose metabolism, weight, and lipid profile. 1
• Always monitor potassium and renal function 1-2 weeks after initiating or up-titrating RAAS inhibitors. 2

Dosing Strategy

Start with low doses and titrate gradually to target doses proven to reduce morbidity and mortality in clinical trials. 2, 7 The maximal blood pressure effect may take 3-6 weeks to manifest. 3 There is no rebound effect after abrupt withdrawal. 3