What are the complications and risks of ramipril (Angiotensin-Converting Enzyme (ACE) inhibitor) in patients, particularly the elderly and those with pre-existing kidney disease, heart failure, or diabetes?

Complications and Risks of Ramipril

Common Adverse Effects

The most frequent side effects of ramipril include headache (5.4%), dizziness (2.2%), and fatigue/asthenia (2.0%), though these are generally mild and transient. 1

• Cough occurs in approximately 12% of patients and is the most common reason for discontinuation (1.0% of patients), characterized by a persistent non-productive "tickle" in the throat that appears within the first months of therapy 2, 1
• Cough frequency varies by ethnicity: 5-10% in white patients of European descent, rising to nearly 50% in Chinese patients 2
• Overall discontinuation due to side effects occurs in approximately 3% of patients 1
• Other common reasons for discontinuation include dizziness (0.5%) and impotence (0.4%) 1

Cardiovascular Complications

Hypotension

Symptomatic hypotension is the most common cardiovascular adverse effect, occurring most frequently during the first few days of therapy or after dose increases. 2

• Blood pressure declines without symptoms in nearly every patient, but hypotension is only concerning when accompanied by postural symptoms, worsening renal function, blurred vision, or syncope 2
• Highest risk occurs in patients with hypovolemia, recent marked diuresis, or severe hyponatremia (serum sodium <130 mmol/L) 2
• Symptomatic hypotension reported in 0.5% of patients in U.S. trials 1
• In heart failure patients post-MI, initial doses should be reduced to 1.25 mg if 2.5 mg cannot be tolerated 1

Renal Complications

Worsening Renal Function

ACE inhibition may cause functional renal insufficiency because glomerular filtration becomes critically dependent on angiotensin-mediated efferent arteriolar vasoconstriction in states of reduced renal perfusion. 2

• Significant creatinine increase (>0.3 mg/dL) occurs in 15-30% of patients with severe heart failure, but only 5-15% with mild to moderate symptoms 2
• Risk is highest in Class IV or hyponatremic patients who are most dependent on the renin-angiotensin system 2
• Substantially greater risk in patients with bilateral renal artery stenosis or those taking NSAIDs 2
• Minor, usually transient increases in blood urea nitrogen and serum creatinine can occur, especially when combined with diuretics 1
• Renal function usually improves after reducing diuretic dose 2

Acute Renal Failure

• Can occur in conditions where glomerular filtration is critically dependent on angiotensin II-mediated efferent tone (post-stenotic kidney, heart failure with severe volume depletion) 3
• Reversible after drug withdrawal 3

Electrolyte Disturbances

Hyperkalemia

Hyperkalemia can occur and may be sufficiently severe to cause cardiac conduction disturbances. 2

• Generally seen in patients whose renal function deteriorates or who are taking oral potassium supplements, potassium-sparing diuretics, or aldosterone antagonists 2
• Especially high risk in diabetic patients with renal impairment 2
• Frequent monitoring of serum potassium required when combined with potassium-sparing agents 1

Serious Hypersensitivity Reactions

Angioedema

Angioedema is a potentially life-threatening complication that requires immediate discontinuation of ramipril. 1

• Reported in 0.3% of patients in U.S. clinical trials 1
• Higher rate in Black patients (0.20%) compared to non-Black patients (0.09%) 1
• Can involve face, lips, tongue, glottis, and/or larynx 1
• Intestinal angioedema presents with abdominal pain (with or without nausea/vomiting), sometimes without prior facial angioedema 1

Anaphylactoid Reactions

• Life-threatening reactions reported during desensitization treatment with hymenoptera venom 1
• Reactions reported in patients dialyzed with high-flux membranes 1
• Reactions during low-density lipoprotein apheresis with dextran sulfate absorption 1

Hepatic Complications

Rarely, ACE inhibitors have been associated with a syndrome starting with cholestatic jaundice and progressing to fulminant hepatic necrosis and sometimes death. 1

• Discontinue ramipril if patient develops jaundice or marked elevations of hepatic enzymes 1
• Patients with impaired liver function could develop markedly elevated plasma levels of ramipril 1

Hematologic Complications

Blood Cell Abnormalities

In rare instances, ACE inhibitors may cause mild reductions in red blood cell count and hemoglobin, or more serious hematologic reactions. 1

• Decreases in hemoglobin or hematocrit (≥5 g/dL or ≥5%) rare: 0.4% with ramipril alone, 1.5% with ramipril plus diuretic 1
• Isolated cases of agranulocytosis, pancytopenia, and bone marrow depression may occur 1
• Hemolytic anemia and thrombocytopenia reported 1

High-Risk Populations

Hematologic reactions more likely in patients with collagen-vascular disease (systemic lupus erythematosus, scleroderma) and renal impairment. 1

• Consider monitoring white blood cell counts in these patients, especially with impaired renal function 1

Dermatologic Reactions

• Apparent hypersensitivity reactions: urticaria, pruritus, rash (with or without fever) 1
• Photosensitivity, purpura, onycholysis 1
• Severe reactions: pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome 1

Gastrointestinal Complications

• Hepatic failure, hepatitis, jaundice 1
• Pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis) 1
• Anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis 1

Neurologic and Psychiatric Effects

• Anxiety, amnesia, convulsions, depression 1
• Hearing loss, tinnitus 1
• Insomnia, nervousness, neuralgia, neuropathy, paresthesia 1
• Somnolence, tremor, vertigo, vision disturbances 1

Metabolic Effects

Hypoglycemia

Rare reports of hypoglycemia when ramipril given concomitantly with oral hypoglycemic agents or insulin, though causal relationship unknown. 1

Drug Interactions Leading to Complications

With Diuretics

• Excessive blood pressure reduction, especially when diuretic therapy recently instituted 1
• Increased risk of lithium toxicity when combined with diuretics 1

With NSAIDs

In elderly, volume-depleted, or renally compromised patients, NSAIDs (including COX-2 inhibitors) with ramipril may cause deterioration of renal function, including possible acute renal failure. 1

• Antihypertensive effect may be attenuated by NSAIDs 1

With Other RAS Inhibitors

Concomitant use of telmisartan and ramipril results in increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared to either drug alone. 1

• Dual blockade of renin-angiotensin-aldosterone system not recommended 1

With Potassium-Sparing Agents

• Potassium-sparing diuretics or potassium supplements increase risk of hyperkalemia 1
• Frequent serum potassium monitoring required 1

Surgery and Anesthesia Risks

During surgery or anesthesia with hypotensive agents, ramipril may block compensatory angiotensin II formation, leading to hypotension correctable by volume expansion. 1

Special Population Risks

Elderly Patients

• Should start with lower initial doses (1.25-2.5 mg daily) with gradual titration 4
• Monitor for orthostatic hypotension in both sitting and standing positions 4

Patients with Pre-existing Renal Disease

ACE inhibitors should not be withheld in high-risk patients (heart failure, diabetes, chronic renal failure) as they can expect the greatest benefit, but dosages should be carefully titrated with monitoring of renal function and serum potassium. 3

• Contraindicated in bilateral renal artery stenosis 2

Diabetic Patients

• Particularly beneficial but require careful monitoring of renal function and potassium levels 5
• Higher risk of hyperkalemia, especially with renal impairment 2