6.1 Cardiovascular Pharmacotherapy & Evidence-Based Guidelines

Hypertension Management and Canadian Guidelines

Hypertension is the single leading modifiable risk factor for cardiovascular disease, stroke, and chronic kidney disease in Canada. Hypertension Canada publishes evidence-based clinical practice guidelines outlining diagnostic thresholds, blood pressure (BP) measurement methodologies, glycemic and renal comorbidities, and pharmacological selection algorithms.

Blood Pressure Measurement and Diagnostic Thresholds

Accurate diagnosis relies on standardized measurement. Automated Office Blood Pressure (AOBP)—the preferred clinic-based method—involves an automated device taking multiple consecutive oscillometric readings while the patient rests alone in a quiet room, substantially reducing the white-coat effect.

Target Blood Pressure Levels

Hypertension Canada establishes risk-stratified BP targets:

• Standard Target: $< 140/90\text{ mmHg}$ for general hypertensive adults without diabetes or high cardiovascular risk.
• Diabetes Mellitus Target: $< 130/80\text{ mmHg}$ to reduce microvascular (nephropathy, retinopathy) and macrovascular complications.
• Intensive / High-Risk Target (SPRINT Criteria): Systolic BP $< 120\text{ mmHg}$ (measured by AOBP) for individuals aged $\ge 50$ years with high cardiovascular risk (established clinical or subclinical cardiovascular disease, CKD with eGFR $20-59\text{ mL/min}/1.73\text{ m}^2$, Framingham Risk Score $\ge 15%$, or age $\ge 75$ years). Intensive control requires close monitoring for hypotension, syncope, acute kidney injury, and electrolyte disturbances.

First-Line Pharmacotherapy and Combination Strategies

For adults without compelling indications, first-line monotherapy includes:

1. Thiazide / Thiazide-like Diuretics: Chlorthalidone ($12.5-25\text{ mg}$ daily) and Indapamide ($1.25-2.5\text{ mg}$ daily) are preferred over hydrochlorothiazide (HCTZ) due to longer duration of action and superior cardiovascular outcome data.
2. Angiotensin-Converting Enzyme (ACE) Inhibitors: (e.g., ramipril, perindopril, enalapril) or Angiotensin Receptor Blockers (ARBs): (e.g., candesartan, valsartan, telmisartan). ARBs are preferred alternatives when ACE inhibitors cause bradykinin-mediated dry cough or angioedema.
3. Dihydropyridine Calcium Channel Blockers (CCBs): (e.g., amlodipine, felodipine). Effective across all age groups and ethnicities, causing peripheral vasodilation (common adverse effect: dose-dependent peripheral edema).

Important Clinical Pearl: Beta-blockers are not recommended as first-line monotherapy in uncomplicated hypertension for patients aged $\ge 60$ years due to inferior stroke and cardiovascular event reduction compared to other first-line agents.

Dual Combination Therapy: Upfront initiation of two first-line antihypertensives (preferably as a single-pill combination) is recommended when baseline systolic BP is $\ge 20\text{ mmHg}$ above target or diastolic BP is $\ge 10\text{ mmHg}$ above target. Synergistic combinations include ACEi/ARB + Dihydropyridine CCB or ACEi/ARB + Thiazide-like diuretic. Dual renin-angiotensin-aldosterone system (RAAS) blockade (ACEi + ARB + direct renin inhibitor) is strictly contraindicated due to increased risks of hyperkalemia, syncope, and acute kidney injury without added clinical benefit.

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Dyslipidemia and Atherosclerotic Risk Reduction

The Canadian Cardiovascular Society (CCS) dyslipidemia guidelines prioritize comprehensive cardiovascular risk assessment using the modified Framingham Risk Score (FRS) or Cardiovascular Life Expectancy Model (CLEM), stratifying 10-year risk of cardiovascular events into Low ($< 10%$), Intermediate ($10-19.9%$), and High ($\ge 20%$).

Statin-Indicated Conditions (Automatic High Risk)

Patients meeting any of the following criteria are designated high risk and warrant immediate statin therapy regardless of baseline FRS:

1. Clinical Atherosclerotic Cardiovascular Disease (ASCVD): Acute coronary syndrome, stable angina, prior MI, CABG/PCI, stroke, TIA, peripheral arterial disease (PAD).
2. Abdominal Aortic Aneurysm (AAA): Infrarenal aortic diameter $\ge 3.0\text{ cm}$ or prior aneurysm repair.
3. Diabetes Mellitus: Age $\ge 40$ years, or age $\ge 30$ with disease duration $\ge 15$ years, or microvascular disease (retinopathy, nephropathy, neuropathy).
4. Chronic Kidney Disease (CKD): Age $\ge 50$ years with eGFR $< 60\text{ mL/min}/1.73\text{ m}^2$ or urinary albumin-to-creatinine ratio (ACR) $\ge 3.0\text{ mg/mmol}$ on $\ge 2$ occasions.
5. Severe Hypercholesterolemia: Baseline $\text{LDL-C} \ge 5.0\text{ mmol/L}$ (suggestive of Familial Hypercholesterolemia) or Genetic Dyslipidemias.

Lipid Targets and Pharmacotherapy Escalation

• Primary Target: $\text{LDL-C} < 2.0\text{ mmol/L}$ or $\ge 50%$ reduction from baseline.
• Secondary Targets: Non-HDL-C $< 2.6\text{ mmol/L}$ or Apolipoprotein B (ApoB) $< 0.8\text{ g/L}$.

+-------------------------------------------------------------------------+
|                   CCS DYSLIPIDEMIA ESCALATION ALGORITHM                 |
+-------------------------------------------------------------------------+
|  1. MAXIMALLY TOLERATED HIGH-INTENSITY STATIN                           |
|     (Atorvastatin 40-80 mg daily OR Rosuvastatin 20-40 mg daily)        |
|                                |                                        |
|                                v  (If LDL-C remains >= 2.0 mmol/L)      |
|  2. ADD EZETIMIBE 10 mg DAILY (NPC1L1 Inhibitor; IMPROVE-IT Trial)       |
|                                |                                        |
|                                v  (If High-Risk/Secondary Prevention    |
|                                |   and LDL-C remains >= 2.0 mmol/L)     |
|  3. ADD PCSK9 INHIBITOR (Evolocumab 140 mg SC q2w or Alirocumab)        |
|                                                                         |
|  *SPECIAL INDICATION (REDUCE-IT Criteria):                              |
|   If established CVD or DM + 2 risk factors, on statin, with fasting    |
|   Triglycerides 1.5 - 5.6 mmol/L -> Add ICOSAPENT ETHYL 2g PO BID       |
+-------------------------------------------------------------------------+

Statin Safety and Statin-Associated Muscle Symptoms (SAMS)

Statin myopathy spans benign myalgia (muscle ache without CK elevation) to severe rhabdomyolysis (muscle breakdown, $\text{CK} > 10 \times \text{ULN}$, myoglobinuria, acute renal failure). When managing SAMS:

1. Check serum creatine kinase (CK) and thyroid-stimulating hormone (TSH; untreated hypothyroidism predisposes to statin myopathy).
2. Discontinue statin until symptoms resolve completely (dechallenge).
3. Rechallenge with a lower dose of the same statin or switch to a hydrophilic statin (rosuvastatin or pravastatin) or alternate-day dosing (e.g., rosuvastatin $5-10\text{ mg}$ two to three times weekly).

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Heart Failure with Reduced Ejection Fraction (HFrEF)

Heart failure with reduced ejection fraction ($\text{LVEF} \le 40%$) requires aggressive neurohormonal blockade. Canadian Cardiovascular Society guidelines mandate rapid uptitration of the "Four Pillars" of Guideline-Directed Medical Therapy (GDMT) to reduce cardiovascular mortality and heart failure hospitalizations.

The Four Pillars of GDMT

1. Angiotensin Receptor-Neprilysin Inhibitor (ARNI):
   • Sacubitril/valsartan (Entresto) is preferred over ACE inhibitors or ARBs for symptomatic HFrEF (NYHA Class II-IV).
   • Neprilysin Inhibition: Prevents degradation of natriuretic peptides (BNP, ANP, bradykinin), promoting vasodilation, natriuresis, and antifibrotic effects.
   • Safety Rule: A mandatory 36-hour washout period is required when switching from an ACE inhibitor to an ARNI to prevent life-threatening angioedema caused by dual bradykinin accumulation.
2. Evidence-Based Beta-Blockers:
   • Only three beta-blockers demonstrate mortality reduction in HFrEF: Bisoprolol, Carvedilol, and Metoprolol Succinate (sustained-release). Atenolol, metoprolol tartrate, and propranolol do not confer equivalent survival benefits.
   • Initiate only in stable, euvolemic patients at low starting doses ("start low, go slow") and titrate every 2-4 weeks to target doses.
3. Mineralocorticoid Receptor Antagonists (MRAs):
   • Spironolactone ($12.5-50\text{ mg}$ daily) or Eplerenone ($25-50\text{ mg}$ daily).
   • Monitor serum potassium and renal function at 1, 4, 8, and 12 weeks. Withhold or reduce dose if serum $\text{potassium} > 5.5\text{ mmol/L}$ or $\text{eGFR} < 30\text{ mL/min}/1.73\text{ m}^2$.
4. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors:
   • Dapagliflozin ($10\text{ mg}$ daily) or Empagliflozin ($10\text{ mg}$ daily).
   • Indicated for all symptomatic HFrEF patients regardless of whether the patient has diabetes mellitus (based on DAPA-HF and EMPEROR-Reduced trials).
   • Mechanism: Promotes osmotic diuresis, reduces preload/afterload, improves myocardial energetics, and preserves renal function.

Adjunctive Heart Failure Therapies

• Loop Diuretics (Furosemide): Titrated to maintain euvolemia; provides symptom relief from pulmonary and peripheral congestion without mortality reduction.
• Ivabradine: Inhibits the hyperpolarization-activated cyclic nucleotide-gated ($I_f$) pacemaker channel in the SA node. Indicated in patients with $\text{LVEF} \le 35%$, in normal sinus rhythm with resting heart rate $\ge 70\text{ bpm}$ despite maximally tolerated beta-blocker therapy.
• HF with Preserved Ejection Fraction (HFpEF, $\text{LVEF} \ge 50%$): SGLT2 inhibitors are the first class to demonstrate significant reductions in cardiovascular death and hospitalizations in HFpEF (EMPEROR-Preserved, DELIVER), alongside MRA therapy and diuretics for fluid management.

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Ischemic Heart Disease and Acute Coronary Syndromes (ACS)

Chronic Coronary Syndromes (Stable Angina)

• Symptom Control (Antianginal Therapy): First-line therapy is a Beta-Blocker (titrated to resting HR $55-60\text{ bpm}$). Second-line additions include Dihydropyridine CCBs, Long-acting Nitrates (requiring a daily 10-12 hour nitrate-free interval to prevent nitrate tolerance), or Non-dihydropyridine CCBs (diltiazem, verapamil).
• Cardioprotective Vasculoprotection: Low-dose Acetylsalicylic Acid (ASA $81\text{ mg}$ daily), High-intensity Statin, and ACE Inhibitor/ARB (especially if concurrent hypertension, diabetes, or CKD).

Acute Coronary Syndromes (STEMI and NSTEMI/Unstable Angina)

1. Emergency Medical Management: ASA $160-325\text{ mg}$ chewed immediately, Sublingual Nitroglycerin ($0.4\text{ mg}$ q5min up to 3 doses; contraindicated if phosphodiesterase-5 inhibitors used within 24-48 hours), supplemental oxygen (only if $\text{SpO}_2 < 90%$), and unfractionated heparin or enoxaparin.
2. Dual Antiplatelet Therapy (DAPT):
   • ASA ($81\text{ mg}$ daily indefinitely) PLUS a potent $\text{P2Y}_{12}$ Receptor Inhibitor for a standard duration of 12 months following percutaneous coronary intervention (PCI).
   • Ticagrelor ($90\text{ mg}$ PO BID; PLATO trial) or Prasugrel ($10\text{ mg}$ PO daily; TRITON-TIMI 38 trial) are preferred over Clopidogrel ($75\text{ mg}$ daily) due to superior efficacy and faster, more consistent platelet inhibition.
   • Contraindications: Prasugrel is contraindicated in patients with a history of stroke or TIA (excess intracranial hemorrhage risk). Ticagrelor causes dyspnea and ventricular pauses, and is contraindicated in active bleeding or history of intracranial hemorrhage.

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Atrial Fibrillation: Rate vs. Rhythm Control and Anticoagulation

Atrial fibrillation (AF) management encompasses rate/rhythm control and stroke prevention.

Stroke Risk Assessment: The CHADS-65 Algorithm

+-------------------------------------------------------------------------+
|                     CCS CHADS-65 DECISION ALGORITHM                     |
+-------------------------------------------------------------------------+
|                                                                         |
|  Assess CHADS Criteria:                                                 |
|    C = Congestive Heart Failure                                         |
|    H = Hypertension                                                     |
|    A = Age >= 65 Years                                                  |
|    D = Diabetes Mellitus                                                |
|    S = Stroke / TIA / Systemic Embolism (Prior) [Scores 2 points]       |
|                                                                         |
|  Decision Rules:                                                        |
|  - Is Age >= 65 OR is any CHADS risk factor present?                    |
|      YES -> Oral Anticoagulation Indicated                              |
|      NO  -> Assess for Coronary/Vascular Disease:                       |
|             - If Vascular Disease present -> ASA 81 mg daily            |
|             - If No Vascular Disease -> No Antithrombotic Therapy       |
+-------------------------------------------------------------------------+

Anticoagulant Selection: DOACs vs. Warfarin

Direct Oral Anticoagulants (DOACs) are strongly preferred over warfarin for non-valvular AF due to lower rates of intracranial hemorrhage and all-cause mortality, rapid onset, predictable pharmacokinetics, and lack of routine INR monitoring.

Reversal Agents for Life-Threatening Bleeding

• Dabigatran: Idarucizumab (Praxbind) — humanized monoclonal antibody fragment ($5\text{ g}$ IV).
• Apixaban / Rivaroxaban: Andexanet alfa or Prothrombin Complex Concentrate (4-Factor PCC / Octaplex / Beriplex).
• Warfarin: Vitamin K1 (Phytomenadione) IV/PO plus 4-Factor PCC for rapid reversal.