The overwhelming majority of persons with BP sufficiently elevated to warrant pharmacological therapy may be best treated initially with 2 agents (see Section 8.1.6.1). When initiation of pharmacological therapy with a single medication is appropriate, primary consideration should be given to comorbid conditions (eg, HF, CKD) for which specific classes of BP-lowering medication are indicated (see Section 9). In the largest head-to-head comparison of first-step drug therapy for hypertension, the thiazide-type diuretic chlorthalidone was superior to the CCB amlodipine and the ACE inhibitor lisinopril in preventing HF, a BP-related outcome of increasing importance in the growing population of older persons with hypertension. Additionally, ACE inhibitors were less effective than thiazide diuretics and CCBs in lowering BP and in prevention of stroke. For black patients, ACE inhibitors were also notably less effective than CCBs in preventing HF and in the prevention of stroke (see Section 10.1). ARBs may be better tolerated than ACE inhibitors in black patients, with less cough and angioedema, but according to the limited available experience they offer no proven advantage over ACE inhibitors in preventing stroke or CVD in this population, making thiazide diuretics (especially chlorthalidone) or CCBs the best initial choice for single-drug therapy. For stroke, in the general population, beta blockers were less effective than CCBs (36% lower risk) and thiazide diuretics (30% lower risk).

Synopsis
The overwhelming majority of persons with BP sufficiently elevated to warrant pharmacological therapy may be best treated initially with 2 agents (see Section 8.1.6.1). When initiation of pharmacological therapy with a single medication is appropriate, primary consideration should be given to comorbid conditions (eg, HF, CKD) for which specific classes of BP-lowering medication are indicated (see Section 9). In the largest head-to-head comparison of first-step drug therapy for hypertension, the thiazide-type diuretic chlorthalidone was superior to the CCB amlodipine and the ACE inhibitor lisinopril in preventing HF, a BP-related outcome of increasing importance in the growing population of older persons with hypertension. Additionally, ACE inhibitors were less effective than thiazide diuretics and CCBs in lowering BP and in prevention of stroke. For black patients, ACE inhibitors were also notably less effective than CCBs in preventing HF and in the prevention of stroke (see Section 10.1). ARBs may be better tolerated than ACE inhibitors in black patients, with less cough and angioedema, but according to the limited available experience they offer no proven advantage over ACE inhibitors in preventing stroke or CVD in this population, making thiazide diuretics (especially chlorthalidone) or CCBs the best initial choice for single-drug therapy. For stroke, in the general population, beta blockers were less effective than CCBs (36% lower risk) and thiazide diuretics (30% lower risk).

Background: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice.

Methods: We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested.

Findings: Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.

Interpretation: This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers.

Funding: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.

The goals of antihypertensive therapy are to lower blood pressure and prevent end-organ damage without side effects, which affect quality of life. The antihypertensive drugs, regardless of class, all lower blood pressure, but they vary in their mechanisms of action, side-effect profiles, suitability for patients with other comorbid conditions, and ability to protect against the long-term sequelae of hypertension. The Sixth Report of the Joint National Committee on Prevention, Evaluation, and Treatment of High Blood Pressure (JNC-VI) recommends diuretics and beta-blockers as first-line therapy for uncomplicated hypertension, with diuretics also being strongly preferred for patients with isolated systolic hypertension or hypertension and heart failure and beta-blockers being strongly preferred for patients who have had a myocardial infarction (MI) and those with hypertension and angina, atrial tachycardia, or atrial fibrillation. Because angiotensin-converting enzyme (ACE) inhibitors have been shown to be cardioprotective and renoprotective in patients with diabetes or impaired left ventricular (LV) function, the JNC-VI recommends them as first-line therapy in patients with diabetes with proteinuria, heart failure, and MI complicated by LV dysfunction. It recommends calcium channel blockers for hypertensive patients with angina, long-acting dihydropyridines for those with isolated systolic hypertension, and the nondihydropyridines for those with atrial tachycardia or fibrillation, diabetes, and proteinuria. The angiotensin II receptor blockers (ARBs) share many of the organ-protective effects of ACE inhibitors when studied in animal models. They are effective in lowering blood pressure and have a very benign side-effect profile; however, these agents have not been available long enough to ascertain their efficacy in protecting against long-term complications.

CCBs are added to, or substituted for, β-blockers when BP remains elevated, when angina persists, or when drug side effects or contraindications mandate. As a class, CCBs reduce myocardial oxygen demand by decreasing peripheral vascular resistance and lowering BP and increase myocardial oxygen supply by coronary vasodilation. The nondihydropyridine agents, diltiazem and verapamil, also decrease the sinus node discharge rate and slow atrioventricular nodal conduction. Long-acting dihydropyridine agents are preferred over nondihydropyridines for use in combination with β-adrenoreceptor blockers, to avoid excessive bradycardia or heart block. Diltiazem or verapamil should not be used in patients with HF or LV systolic dysfunction, and short-acting nifedipine should be avoided because it causes reflex sympathetic activation and worsening myocardial ischemia.
Although CCBs are useful in the management of angina, there is no consensus about their role in preventing cardiovascular events in patients with established CAD. The INVEST investigators randomized >22 000 hypertensive patients with chronic CAD to the nondihydropyridine CCB verapamil or the β-blocker atenolol. By 24 months, the ACE inhibitor trandolapril had to be added in 63% of verapamil patients and 52% of atenolol patients, and hydrochlorothiazide was added in 44% of verapamil and 60% of atenolol patients, respectively. There was no difference between the groups in the composite end point of death, MI, or stroke over a mean follow-up of 2.7 years.

As a class, CCBs reduce myocardial oxygen demand by decreasing peripheral vascular resistance and lowering BP and increase myocardial oxygen supply by coronary vasodilation. The nondihydropyridine agents diltiazem and verapamil also decrease the sinus node discharge rate and slow atrioventricular nodal conduction.
CCBs or long-acting nitrates should be prescribed for the relief of symptoms when β-blockers are contraindicated or cause unacceptable side effects in patients with stable angina (Class IIa; Level of Evidence B). CCBs or long-acting nitrates in combination with β-blockers should be prescribed for the relief of symptoms when initial therapy with β-blockers is unsuccessful in patients with stable angina (Class IIa; Level of Evidence B). CCBs are added to, or substituted for, β-blockers when BP remains elevated, when angina persists, or when drug side effects or contraindications mandate. Long-acting dihydropyridine agents are preferred over nondihydropyridines (diltiazem or verapamil) for use in combination with β-blockers to avoid excessive bradycardia or heart block. Diltiazem or verapamil should not be used in patients with HF or LV systolic dysfunction, and short-acting nifedipine should be avoided because it causes reflex sympathetic activation and worsening myocardial ischemia.
Although CCBs are useful in the management of hypertension in patients with stable angina, there is no consensus about their role in preventing cardiovascular events in patients with established CAD. The INVEST investigators randomized >22 000 hypertensive patients with chronic CAD to the nondihydropyridine CCB verapamil or the β-blocker atenolol.