Renin system analysis defines the special value of combination antihypertensive therapy using an antirenin agent (CEI) with a long-acting calcium channel blocker (CCB)

As recently as 35 years ago renin had no known role in biology, and human essential hypertension was viewed as a single disorder of unknown cause. In 1960 we showed that unabated renin release by the kidneys causes human malignant hypertension, its accompanying massive increases in aldosterone secretion, and its ischemic vascular injury in the heart, brain, and kidneys, with accompanying early death. The syndrome can be arrested by propranolol treatment, which markedly suppresses plasma renin levels, or by a converting enzyme inhibitor, which blocks angiotensin II formation. It is also completely reversed by total nephrectomy, after which plasma renin levels promptly fall to zero.

More recently, we showed that blockade of plasma angiotensin II action, using a specific type I angiotensin II (AII) receptor antagonist (losartan) also strikingly arrests the heart, brain, and kidney ischemic vascular lesions of both stroke-prone spontaneously hypertensive (SHRsp) and salt-sensitive (S) Dahl rats, even when the blood pressure is not corrected.

We demonstrated that the renin-angiotensin-aldosterone hormonal cascade is a major servocontrol for blood pressure, as well as body sodium and potassium homeostasis, in normal individuals, in whom salt depletion or hypotension turns on renal renin release, whereas excess dietary salt or hypertension promptly turns it off.

This work enabled us to implicate milder, albeit inappropriate, increases in plasma renin levels in causing hypertension and the attendant vascular diseases of much of human hypertension (ie, that present in 70% of essential hypertensive patients with medium or high renin levels).

Our epidemiologic studies showed that heart attacks and strokes that occur in patients with essential hypertension are also confined largely to those patients with medium or high renin levels, and in them, the occurrence of these events is directly related to the height of the baseline plasma renin.

We showed that blocking plasma renin-angiotensin activity in three different ways—using β-blockers to suppress renal renin secretion, saralasin to block angiotensin II action, or the converting enzyme inhibitor teprotide, from snake venom, to reduce AII formation—all lowered blood pressure in medium- or high-renin hypertensive patients according to the height of the preexisting plasma renin value. Moreover, all three agents did not lower pressure in low-renin patients. We further showed that the “normal” renin values are not normal in hypertension, because normal people will promptly turn off all plasma renin when their blood pressure is elevated.

This research led to the development of captopril, the orally active analog of teprotide, thereby launching the field of converting enzyme inhibitors. This enterprise has revolutionized the treatment of hypertension and now appears to have an equal impact on the treatment or prevention of myocardial infarction, congestive heart failure, and renal failure. Thus, in more than 100,000 coronary care unit (CCU) patients (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocordio [GISSI-3] and the Fourth International Study of Infarct Survival [ISIS-4]), it has been shown that heart attack rates are promptly and persistently reduced by daily antirenin system drug therapy, using either a β-blocker, a converting enzyme inhibitor (CEI), or both. Moreover, this drug-related benefit involves primarily those cardiac patients presenting with medium or high plasma renin and angiotensin levels and is not apparent in low-renin patients.

Renin system analysis for diagnosis and treatment of hypertensive patients

Since the introduction of antihypertensive drugs it has generally been assumed that the main and only goal of drug therapy was to find a drug or drug combination that effectively subdues blood pressure to a goal within the normal range. This strategy was based on the monolithic notion that assumes that all benefits of antihypertensive therapy are entirely and directly related to the beneficial consequences of blood pressure reduction per se, irrespective of the means (ie, drug type) by which the hypotension is achieved. An implicit corollary of this assumption, embraced by many, is that hypertension is a single homogeneous process, although some would also claim that it may nonetheless be caused by multifactoral influences. Such metaphysics have little scientific support.

In fact, it has become abundantly clear that human essential hypertension is heterogeneous, because it does not involve the same mechanisms in different people; patients with similar degrees of hypertension vary greatly in their likelihood of developing premature morbid or mortal events; and patients with similar degrees of hypertension respond quite differently to similar drug treatments. This individual fingerprint of drug responsiveness—or lack of it—to particular drugs remains constant for an individual, but differs strikingly among unselected patients receiving one of the five major types of drugs (ie, diuretics, β-blockers, α-blockers, calcium channel blockers [CCB], converting enzyme inhibitors or angiotensin II antagonists). However, much overlap in response type occurs among those patients responsive to the antirenin-system–type agents (β-blockers, CEI, AII antagonists) and also among those patients who are responsive instead to antisodium-volume agents, ie, diuretics, α-blockers, and calcium blockers. All of these latter agents promote natriuresis and may also directly oppose sodium-induced vasoconstrictor mechanisms. These patterns form a basis for the vasoconstriction-volume (renin/sodium) model for the twin reciprocal support of normotension or hypertension.

The vasoconstriction volume model allows the physician to analyze each patient individually to find out whether a renin or sodium-volume pressor mechanism predominates and so plan primary drug treatment accordingly. The goal of this analysis is to identify the primary pressor mechanism and treat it with the fewest number of drugs in the lowest amount and frequency possible.

Finding the best-fit drug or drug combination for each patient is greatly facilitated by obtaining a baseline plasma renin activity value for every new patient, while the patient is quietly seated in the clinic setting. However, even in the absence of knowing the plasma renin value, a thinking physician can, in time, arrive at the best fit drug by testing one drug type at a time to reveal the single-file effectiveness of an antirenin system agent (β-blockers, CEI, losartan, or valsartan), as opposed to that of an antivolume agent (diuretics, spironolactone, CCB, or α-blocker) given alone. Then, if necessary, the clinician can test the combination of an antirenin agent and an antisodium-volume drug to block both limbs. We believe that this single-file testing process should usually be started with a CEI because a response or lack of it for this class is the most specific for revealing underlying disease mechanisms. Accordingly, a dramatic response or a total lack of response to acute captopril testing in an individual patient strongly suggests either a renin or a sodium-volume pressor mechanism, respectively.

In sum, the plasma renin activity (PRA) measurement in untreated patients is valuable because it rules out or in the possibility of curable renovascular (values always ≥ 1.5 ng/mL/h) or curable primary aldosteronism (values ≤ 0.65 ng/mL/h). If the PRA is ≥ 1.5 ng/mL/h it implies a progressively corresponding risk of subsequent cardiac and vascular events. Finally, the PRA test guides, simplifies, and hastens the selection of the right single drug for each patient, and, when needed, it rationalizes the design of combination therapy. The PRA test is now performed according to our technique¹⁹ by Metpath Laboratories and is reported in 48 h with an interpretation. This test is extremely accurate and is inexpensive.

In already treated patients, the PRA test also informs about compliance because diuretics, CEI, and angiotensin-receptor blockers consistently raise the PRA value if blood pressure has been reduced by the drug. Conversely, β-blockers consistently produce large reductions in PRA and AII levels for as long as they are taken.

As discussed above, the modern goal of antihypertensive drug therapy is no longer reduction of blood pressure per se. Rather it is to pick the drug type or drug combination most likely to prolong useful life. More specifically, this means that the primary goal of antihypertensive therapy is to pick the drug type or drug combination most likely to prevent cardiac events, which collectively account for 85% of the premature morbidity and mortality associated with hypertension. These events involve left ventricular hypertrophy, cardiac arrhythmias, sudden death, and congestive heart failure. Antihypertensive agents proven to prevent these cardiac events are β-blockers and converting enzyme inhibitors, each of which by different mechanisms sharply curtails AII levels. We need more evidence on diuretics, which did show a small cardioprotective benefit in the Systolic Hypertension in the Elderly Program (SHEP) trial but no significant cardioprotection in many others. CCB might also prove effective in this regard, but so far have never been critically tested, except for verapamil and diltiazem, each of which have produced promising cardioprotection in postmyocardial infarction patients. Unfortunately, these results cannot be extrapolated to the more commonly used dihydropyridines (eg, nifedipine) because the short-acting forms of this class actually can promote reinfarction in CCU patients. As yet, we have no positive data on longer-acting dihydropyridines, such as amlodipine.

The use of two-drug combinations to treat hypertension

A two-drug combination of proven value and with a sound physiologic basis is the use of an antisodium-volume agent together with an antirenin agent. Thus, β-blockers or converting enzyme inhibitors or, more recently, losartan, valsartan, and avapro, all work better with a diuretic because as its volume depletes, the diuretic raises renin levels, which are then blocked from restoring hypertension by the presence of the antirenin agent in the combination. In fact, in this way patients with low-renin essential hypertension, who are generally unresponsive to a CEI or β-blocker alone, will become responsive as the renin is raised by reaction to the diuretic-induced natriuresis.

Combining a CCB with a β-blocker also has a sound physiologic basis, because β-blockers eliminate the reflex tachycardia, reactive stimulation of renin and aldosterone, and edema formation associated with the use of dihydropyridines. The only problem with this combination is the reduced vigor sometimes caused by β-blockers.

More recently it has become apparent that combining a converting-enzyme inhibitor with a calcium-channel–blocking drug may have special advantages. This is because, for some unknown reason, the CEI addition not only knocks out the reactive tachycardia typically produced by dihydropyridines given alone, but it also corrects the local tissue edema so often caused by the dihydropyridine calcium channel blockers.

This combination, as evidenced recently by Lotrel (a combination of amlodipine and benazepril; Norvartis, Summit, NJ), is thus conceptually attractive because it not only contains or eliminates the unwanted side effects of CCB, ie, tachycardia, headache, and edema, it also avoids the problems of diuretic therapy, such as hypokalemia and glucose intolerance. Longer-term trials are needed to determine whether drugs such as Lotrel will prove to be cardioprotective. Meanwhile, it does have an attractive efficacy and side-effect profile, all packaged in a single once-a-day pill that is likely to correct hypertension in 70% to 90% of patients while, as indicated, providing a minimum of unwanted side effects.

Of course, once-a-day therapy with a single agent directed against either the renin factor or the sodium-volume factor is, for me, a primary and gratifying therapeutic goal. However, such monotherapy may only be fully effective in about 40% of patients. For many of those refractory to monotherapy, a drug-induced reactive rise in either the unblocked renin or the unblocked sodium-volume factor prevents full correction of hypertension and a second drug is needed to counter this reaction and achieve full correction.

Altogether, the vasoconstriction (renin)-volume (sodium) model enables us to better identify and specifically treat the renin and sodium-volume–induced vasoconstrictor factors that may operate together to sustain chronic hypertension. We are thereby able to perhaps better achieve the primary goal of treatment, ie, reducing or eliminating the risk of premature cardiac morbid events that shorten useful life.^{1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42}